Infectious hepatitis E virus is associated with the mature sperm head.

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide. HEV associated pregnancy mortality has been reported as up to 30% in humans. Recent findings suggest HEV may elicit effects directly in the reproductive system with HEV protein found in the testis, viral RNA in semen, and viral replication occurring in placental cell types. Using a natural host model for HEV infection, pigs, we demonstrate infectious HEV within the mature spermatozoa and altered sperm viability from HEV infected pigs. HEV isolated from sperm remained infectious suggesting a potential transmission route via sexual partners. Our findings suggest that HEV should be explored as a possible sexually transmittable disease. Our findings propose that infection routes outside of oral and intravenous infection need to be considered for their potential to contribute to higher mortality in HEV infections when pregnancy is involved and in HEV disease in general.

Enhanced mucosal immune responses and reduced viral load in the respiratory tract of ferrets to intranasal lipid nanoparticle-based SARS-CoV-2 proteins and mRNA vaccines.

BACKGROUND: Unlike the injectable vaccines, intranasal lipid nanoparticle (NP)-based adjuvanted vaccine is promising to protect against local infection and viral transmission. Infection of ferrets with SARS-CoV-2 results in typical respiratory disease and pathology akin to in humans, suggesting that the ferret model may be ideal for intranasal vaccine studies. RESULTS: We developed SARS-CoV-2 subunit vaccine containing both Spike receptor binding domain (S-RBD) and Nucleocapsid (N) proteins (NP-COVID-Proteins) or their mRNA (NP-COVID-mRNA) and NP-monosodium urate adjuvant. Both the candidate vaccines in intranasal vaccinated aged ferrets substantially reduced the replicating virus in the entire respiratory tract. Specifically, the NP-COVID-Proteins vaccine did relatively better in clearing the virus from the nasal passage early post challenge infection. The immune gene expression in NP-COVID-Proteins vaccinates indicated increased levels of mRNA of IFNα, MCP1 and IL-4 in lungs and nasal turbinates, and IFNγ and IL-2 in lungs; while proinflammatory mediators IL-1ß and IL-8 mRNA levels in lungs were downregulated. In NP-COVID-Proteins vaccinated ferrets S-RBD and N protein specific IgG antibodies in the serum were substantially increased at both day post challenge (DPC) 7 and DPC 14, while the virus neutralizing antibody titers were relatively better induced by mRNA versus the proteins-based vaccine. In conclusion, intranasal NP-COVID-Proteins vaccine induced balanced Th1 and Th2 immune responses in the respiratory tract, while NP-COVID-mRNA vaccine primarily elicited antibody responses. CONCLUSIONS: Intranasal NP-COVID-Proteins vaccine may be an ideal candidate to elicit increased breadth of immunity against SARS-CoV-2 variants.

Relationship between the EULAR/ACR classification criteria and organ damage in systemic lupus erythematosus.

OBJECTIVES: To study the relationship between the 2019 EULAR/ACR classification criteria and organ damage in patients with systemic lupus erythematosus (SLE). METHODS: Patients involved in a cross-sectional validation study of the EULAR/ACR criteria and judged by a panel of rheumatologists to be clinical SLE were studied. Those who fulfilled the EULAR/ACR criteria at their last clinic visit were stratified into 2 groups based on a cutoff score of 20. The last SLE International Collaborating Clinic (SLICC) Organ Damage Index (SDI) was compared between these two groups. Relationship among the domains of the EULAR/ACR criteria and SDI in all patients was studied by using Spearman's rank correlation. RESULTS: A total of 562 SLE patients were studied (93.6% women; age 36.5 ± 14.1 years; follow-up duration 11.6 ± 6.6 years). The mean and median EULAR/ACR criteria scores in those who fulfilled the EULAR/ACR criteria (N = 542) were 24.6 ± 7.3 and 24 (interquartile range 19-30), respectively. A total of 392 patients had EULAR/ACR scores of ≥20 (group 1), and 150 patients had scores of 10-19 (group 2). Group 1 patients had significantly higher prevalence of fever, alopecia, oral ulcers, acute lupus skin lesions, arthritis, serositis, seizure, hemolytic anemia, leukopenia, and renal disease and so were the anti-dsDNA, anti-Sm, antiphospholipid antibodies, and low complement state. Organ damage (SDI score of ≥1) occurred in 232 (42.8%) patients. Patients in group 1 had significantly higher SDI scores in the renal, cardiovascular, dermatological, and gonadal domains than group 2. The renal, neuropsychiatric, and antiphospholipid antibody domain scores of the EULAR/ACR criteria correlated positively with the total SDI. The renal domain of the EULAR/ACR criteria had the strongest correlation with renal damage (Rho 0.30; p < 0.001). Patients who scored 10 points in the renal domain had significantly higher renal damage score than those scored 8 points or 4 points. Gonadal damage score was also significantly more common in the 10-point than in the 8-point group. CONCLUSION: In addition to disease classification, the EULAR/ACR SLE criteria may have value in predicting prognosis.

Unravelling the landscape of skin cancer through single-cell transcriptomics.

The human skin is a complex organ that forms the first line of defense against pathogens and external injury. It is composed of a wide variety of cells that work together to maintain homeostasis and prevent disease, such as skin cancer. The exponentially rising incidence of skin malignancies poses a growing public health challenge, particularly when the disease course is complicated by metastasis and therapeutic resistance. Recent advances in single-cell transcriptomics have provided a high-resolution view of gene expression heterogeneity that can be applied to skin cancers to define cell types and states, understand disease evolution, and develop new therapeutic concepts. This approach has been particularly valuable in characterizing the contribution of immune cells in skin cancer, an area of great clinical importance given the increasing use of immunotherapy in this setting. In this review, we highlight recent skin cancer studies utilizing bulk RNA sequencing, introduce various single-cell transcriptomics approaches, and summarize key findings obtained by applying single-cell transcriptomics to skin cancer.

Multidisciplinary collaboration on exoskeleton development adopting user-centered design: a systematic integrative review.

Purpose: The world population is ageing, along with an increasing possibility of functional limitations that affect independent living. Assistive technologies such as exoskeletons for rehabilitative purposes and daily activities assistance maintaining the independence of people with disabilities, especially older adults who wish to ageing-in-place. The purpose of this systematic integrative review was threefold: to explore the development team compositions and involvement, to understand the recruitment and engagement of stakeholders, and to synthesise reported or anticipated consequences of multidisciplinary collaboration.Methods: Databases searched included PubMed, CINAHL Plus, PsycINFO, Web of Science, Scopus, and IEEE Xplore. A total of 34 studies that reported the development of exoskeleton adopting user-centered design (UCD) method in healthcare or community settings that were published in English from 2000 to July 2022 were included.Results: Three major trends emerged from the analysis of included studies. First, there is a need to redefine multidisciplinary collaboration, from within-discipline collaboration to cross-discipline collaboration. Second, the level of engagement of stakeholders during the exoskeleton development remained low. Third, there was no standardised measurement to quantify knowledge production currently.Conclusion: As suggested by the synthesised results in this review, exoskeleton development has been increasing to improve the functioning of people with disabilities. Exoskeleton development often required expertise from different disciplines and the involvement of stakeholders to increase acceptance, thus we propose the Multidisciplinary Collaboration Appraisal Tool to assess multidisciplinary collaboration using the UCD approach. Future research is required to understand the effectiveness of multidisciplinary collaboration on exoskeleton development using the UCD approach.IMPLICATIONS FOR REHABILITATIONGlobal trend of population ageing causes a higher risk of disability in older adults who require rehabilitation and assistance in daily living.Assistive technologies such as exoskeletons have the potential to contribute to rehabilitation training and daily activity assistance demand closer multidisciplinary collaboration.A Multidisciplinary Collaboration Appraisal Tool using user-centered design approach (MCAT) is proposed to understand the effectiveness as well as limitations and barriers associated with multidisciplinary collaboration in developing exoskeletons.

Validation of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in ANA-positive Chinese patients.

Background: The aim of this study was to validate the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for systemic lupus erythematosus (SLE) in antinuclear antibody (ANA)-positive Chinese patients. Methods: Medical records of all adult patients who attended the rheumatology out-patient clinics between May and September 2019 were reviewed. Patients with ever ANA positive (titre ⩾1:80) were included and evaluated for the fulfilment of the 2019 EULAR/ACR, 2012 Systemic Lupus International Collaborating Clinics (SLICC) and 1997 ACR criteria for SLE classification. The performance of these criteria in predicting a clinical diagnosis of SLE as judged by an independent panel of rheumatologists was studied and compared in different subgroups. Results: A total of 1533 patients (88.2% women; age at first clinic attendance 45.5 ± 15.6 years) were studied and 562 patients were judged to be clinical SLE. The sensitivity and specificity of the EULAR/ACR (⩾10 points), SLICC and ACR criteria for a clinical diagnosis of SLE was 96.1%, 97.9% and 86.1%; and 85.8%, 86.3% and 94.3%, respectively. Applying the attribution rule to the non-SLE controls, the specificity of the three criteria increased to 95.0%, 92.5% and 98.8%, respectively. The specificity of the EULAR/ACR criteria was higher in male patients (97.9%), those aged >50 years (97.0%) and disease duration of ⩽3 years (97.6%). Using a cut-off of 12 points, the specificity of the EULAR/ACR criteria was further increased (96.6%) while a high sensitivity (95.0%) was maintained. Conclusion: In Chinese patients with a positive ANA, the EULAR/ACR criteria for clinical SLE perform equally well to the SLICC criteria. Both the EULAR/ACR and SLICC are more sensitive but less specific than the ACR criteria. The specificity of all the three criteria is enhanced by applying the attribution rule to controls. The specificity of the EULAR/ACR criteria is higher in certain patient subgroups or when the cut-off score is raised.

Characterization of the Cross-Species Transmission Potential for Porcine Deltacoronaviruses Expressing Sparrow Coronavirus Spike Protein in Commercial Poultry.

Avian species often serve as transmission vectors and sources of recombination for viral infections due to their ability to travel vast distances and their gregarious behaviors. Recently a novel deltacoronavirus (DCoV) was identified in sparrows. Sparrow deltacoronavirus (SpDCoV), coupled with close contact between sparrows and swine carrying porcine deltacoronavirus (PDCoV) may facilitate recombination of DCoVs resulting in novel CoV variants. We hypothesized that the spike (S) protein or receptor-binding domain (RBD) from sparrow coronaviruses (SpCoVs) may enhance infection in poultry. We used recombinant chimeric viruses, which express S protein or the RBD of SpCoV (icPDCoV-SHKU17, and icPDCoV-RBDISU) on the genomic backbone of an infectious clone of PDCoV (icPDCoV). Chimeric viruses were utilized to infect chicken derived DF-1 cells, turkey poults, and embryonated chicken eggs (ECEs) to examine permissiveness, viral replication kinetics, pathogenesis and pathology. We demonstrated that DF-1 cells in addition to the positive control LLC-PK1 cells are susceptible to SpCoV spike- and RBD- recombinant chimeric virus infections. However, the replication of chimeric viruses in DF-1 cells, but not LLC-PK1 cells, was inefficient. Inoculated 8-day-old turkey poults appeared resistant to icPDCoV-, icPDCoV-SHKU17- and icPDCoV-RBDISU virus infections. In 5-day-old ECEs, significant mortality was observed in PDCoV inoculated eggs with less in the spike chimeras, while in 11-day-old ECEs there was no evidence of viral replication, suggesting that PDCoV is better adapted to cross species infection and differentiated ECE cells are not susceptible to PDCoV infection. Collectively, we demonstrate that the SpCoV chimeric viruses are not more infectious in turkeys, nor ECEs than wild type PDCoV. Therefore, understanding the cell and host factors that contribute to resistance to PDCoV and avian-swine chimeric virus infections may aid in the design of novel antiviral therapies against DCoVs.

MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET.

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. SIGNIFICANCE: Downregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Mutant collagen COL11A1 enhances cancerous invasion.

Collagens are the most abundant proteins in the body and comprise the basement membranes and stroma through which cancerous invasion occurs; however, a pro-neoplastic function for mutant collagens is undefined. Here we identify COL11A1 mutations in 66 of 100 cutaneous squamous cell carcinomas (cSCCs), the second most common U.S. cancer, concentrated in a triple helical region known to produce trans-dominant collagens. Analysis of COL11A1 and other collagen genes found that they are mutated across common epithelial malignancies. Knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo. Compared to otherwise genetically identical COL11A1 wild-type tissue, gene-edited mutant COL11A1 skin is characterized by induction of ß1 integrin targets and accelerated neoplastic invasion. In mosaic tissue, mutant COL11A1 cells enhanced invasion by neighboring wild-type cells. These results suggest that specific collagens are commonly mutated in cancer and that mutant collagens may accelerate this process.

Outcomes of Percutaneous Coronary Intervention in Patients with Spontaneous Coronary Artery Dissection.

OBJECTIVES: To compare outcomes of percutaneous coronary intervention (PCI) in spontaneous coronary artery dissection (SCAD) patients versus conservative therapy. BACKGROUND: SCAD is an important cause of myocardial infarction (MI) in young-to-middle-aged women. Percutaneous coronary intervention (PCI) is often pursued, but outcomes compared to conservative therapy are unclear. METHODS: 403 nonatherosclerotic SCAD patients were enrolled between 2011 and 2017 and prospectively followed up in our Vancouver General Hospital registries. Detailed baseline, hospital, PCI, and outcomes were recorded. We explored the outcomes of SCAD patients who underwent PCI during their initial presentation. RESULTS: PCI was performed in 75 patients, the average age was 48.9 ± 10.1 yrs, and 94.7% were women. All presented with MI; 50.7% STEMI, 49.3% NSTEMI, and 13.3% had VT/VF. PCI was successful in 34.7%, partially successful in 37.3%, and unsuccessful in 28.0%. Stents were deployed in 73.3%, 16.0% had balloon angioplasty alone, 10.7% had wiring attempts only, and 5.3% required bailout surgery. Major adverse cardiovascular event rates (MACE) were significantly higher with the PCI group in hospital (29.3% versus 2.8%, p < 0.001), and at median follow-up of 3.7 yrs (58.7% versus 22.6% (p < 0.001) compared to the non-PCI group. CONCLUSION: PCI in SCAD patients was associated with high failure rate and MACE in hospital and at long-term follow-up. These findings support the recommendation of conservative therapy as first-line management unless high-risk features are present.

The creation of a White Coat Ceremony.

Historically, the White Coat Ceremony has had a medical school connotation. While not exclusive to the discipline of medicine, the White Coat Ceremony is a recently adopted ritual embraced by a variety of health care professions. The white coat serves as a symbol of achievement into one's professional program. The purpose of this article is to provide an overview of the White Coat Ceremony as an emblematic transition into professional nursing education, to provide context of the use of symbolic ceremony in nursing, to describe the details of a White Coat Ceremony currently in place in a nursing college, and to discuss suggestions for replication. A survey to elicit student responses to the ceremonial event was achieved through an IRB study. Results obtained through a student survey were strongly favorable to the personal meaning as to participating in a White Coat Ceremony. The authors endorse the use of such a ceremony in professional nursing education settings.

Promoting Faculty Education on Needs and Resources for Military-Active and Veteran Students.

BACKGROUND: The numbers of post-9/11 service members transitioning out of the military are escalating. Our diverse nursing student population will increasingly include Veterans or those engaged in military service. METHOD: This article describes an educational session directed at nurse faculty about the needs of these students. The event focused on the array of experiences and issues experienced by active military students or Veterans as they are deployed, transition back into civilian life, or return to college. RESULTS: This educational forum was well attended and praised by nurse faculty who reported increased levels of awareness, knowledge, and resources pertinent to this student population. CONCLUSION: Student-centeredness is valued in nursing education. Compliance with pertinent policies, engagement with community resources, and conveying personal interest in our students is especially valuable for students engaged in military service. Other nursing programs are encouraged to adopt a similarly designed event. [J Nurs Educ. 2019;58(6):347-353.].

Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis.

Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall-associated proteins, including an antigen that stimulates mucosal T helper 17 (TH17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)-dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal TH17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.

Qualitative approach to comparative exposure in alternatives assessment.

Most alternatives assessments (AAs) published to date are largely hazard-based rankings, thereby ignoring potential differences in human and/or ecosystem exposures; as such, they may not represent a fully informed consideration of the advantages and disadvantages of possible alternatives. Building on the 2014 US National Academy of Sciences recommendations to improve AA decisions by including comparative exposure assessment into AAs, the Health and Environmental Sciences Institute's (HESI) Sustainable Chemical Alternatives Technical Committee, which comprises scientists from academia, industry, government, and nonprofit organizations, developed a qualitative comparative exposure approach. Conducting such a comparison can screen for alternatives that are expected to have a higher or different routes of human or environmental exposure potential, which together with consideration of the hazard assessment, could trigger a higher tiered, more quantitative exposure assessment on the alternatives being considered, minimizing the likelihood of regrettable substitution. This article outlines an approach for including chemical ingredient- and product-related exposure information in a qualitative comparison, including ingredient and product-related parameters. A classification approach was developed for ingredient and product parameters to support comparisons between alternatives as well as a methodology to address exposure parameter relevance and data quality. The ingredient parameters include a range of physicochemical properties that can impact routes and magnitude of exposure, whereas the product parameters include aspects such as product-specific exposure pathways, use information, accessibility, and disposal. Two case studies are used to demonstrate the application of the methodology. Key learnings and future research needs are summarized. Integr Environ Assess Manag 2018;00:000-000. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and Metastatic Cutaneous Squamous Cell Carcinoma.

OBJECTIVE: To characterize programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) positivity for locally aggressive or regionally metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC). STUDY DESIGN: Retrospective chart review, followed by immunohistochemical staining of archived tumor specimens. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: After identification of 101 patients treated surgically for locally advanced or regionally metastatic cHNSCC, archived tissue was stained and graded for PD-L1 expression in addition to TIL presence. Cross-tabulation was performed to examine the association between either of these variables and clinicopathologic features and outcomes. RESULTS: A total of 101 patients met inclusion criteria, but archived tissue was available only for 83 (31 primaries, 52 metastases). The majority of primary tumors demonstrated grade 1 PD-L1 staining, while grade 2 staining was more likely for metastases. Neither high- nor low-grade PD-L1 expression correlated with any clinicopathologic variable for primary tumors. However, for metastases, high-grade staining was significantly associated with regional recurrence (15 of 19, P = .02). TILs were present for 65% of primary tumors and 90% of regional metastases but did not correlate with any clinicopathologic variables. CONCLUSION: Diffuse expression of PD-L1 in this study highlights the possibility of using immunotherapy in the form of programmed death 1/PD-L1 blockade to improve treatment for this devastating disease. However, further studies are needed to clarify the significance of PD-L1 expression and TIL positivity for locally advanced or regionally metastatic cHNSCC.

Case reports of coronary fibromuscular dysplasia and spontaneous coronary artery dissections.

Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome especially in women. The most common underlying predisposing cause of SCAD is fibromuscular dysplasia (FMD), a non-inflammatory arteriopathy that results in weakening of the affected arteries, and can cause dissection or aneurysm. Coronary FMD (CFMD) was described as rare, and was shown to cause SCAD in histopathological case reports. Unfortunately, CFMD is challenging to diagnose on coronary angiography, as the findings can be similar to other causes of coronary artery disease. Therefore, we illustrate two case examples of CFMD on coronary angiography, and highlight findings on optical coherence tomography to aid diagnosis.

Very early antepartum pregnancy-associated spontaneous coronary artery dissection case report.

Spontaneous coronary artery dissection (SCAD) is an elusive cardiovascular disease that is increasingly recognized. Classically, pregnancy had been perceived as a notable risk factor for SCAD. However, modern studies had revealed that pregnancy-associated SCAD (PASCAD) accounted for fewer cases than previously thought. The majority of PASCAD cases occur in women post-partum. We describe a case of a 30-year-old woman who presented with SCAD while 10 days pregnant, which is the earliest PASCAD case reported in the literature.