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Introduction: Pulmonary embolism (PE) is an imperative diagnosis to make given its associated morbidity. There is no current consensus in the initial workup of pregnant patients suspected of a PE. Prospective studies have been conducted in Europe using a pregnancy-adapted YEARS algorithm, which showed safe reductions in computed tomography pulmonary angiography (CTPA) imaging in pregnant patients suspected of PE. Our objective in this study was 1) to measure the potential avoidance of CTPA use in pregnant patients if the pregnancy-adapted YEARS algorithm had been applied and 2) to serve as an external validation study of the use of this algorithm in the United States.Methods: This study was a single-system retrospective chart analysis. Criteria for inclusion in the cohort consisted of keywords: pregnant; older than 18; chief complaints of shortness of breath, chest pain, tachycardia, hemoptysis, deep vein thromboembolism (DVT), and D-dimer—from January 1, 2019– May 31,2022. We then analyzed this cohort retrospectively using the pregnancy-adapted YEARS algorithm, which includes clinical signs of a DVT, hemoptysis, and PE as the most likely diagnosis with a D-dimer assay. Patients within the cohort were then subdivided into two categories: aligned with the YEARS algorithm, or not aligned with the YEARS algorithm. Patients who did not receive a CTPA were analyzed for a subsequent diagnosis of a PE or DVT within 30 days.Results: A total of 74 pregnant patients were included in this study. There was a PE prevalence of 2.7% (two patients). Of the 36 patients who did not require imaging by the algorithm, seven CTPA were performed. Of the patients who did not receive an initial CTPA, zero were diagnosed with PE or DVT within a 30-day follow-up. In total, 85.1% of all the patients in this study were treated in concordance with the pregnancy-adapted YEARS algorithm.Conclusion: The use of the pregnancy-adapted YEARS algorithm could have resulted in decreased utilization of CTPA in the workup of PE in pregnant patients, and the algorithm showed similar reductions compared to prospective studies done in Europe. The pregnancy-adapted YEARS algorithm was also shown to be similar to the clinical rationale used by clinicians in the evaluation of pregnant patients, which indicates its potential for widespread acceptance into clinical practice.

Clostridium difficile infection (CDI) is mediated by two major exotoxins, toxin A (TcdA) and toxin B (TcdB), that damage the colonic epithelial barrier and induce inflammatory responses. The function of the colonic vascular barrier during CDI has been relatively understudied. Here we report increased colonic vascular permeability in CDI mice and elevated vascular endothelial growth factor A (VEGF-A), which was induced in vivo by infection with TcdA- and/or TcdB-producing C. difficile strains but not with a TcdA-TcdB- isogenic mutant. TcdA or TcdB also induced the expression of VEGF-A in human colonic mucosal biopsies. Hypoxia-inducible factor signalling appeared to mediate toxin-induced VEGF production in colonocytes, which can further stimulate human intestinal microvascular endothelial cells. Both neutralization of VEGF-A and inhibition of its signalling pathway attenuated CDI in vivo. Compared to healthy controls, CDI patients had significantly higher serum VEGF-A that subsequently decreased after treatment. Our findings indicate critical roles for toxin-induced VEGF-A and colonic vascular permeability in CDI pathogenesis and may also point to the pathophysiological significance of the gut vascular barrier in response to virulence factors of enteric pathogens. As an alternative to pathogen-targeted therapy, this study may enable new host-directed therapeutic approaches for severe, refractory CDI.

Newborns admitted to neonatal intensive care units (NICU) are at increased risk of health care-associated infections. Serratia marcescens represent the third most common pathogen in NICU outbreaks. Here we present an outbreak investigation performed using Whole Genome Sequencing (WGS) analyses and the control measures implemented to limit the spread of S. marcescens in the NICU of an Italian hospital. In February 2023 S. marcescens was isolated from six newborns, when in 2022 this pathogen was isolated only from two samples in the same ward. Measures for infection prevention were adopted. Routinary surveillance screening, performed with rectal swabs collected at admission and weekly thereafter, was implemented to search for S. marcescens presence. Environmental samples were collected. All the isolates, obtained from the conjunctival swab of six newborns, from rectal swab of two newborns who did not develop infections, as well as from the aerators of two faucets, were sequenced. WGS analyses showed no correlation between the isolates from newborns and environmental isolates. The implementation of the measures for infection prevention and control had enabled us to successfully control the outbreak within a short period. WGS analyses proved to be crucial in outbreak investigation to limit the spreading of the pathogens. [ABSTRACT FROM AUTHOR]

Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis. However, the mechanisms underlying this restoration of gut structure and function remain largely unknown. In this review, we examine current knowledge supporting a role for impaired intestinal epithelial permeability in hypertension, focusing on electrolyte movement, the renin-angiotensin-aldosterone system, and the restorative effects of orally administered antihypertensive medications and antibiotics. Further work is required to determine if the association between intestinal dysfunction and hypertension is causal. This is a rapidly evolving field, with intestinal dysfunction and dysbiosis representing an area that may be exploited to improve treatment of hypertension and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Mpox virus (MPXV) has recently spread outside of sub-Saharan Africa. This large multicentre study was conducted in Lombardy, the most densely populated Italian region accounting for more than 40% of Italian cases. The present study aims to: i) evaluate the presence and the shedding duration of MPXV DNA in different body compartments correlating the MPXV viability with the time to onset of symptoms; ii) provide evidence of MPXV persistence in different body compartment as a source of infection and iii) characterize the MPXV evolution by whole genome sequencing (WGS) during the outbreak occurred in Italy. The study included 353 patients with a laboratory-confirmed diagnosis of MPXV infection screened in several clinical specimens in the period May 24th - September 1st, 2022. Viral isolation was attempted from different biological matrices and complete genome sequencing was performed for 61 MPXV strains. MPXV DNA detection was more frequent in the skin (94.4%) with the longest median time of viral clearance (16 days). The actively-replicating virus in cell culture was obtained for 123/377 (32.6%) samples with a significant higher viral quantity on isolation positive samples (20 vs 31, p < 0.001). The phylogenetic analysis highlighted the high genetic identity of the MPXV strains collected, both globally and within the Lombardy region. Skin lesion is gold standard material and the high viral load and the actively-replicating virus observed in genital sites confirms that sexual contact plays a key role in the viral transmission. • MPXV detection was more frequent from the skin lesions (289 of 306, 94·4%). • The median clearance time of MPXV DNA was 16 days in the skin, 14 days in the oropharynx. • Higher isolation rate was observed in semen, urine, anogenital, urethral and skin samples. • Higher isolation rate was observed in samples collected between 0 and 7 days (65/158, 41.1%) from the onset of symptoms. • Our 61 genomes are distributed in 37 local subclusters of the outbreak clade. [ABSTRACT FROM AUTHOR]

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In early breast cancer, local relapses represent a determinant and not simply an indicator of risk for distant relapse and death. Notably, 90% of local recurrences occur at or close to the same quadrant of the primary cancer. Relevance of PI3K/mTOR/p70S6K signaling in breast tumorigenesis is very well documented. However, the pathway/s involved in the process of breast cancer local relapse are not well understood. The ribosomal protein p70S6K has been implicated in breast cancer cell response to post‐surgical inflammation, supporting the hypothesis that it may be crucial also for breast cancer recurrence. Here, we show that p70S6K activity is required for the survival of breast cancer cells challenged in “hostile” microenvironments. We found that impairment of p70S6K activity in breast cancer cells strongly decreased their tumor take rate in nude mice. In line with this observation, if cells were challenged to grow in anchorage independence or in clonogenic assay, growth of colonies was strongly dependent on an intact p70S6K signaling. This in vitro finding was particularly evident when breast cancer cells were grown in the presence of wound fluids harvested following surgery from breast cancer patients, suggesting that the stimuli present in the post‐surgical setting at least partially relied on activity of p70S6K to stimulate breast cancer relapse. From a mechanistic point of view, our results indicated that p70S6K signaling was able to activate Gli1 and up‐regulate the anti‐apoptotic protein Bcl2, thereby activating a survival response in breast cancer cells challenged in hostile settings. Our work highlights a previously poorly recognized function of p70S6K in preserving breast cancer cell survival, which could eventually be responsible for local relapse and opens the way to the design of new and more specific therapies aiming to restrain the deleterious effects of wound response. Highlights: p70S6K is activated in breast cancer cells exposed to post‐surgical wound fluids.p70S6K activity is necessary to prevent cell death in “hostile” environments.Inhibition of p70S6K1 leads to different outcomes respect to inhibition of mTOR.The p70S6K/Gli1/Bcl2 signaling axis is necessary to elicit a survival response.p70S6K represents a promising target to prevent breast cancer local recurrence. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the toxicity and cosmetic results in breast cancer patients undergoing adjuvant partial breast irradiation (PBI) to a total dose of 40 Gy in 10 daily fractions (4 Gy/fraction). Methods and materials: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1–T2 pN0–N1a) invasive ductal carcinoma. Results: 77 patients were enrolled. Median follow-up was 18 months. The proposed schedule was well tolerated. One patient reported Grade 3 pain at the site of irradiation. Four (5%) patients experience Grade 2 erythema. Late Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Cosmesis was judged “good/excellent” and “poor” in 75 (97%) and in 2 (3%) patients, respectively. Conclusions: 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. [Copyright &y& Elsevier]

Rational and Objectives: To investigate whether a nonlinear-blending algorithm improves tumor conspicuity and image quality in the evaluation of renal masses at dual-energy computed tomography (DECT) during nephrographic phase of enhancement. Materials and Methods: The Institutional Review Board approved this retrospective study from archival material from patients consenting to the use of medical records for research purposes. A retrospective review of contrast-enhanced abdominal DECT scans in 45 patients (mean age, 59.5 years; range, 24–84 years) was performed. DECT data were reconstructed using nonlinear and linear blending. A region of interest was located within tumors and adjacent normal parenchyma; attenuation differences and contrast-to-noise ratios (CNRs) were calculated for renal masses on nonlinear- and linear-blended images. The two datasets were subjectively compared in terms of tumor detection and image quality. An exact Wilcoxon''s matched pairs signed rank and marginal homogeneity tests were used to test whether differences in attenuation, CNR, and subjective assessment were greater using nonlinear blending. Results: The mean difference in attenuation for renal masses and adjacent portion of renal parenchyma was 138.4 Hounsfield units ± 28.9 SD using nonlinear blending, and 121.6 HU ± 18.0 SD using linear blending (P < .001). Mean CNR was 12.6 ± 2.5 SD using nonlinear blending, and 9.6 ± 2.2 SD using 0.3 linear-blended (P < .001). No significant difference in tumor detection was observed between the two algorithms. Image quality was significantly better (P < .001) using nonlinear blending. Conclusion: Compared with standard linear blending, nonlinear-blending algorithm improves tumor conspicuity and image quality in renal masses at DECT evaluation during nephrographic phase of enhancement. [Copyright &y& Elsevier]

Summary: Introduction: Almost all organs can be involved in the infection by Epstein–Barr virus and consequently, the beginning symptoms of infectious mononucleosis may be different. Materials and methods: We report a case of infection by Epstein–Barr virus in a 17-year-old girl whose primary manifestation was an initially monolateral and subsequently bilateral dacryoadenitis. Results: The incidence of acute dacryoadenitis by Epstein–Barr virus is valued around one case per million people per year, but it is probably underestimated: it is due to infiltration of the lacrimal gland by activated lymphocytes. Discussion: An acute dacryoadenitis, especially when it affects a young adult and when bilateral, should guide the diagnostic and haematochemical and serological investigations towards a systemic disease such as infectious mononucleosis. It is almost always responsive to a systemic corticosteroid therapy, but in some cases it can progress towards a dacryocystitis and exceptionally towards the Sjögren syndrome. Appropriate and timely treatment will be able to reduce any subsequent complications. [Copyright &y& Elsevier]

The protease plasmin is an important wound healing factor, but it is not clear how it affects gastrointestinal infection–mediated damage, such as that resulting from Clostridioides difficile. We investigated the role of plasmin in C difficile –associated disease. This bacterium produces a spore form that is required for infection, so we also investigated the effects of plasmin on spores. C57BL/6J mice expressing the precursor to plasmin, the zymogen human plasminogen (hPLG), or infused with hPLG were infected with C difficile , and disease progression was monitored. Gut tissues were collected, and cytokine production and tissue damage were analyzed by using proteomic and cytokine arrays. Antibodies that inhibit either hPLG activation or plasmin activity were developed and structurally characterized, and their effects were tested in mice. Spores were isolated from infected patients or mice and visualized using super-resolution microscopy; the functional consequences of hPLG binding to spores were determined. hPLG localized to the toxin-damaged gut, resulting in immune dysregulation with an increased abundance of cytokines (such as interleukin [IL] 1A, IL1B, IL3, IL10, IL12B, MCP1, MP1A, MP1B, GCSF, GMCSF, KC, TIMP-1), tissue degradation, and reduced survival. Administration of antibodies that inhibit plasminogen activation reduced disease severity in mice. C difficile spores bound specifically to hPLG and active plasmin degraded their surface, facilitating rapid germination. We found that hPLG is recruited to the damaged gut, exacerbating C difficile disease in mice. hPLG binds to C difficile spores, and, upon activation to plasmin, remodels the spore surface, facilitating rapid spore germination. Inhibitors of plasminogen activation might be developed for treatment of C difficile or other infection-mediated gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Australia is a sink for low pathogenicity avian influenza viruses, with isolated circulation occurring on the continent. We report the incursion of a Eurasian low pathogenicity avian influenza H5 virus into Australia. This report benefits surveillance and diagnostic work because of the risk and current absence of highly pathogenic avian influenza A(H5N1).

Background: A fatal case of Japanese encephalitis (JE) occurred in a resident of the Tiwi Islands, in the Northern Territory of Australia in February 2021, preceding the large JE outbreak in south-eastern Australia in 2022. This study reports the detection, whole genome sequencing and analysis of the virus responsible (designated JEV/Australia/NT&#95;Tiwi Islands/2021)., Methods: Reverse transcription quantitative PCR (RT-qPCR) testing was performed on post-mortem brain specimens using a range of JE virus (JEV)-specific assays. Virus isolation from brain specimens was attempted by inoculation of mosquito and mammalian cells or embryonated chicken eggs. Whole genome sequencing was undertaken using a combination of Illumina next generation sequencing methodologies, including a tiling amplicon approach. Phylogenetic and selection analyses were performed using alignments of the Tiwi Islands JEV genome and envelope (E) protein gene sequences and publicly available JEV sequences., Results: Virus isolation was unsuccessful and JEV RNA was detected only by RT-qPCR assays capable of detecting all JEV genotypes. Phylogenetic analysis revealed that the Tiwi Islands strain is a divergent member of genotype IV (GIV) and is closely related to the 2022 Australian outbreak virus (99.8% nucleotide identity). The Australian strains share highest levels of nucleotide identity with Indonesian viruses from 2017 and 2019 (96.7-96.8%). The most recent common ancestor of this Australian-Indonesian clade was estimated to have emerged in 2007 (95% HPD range: 1998-2014). Positive selection was detected using two methods (MEME and FEL) at several sites in the E and non-structural protein genes, including a single site in the E protein (S194N) unique to the Australian GIV strains., Conclusion: This case represents the first detection of GIV JEV acquired in Australia, and only the second confirmed fatal human infection with a GIV JEV strain. The close phylogenetic relationship between the Tiwi Islands strain and recent Indonesian viruses is indicative of the origin of this novel GIV lineage, which we estimate has circulated in the region for several years prior to the Tiwi Islands case., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Sikazwe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most of our understanding of the ecology and evolution of avian influenza A virus (AIV) in wild birds is derived from studies conducted in the northern hemisphere on waterfowl, with a substantial bias towards dabbling ducks. However, relevant environmental conditions and patterns of avian migration and reproduction are substantially different in the southern hemisphere. Through the sequencing and analysis of 333 unique AIV genomes collected from wild birds collected over 15 years we show that Australia is a global sink for AIV diversity and not integrally linked with the Eurasian gene pool. Rather, AIV are infrequently introduced to Australia, followed by decades of isolated circulation and eventual extinction. The number of co-circulating viral lineages varies per subtype. AIV haemagglutinin (HA) subtypes that are rarely identified at duck-centric study sites (H8-12) had more detected introductions and contemporary co-circulating lineages in Australia. Combined with a lack of duck migration beyond the Australian-Papuan region, these findings suggest introductions by long-distance migratory shorebirds. In addition, on the available data we found no evidence of directional or consistent patterns in virus movement across the Australian continent. This feature corresponds to patterns of bird movement, whereby waterfowl have nomadic and erratic rainfall-dependant distributions rather than consistent intra-continental migratory routes. Finally, we detected high levels of virus gene segment reassortment, with a high diversity of AIV genome constellations across years and locations. These data, in addition to those from other studies in Africa and South America, clearly show that patterns of AIV dynamics in the Southern Hemisphere are distinct from those in the temperate north., Competing Interests: The authors have declared that no competing interests exist.

Here, we report the complete genome sequence of the African swine fever virus (ASFV) isolate ASFV/Timor-Leste/2019/1, isolated from a domestic pig during the first outbreak of ASF in Timor-Leste in 2019. Using target enrichment short-read Illumina data combined with long-read Oxford Nanopore data, we assembled a full-length genome sequence of 192,237 bp.