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Purpose: to review recent literature concerning long-term health issues and transitional care in esophageal atresia (EA) patients. PubMed, Scopus, Embase and Web of Science databases were screened for studies regarding EA patients aged more than or equal to 11 years, published between August 2014 and June 2022. Sixteen studies involving 830 patients were analyzed. Mean age was 27.4 years (range 11–63). EA subtype distribution was: type C (48.8%), A (9.5%), D (1.9%), E (0.5%) and B (0.2%). 55% underwent primary repair, 34.3% delayed repair, 10.5% esophageal substitution. Mean follow-up was 27.2 years (range 11–63). Long-term sequelae were: gastro-esophageal reflux (41.4%), dysphagia (27.6%), esophagitis (12.4%), Barrett esophagus (8.1%), anastomotic stricture (4.8%); persistent cough (8.7%), recurrent infections (4.3%) and chronic respiratory diseases (5.5%). Musculo-skeletal deformities were present in 36 out of 74 reported cases. Reduced weight and height were detected in 13.3% and 6% cases, respectively. Impaired quality of life was reported in 9% of patients; 9.6% had diagnosis or raised risk of mental disorders. 10.3% of adult patients had no care provider. Meta-analysis was conducted on 816 patients. Estimated prevalences are: GERD 42.4%, dysphagia 57.8%, Barrett esophagus 12.4%, respiratory diseases 33.3%, neurological sequelae 11.7%, underweight 19.6%. Heterogeneity was substantial (> 50%). Conclusion: EA patients must continue follow-up beyond childhood, with a defined transitional-care path by a highly specialized multidisciplinary team due to the multiple long-term sequelae. What is Known:• Survival rates of esophageal atresia patients is now more than 90% thanks to the improvements in surgical techniques and intensive care, therefore patients’ needs throughout adolescence and adulthood must be taken into account. What is New:• This review, by summarizing recent literature concerning long term sequelae of esophageal atresia, may contribute to raise awareness on the importance of defining standardized protocols of transitional and adulthood care for esophageal atresia patients.

Host cell restriction factors are intracellular proteins that can inhibit virus replication. Characterisation of novel host cell restriction factors can provide potential targets for host-directed therapies. In this study, we aimed to assess a member of the Tripartite-motif family protein (TRIM) family, TRIM16, as a putative host cell restriction factor. To this end, we utilized constitutive or doxycycline-inducible systems to overexpress TRIM16 in HEK293T epithelial cells and then tested for its ability to inhibit growth by a range of RNA and DNA viruses. In HEK293T cells, overexpression of TRIM16 resulted in potent inhibition of multiple viruses, however, when TRIM16 was overexpressed in other epithelial cell lines (A549, Hela, or Hep2), virus inhibition was not observed. When investigating the antiviral activity of endogenous TRIM16, we report that siRNA-mediated knockdown of TRIM16 in A549 cells also modulated the mRNA expression of other TRIM proteins, complicating the interpretation of results using this method. Therefore, we used CRISPR/Cas9 editing to knockout TRIM16 in A549 cells and demonstrate that endogenous TRIM16 did not mediate antiviral activity against the viruses tested. Thus, while initial overexpression in HEK293T cells suggested that TRIM16 was a host cell restriction factor, alternative approaches did not validate these findings. These studies highlight the importance of multiple complementary experimental approaches, including overexpression analysis in multiple cell lines and investigation of the endogenous protein, when defining host cell restriction factors with novel antiviral activity.

Infections caused by human respiratory syncytial virus (RSV) are associated with substantial rates of morbidity and mortality. Treatment options are limited, and there is urgent need for the development of efficient antivirals. Pattern recognition receptors such as the cytoplasmic helicase retinoic acid–inducible gene (RIG) I can be activated by viral nucleic acids, leading to activation of interferon-stimulated genes and generation of an “antiviral state.” In the current study, we activated RIG-I with synthetic RNA agonists (3pRNA) to induce resistance to RSV infection in vitro and in vivo. In vitro, pretreatment of human, mouse, and ferret airway cell lines with RIG-I agonist before RSV exposure inhibited virus infection and replication. Moreover, a single intravenous injection of 3pRNA 1 day before RSV infection resulted in potent inhibition of virus replication in the lungs of mice and ferrets, but not in nasal tissues. These studies provide evidence that RIG-I agonists represent a promising antiviral drug for RSV prophylaxis.

BACKGROUND There is limited information about sexual knowledge and behaviours in adults with complex care needs, including those with 22q11.2 deletion syndrome (22q) which represents a group predisposed to intellectual disabilities. METHODS We conducted sexual health assessments with 67 adults with 22q, examining whether those with knowledge deficits and a history of engaging in sexual activities with others would be more likely to engage in high-risk behaviours. RESULTS The majority (65.7%) of adults with 22q were sexually active with others; most (70.1%) had sexual knowledge deficits. Those with intellectual disabilities were more likely (p = .0012) to have deficits in certain topics. In the sexually active subgroup, most (81.8%) engaged in high-risk sexual behaviours, regardless of intellectual disability or knowledge deficits. CONCLUSION The results suggest a need for increased dialogue, repeated education, genetic counselling and preventive healthcare measures related to sexuality in 22q and potentially in other complex care conditions.

All-inorganic CsPbI 3 perovskite solar cells (PSCs) with efficiencies exceeding 20% are ideal candidates for application in large-scale tandem solar cells. However, there are still two major obstacles hindering their scale-up: (i) the inhomogeneous solid-state synthesis process and (ii) the inferior stability of the photoactive CsPbI 3 black phase. Here, we have used a thermally stable ionic liquid, bis (triphenylphosphine)iminium bis (trifluoromethylsulfonyl)imide ([PPN][TFSI]), to retard the high-temperature solid-state reaction between Cs 4 PbI 6 and DMAPbI 3 [dimethylammonium (DMA)], which enables the preparation of high-quality and large-area CsPbI 3 films in the air. Because of the strong Pb-O contacts, [PPN][TFSI] increases the formation energy of superficial vacancies and prevents the undesired phase degradation of CsPbI 3 . The resulting PSCs attained a power conversion efficiency (PCE) of 20.64% (certified 19.69%) with long-term operational stability over 1000 hours. A record efficiency of 16.89% for an all-inorganic perovskite solar module was achieved, with an active area of 28.17 cm 2 .

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Pfizer Background Type 1 long QT syndrome (LQT1) is a genetic channelopathy characterized by both haploinsufficient and dominant-negative loss-of-function pathogenic variants in the KCNQ1-encoded Kv7.1 K+ channels conducting IKs. Patients with LQT1 may manifest QT prolongation and ventricular arrhythmias that can culminate in sudden cardiac death. Purpose With this project, we aim to investigate whether our mutation independent, KCNQ1-specific suppression-replacement (SupRep) gene therapy can restore the deficient K+-channel and thereby restore the healthy phenotype. Methods Our proprietary dual component SupRep gene therapy was created by combining a custom-designed KCNQ1 shRNA and a shRNA-immune (shIMM) KCNQ1 cDNA into AAV9. In vivo AAV9-mediated KCNQ1SupRep gene therapy was performed by targeted intra-aortic root construct injection (1E12 vg/kg body weight) during balloon occlusion using a Swan Ganz catheter. 2 weeks after in vivo gene therapy, 12-lead ECGs were assessed in adult transgenic LQT1 (KCNQ1-Y315S, loss-of IKs) and wild-type (WT) rabbits to determine the effect of SupRep therapy on the rabbit’s QTc. Patch-clamp and calcium transient measurements were performed in isolated ventricular cardiomyocytes to evaluate the effect of SupRep on the cardiomyocyte’s action potential duration (APD90) and Ca2+ transient duration (Ca2+90) both, in vitro – after plasmid transfection, and in vivo – after AAV9-mediated gene therapy. AAV9-KCNQ1-construct expression was verified with immunohistochemistry targeting the GFP-tag. Results After injection of 3 LQT1 rabbits so far, no significant changes were observed in the LQT1 rabbits’ QTc before and after in vivo AAV9-mediated gene therapy. However, at the cellular level, LQT1 cardiomyocytes transfected in vitro with the SupRep-plasmid demonstrated a significant reduction of APD90 (ms, 1Hz stimulation at 37°) compared to LQT1 control cells (SupRep-in-vitro, 358±21 vs. control 447±22, p Conclusion In vivo KCNQ1-suppression-replacement gene therapy normalizes cellular action potential and calcium transient duration in transgenic LQT1 rabbits. Further in vivo experiments will be conducted to evaluate whether this therapeutic correction at the cardiomyocyte level will translate into normalization of the LQT1 rabbits’ QTc both at rest and during stress testing.

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males among job-matched shiftworkers. Thus, we show that female mice are more resilient than males to chronic circadian misalignment and that these differences are conserved in humans.

Simulation of RNA-seq reads is critical in the assessment, comparison, benchmarking, and development of bioinformatics tools. Yet the field of RNA-seq simulators has progressed little in the last decade. To address this need we have developed BEERS2, which combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline. BEERS2 takes input transcripts (typically fully-length mRNA transcripts with polyA tails) from either customizable input or from CAMPAREE simulated RNA samples. It produces realistic reads of these transcripts as FASTQ, SAM, or BAM formats with the SAM or BAM formats containing the true alignment to the reference genome. It also produces true transcript-level quantification values. BEERS2 combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline and is designed to include the effects of polyA selection and RiboZero for ribosomal depletion, hexamer priming sequence biases, GC-content biases in PCR amplification, barcode read errors, and errors during PCR amplification. These characteristics combine to make BEERS2 the most complete simulation of RNA-seq to date. Finally, we demonstrate the use of BEERS2 by measuring the effect of several settings on the popular Salmon pseudoalignment algorithm.

CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (TTS) cells during cancer development is still unclear. We demonstrate that CD4 TTScells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 TTScells and previously defined exhaustion programs, CD4 TTScell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 TTScell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 TTScell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 TTScells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 TTScells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTScells to favor tumor progression.

Although the power conversion efficiency of perovskite solar cells (PSCs) has reached 25.7%, there is still great potential for improvement in their performance and stability. In the past few years, ionic liquids (ILs) have been extensively investigated and demonstrated to enhance the efficiency and stability of devices substantially. Herein, the role of ILs in PSCs as additives, solvents, interface engineering, and charge transport layer is reviewed. Also, this review will guide the researchers in understanding bulk doping and interface engineering for efficient and stable PSCs.

Ectopic protein overexpression in immortalised cell lines is a commonly used method to screen host factors for their antiviral activity against different viruses. However, the question remains as to what extent such artificial protein overexpression recapitulates endogenous protein function. Previously, we used a doxycycline-inducible overexpression system, in conjunction with approaches to modulate the expression of endogenous protein, to demonstrate the antiviral activity of IFITM1, IFITM2, and IFITM3 against influenza A virus (IAV) but not parainfluenza virus-3 (PIV-3) in A549 cells. We now show that constitutive overexpression of the same IFITM constructs in A549 cells led to a significant restriction of PIV-3 infection by all three IFITM proteins. Variable IFITM mRNA and protein expression levels were detected in A549 cells with constitutive versus inducible overexpression of each IFITM. Our findings show that overexpression approaches can lead to levels of IFITM1, IFITM2, and IFITM3 that significantly exceed those achieved through interferon stimulation of endogenous protein. We propose that exceedingly high levels of overexpressed IFITMs may not accurately reflect the true function of endogenous protein, thus contributing to discrepancies when attributing the antiviral activity of individual IFITM proteins against different viruses. Our findings clearly highlight the caveats associated with overexpression approaches used to screen cellular host proteins for antiviral activity.

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.

MARCH1 and MARCH8 are closely related E3 ubiquitin ligases that ubiquitinate an overlapping spectrum of host proteins and restrict replication of certain viruses. While the antiviral activity of MARCH8 has been intensively studied, less is known regarding virus inhibition by MARCH1. Isoforms 1 and 2 of MARCH1 are very similar in overall structure but show major differences in their N-terminal cytoplasmic domain (N-CT). Herein, we used a doxycycline-inducible overexpression system to demonstrate that MARCH1.1 reduces titres of influenza A virus (IAV) released from infected cells whereas MARCH1.2 does not. The deletion of the entire N-CT of MARCH1.2 restored its ability to restrict IAV infectivity and sequential deletions mapped the restoration of IAV inhibition to delete the 16 N-terminal residues within the N-CT of MARCH1.2. While only MARCH1.1 mediated anti-IAV activity, qPCR demonstrated the preferential expression of MARCH1.2 over MARCH1.1 mRNA in unstimulated human peripheral blood mononuclear cells and also in monocyte-derived macrophages. Together, these studies describe the differential ability of MARCH1 isoforms to restrict IAV infectivity for the first time. Moreover, as published immunological, virological and biochemical studies examining the ability of MARCH1 to target particular ligands generally use only one of the two isoforms, these findings have broader implications for our understanding of how MARCH1 isoforms might differ in their ability to modulate particular host and/or viral proteins.

This is a cytometry by time-of-flight (CyTOF) staining protocol for hematopoietic-derived cells, that leverages live-cell barcoding using receptor-type tyrosine-protein phosphatase C (CD45) antibodies conjugated to metal isotopes in combination with DNA-based palladium barcoding to multiplex up to 40 samples. In this protocol, DNA-based barcoding is performed before surface and intracellular immunostaining, which reduces the batch effects that result from day-to-day variations in staining and instrument sensitivity. This protocol also reduces antibody consumption and eliminates the need for repeated instrument adjustment.

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.

The accumulation of public transcriptomic timeseries data enables robust meta-analyses that were not possible until recently. To assess the consistency of biological rhythms across studies, 43 public mouse liver tissue timeseries totaling 805 RNA-seq samples were obtained and analyzed. Only the control groups of each study were included, in order to create comparable data. Technical factors in RNA-seq library preparation were the largest contributors to transcriptome-level differences, beyond biological or experiment-specific factors such as lighting conditions. Core clock genes were remarkably consistent in phase across all studies, while phase distributions of other periodic genes were generally less consistent. Overlap of genes identified as rhythmic across studies was generally low, up to around 50% between some of the highest sample count studies. Distributions of phases of significant genes were remarkably inconsistent across studies, but genes consistently identified as rhythmic clustered near ZT0 and ZT12 in acrophase. Data was integrated across studies in a JIVE analysis, which showed that the top two components of joint within-study variation are determined by time of day. A shape-invariant model with random effects was fit to the genes to identify the underlying shape of the rhythms, consistent across all studies. This revealed the extent of asymmetric and multimodal genes.

RIG-I is an innate sensor of RNA virus infection and its activation induces interferon-stimulated genes (ISGs). In vitro studies using human cells have demonstrated the ability of synthetic RIG-I agonists (3pRNA) to inhibit IAV replication. However, in mouse models of IAV the effectiveness of 3pRNA reported to date differs markedly between studies. Myxoma resistance (Mx)1 is an ISG protein which mediates potent anti-IAV activity, however most inbred mouse strains do not express a functional Mx1. Herein, we utilised C57BL/6 mice that do (B6.A2G-Mx1) and do not (B6-WT) express functional Mx1 to assess the ability of prophylactic 3pRNA treatment to induce ISGs and to protect against subsequent IAV infection. In vitro, 3pRNA treatment of primary lung cells from B6-WT and B6.A2G-Mx1 mice resulted in ISG induction however inhibition of IAV infection was more potent in cells from B6.A2G-Mx1 mice. In vivo, a single intravenous injection of 3pRNA resulted in ISG induction in lungs of both B6-WT and B6.A2G-Mx1 mice, however potent and long-lasting protection against subsequent IAV challenge was only observed in B6.A2G-Mx1 mice. Thus, despite broad ISG induction, expression of a functional Mx1 is critical for potent and long-lasting RIG-I agonist-mediated protection in the mouse model of IAV infection.

While a number of studies have demonstrated that human Mx proteins can inhibit particular herpesvirusesin vitro, we are the first to report the antiviral activity of mouse Mx1 (mMx1) against alphaherpesviruses bothin vitroandin vivo. We demonstrate that both overexpressed mMx1 and endogenous mMx1 potently restrict HSV-1 growthin vitro. mMx1-mediated inhibition of HSV-1 was not associated with inhibition of virus entry and/or import of the viral genome into the nucleus, but rather with inhibition of HSV-1 genomic replication as well as subsequent late gene expression.

Myxovirus resistance (Mx) proteins are dynamin-like GTPases that are inducible by interferons (IFNs) following virus infections. Most studies investigating Mx proteins have focused on their activity against influenza A viruses (IAV), although emerging evidence suggests that some Mx proteins may exhibit broader antiviral activity. Herein, we demonstrate that in addition to IAV, overexpression of mouse Mx1 (mMx1), but not mMx2, resulted in potent inhibition of growth of the human alphaherpesviruses herpes simplex virus 1 (HSV-1) and HSV-2, whereas neither inhibited the mouse betaherpesvirus murine cytomegalovirus (MCMV) in vitro. IFN induction of a functional endogenous mMx1 in primary mouse fibroblasts ex vivo was also associated with inhibition of HSV-1 growth. Using an in vitro overexpression approach, we demonstrate that mutations that result in redistribution of mMx1 from the nucleus to the cytoplasm or in loss of its combined GTP binding and GTPase activity also abrogated its ability to inhibit HSV-1 growth. Overexpressed mMx1 did not inhibit early HSV-1 gene expression but was shown to inhibit both replication of the HSV-1 genome as well as subsequent late gene expression. In a mouse model of cutaneous HSV-1 infection, mice expressing a functional endogenous mMx1 showed significant reductions in the severity of skin lesions as well as reduced HSV-1 titers in both the skin and dorsal root ganglia (DRG). Together, these data demonstrate that mMx1 mediates potent antiviral activity against human alphaherpesviruses by blocking replication of the viral genome and subsequent steps in virus replication. Moreover, endogenous mMx1 potently inhibited pathogenesis in the zosteriform mouse model of HSV-1 infection. IMPORTANCE While a number of studies have demonstrated that human Mx proteins can inhibit particular herpesviruses in vitro, we are the first to report the antiviral activity of mouse Mx1 (mMx1) against alphaherpesviruses both in vitro and in vivo. We demonstrate that both overexpressed mMx1 and endogenous mMx1 potently restrict HSV-1 growth in vitro. mMx1-mediated inhibition of HSV-1 was not associated with inhibition of virus entry and/or import of the viral genome into the nucleus, but rather with inhibition of HSV-1 genomic replication as well as subsequent late gene expression. Therefore, inhibition of human alphaherpesviruses by mMx1 occurs by a mechanism that is distinct from that reported for human Mx proteins against herpesviruses. Importantly, we also provide evidence that expression of a functional endogenous mMx1 can limit HSV-1 pathogenesis in a mouse model of infection.

Objectives This study sought to determine the remote monitoring (RM) alert burden in a multicenter cohort of patients with a cardiac implantable electronic device (CIED). Background RM of CIEDs allows timely recognition of patient and device events requiring intervention. Most RM involves burdensome manual workflow occurring exclusively on weekdays during office hours. Automated software may reduce such a burden, streamlining real-time alert responses. Methods We retrospectively analyzed 26,713 consecutive patients with a CIED undergoing managed RM utilizing PaceMate software between November 2018 and November 2019. Alerts were analyzed according to type, acuity (red indicates urgent, and yellow indicates nonurgent) and CIED category. Results In total, 12,473 (46.7%) patients had a permanent pacemaker (PPM), 9,208 (34.5%) had an implantable cardioverter-defibrillator (ICD), and 5,032 (18.8%) had an implantable loop recorder (ILR). Overall, 82,797 of the 205,804 RM transmissions were alerts, with the remainder being scheduled transmissions. A total of 14,638 (54.8%) patients transmitted at least 1 alert. Permanent pacemakers were responsible for 25,700 (31.0%) alerts, ICDs for 15,643 (18.9%) alerts, and ILRs for 41,454 (50.1%) alerts, with 3,935 (4.8%) red alerts and 78,862 (95.2%) yellow alerts. ICDs transmitted 2,073 (52.7%) red alerts; 5,024 (32.1%) ICD alerts were for ventricular tachyarrhythmias and antitachycardia pacing/shock delivery. Conclusions In an RM cohort of 26,713 patients with CIEDs, 54.8% of patients transmitted at least 1 alert during a 12-month period, totaling over 82,000 alerts. ILRs were overrepresented, and ICDs were underrepresented, in these alerts. The enormity of the number of transmissions and the growing ILR alert burden highlight the need for new management pathways for RM.

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

A systematic review was conducted to provide an overview of the current state of research regarding sexuality and sexual health in adults with limb loss. Five databases (Medline, CINAHL, Scopus, Web of Science and PsycINFO) were searched between January 1, 2000 and April 14, 2019. Two reviewers independently screened all titles and abstracts for primary inclusion and full texts for secondary inclusion. The inclusion criteria were peer-reviewed journal articles that were published in English, that addressed at least one aspect of sexuality or sexual health and included adults (18 years and older) who acquired a major limb amputation. A modified Sackett Scale was used to assign levels of evidence to each study. A total of 29 articles met the inclusion criteria. With regard to sexuality, the most common topics investigated were body image (n = 21), sexual desire (n = 6) and sexual activity (n = 4). The Amputee Body Image Scale was the most commonly used outcome measure to assess body image (n = 10). In terms of sexual health, the most frequently studied issues were sexual functioning (n = 5) and sexual counselling (n = 2). Sexuality and sexual health issues affect the health and wellbeing of adults with limb loss. The majority of studies were low in evidence; indicating that more robust intervention studies are needed to help people cope with limb loss as it relates to their sexual health and sexuality. In particular, more targeted efforts for women and individuals with upper limb loss are needed.

PurposeThis paper builds on previous research in information systems (IS) project management by focusing on key antecedents proposed to play important roles in influencing normative commitment within the IS project environment. The study also further investigates the influence of normative commitment on intentions to continue.Design/methodology/approachTo collect data for this study, a field survey was administered online, and individuals were selected for participation by a member of upper management from Fortune 500 companies located in the United States. Two-hundred and thirty two (232) survey responses were collected. The model was analyzed using PLS-SEM.FindingsThe results indicated that personal investment, personal responsibility, voluntariness, project-specific self-efficacy and problem-solving competency were all significantly related to normative commitment. Project-specific self-efficacy, problem-solving competency and normative commitment directly influenced intention to continue. Additionally, problem-solving competency moderated both the relationships of project-specific self-efficacy to normative commitment and project-specific self-efficacy to intention to continue. The resulting model explains 63% of intention to continue and 58% of normative commitment.Originality/valueThe findings from this study contribute to commitment theory and enhance one’s understanding of IS project environments by exploring specific antecedents related to developing normative commitment. Additionally, the impact of normative commitment on intention to continue was enhanced by examining key moderating relationships to the model.

This systematic review sought to summarize published professionalism curricula in postgraduate medical education (PGME) and identify best practices for teaching professionalism.Three databases (MEDLINE, Embase, ERIC) were searched for articles published from 1980 through September 7, 2017. English-language articles were included if they (1) described an educational intervention addressing professionalism, (2) included postgraduate medical trainees, and (3) evaluated professionalism outcomes.Of 3,383 articles identified, 50 were included in the review. The majority evaluated pre- and posttests for a single group (24, 48%). Three (6%) were randomized controlled trials. The most common teaching modality was small-group discussions (28, 56%); other methods included didactics, reflection, and simulations. Half (25, 50%) used multiple modalities. The professionalism topics most commonly addressed were professional values/behavior (42, 84%) and physician well-being (23, 46%). Most studies measured self-reported outcomes (attitude and behavior change) (27, 54%). Eight (16%) evaluated observed behavior and 3 (6%) evaluated patient outcomes. Of 35 studies that evaluated statistical significance, 20 (57%) reported statistically significant positive effects. Interventions targeting improvements in knowledge were most often effective (8/12, 67%). Curriculum duration was not associated with effectiveness. The 45 quantitative studies were of moderate quality (Medical Education Research Study Quality Instrument mean score = 10.3).Many published curricula addressing professionalism in PGME are effective. Significant heterogeneity in curricular design and outcomes assessed made it difficult to synthesize results to identify best practices. Future work should build upon these curricula to improve the quality and validity of professionalism teaching tools.