Population structure and pathogen interaction of Escherichia coli in freshwater: Implications of land-use for water quality and public health in Aotearoa New Zealand.

Freshwater samples (n = 199) were obtained from 41 sites with contrasting land-uses (avian, low impact, dairy, urban, sheep and beef, and mixed sheep, beef and dairy) and the E. coli phylotype of 3980 isolates (20 per water sample enrichment) was determined. Eight phylotypes were identified with B1 (48.04%), B2 (14.87%) and A (14.79%) the most abundant. Escherichia marmotae (n = 22), and Escherichia ruysiae (n = 1), were rare (0.68%) suggesting that these environmental strains are unlikely to confound water quality assessments. Phylotypes A and B1 were overrepresented in dairy and urban sites (p < 0.0001), whilst B2 were overrepresented in low impact sites (p < 0.0001). Pathogens ((Salmonella, Campylobacter, Cryptosporidium or Giardia) and the presence of diarrhoeagenic E. coli-associated genes (stx and eae) were detected in 89.9% (179/199) samples, including 80.5% (33/41) of samples with putative non-recent faecal inputs. Quantitative PCR to detect microbial source tracking targets from human, ruminant and avian contamination were concordant with land-use type and E. coli phylotype abundance. This study demonstrated that a potential recreational health risk remains where pathogens occurred in water samples with low E. coli concentration, potential non-recent faecal sources, low impact sites and where human, ruminant and avian faecal sources were absent.

Risk Factors Associated with Occult Nodal Metastasis and Outcomes for cT1-2N0 Maxillary and Mandibular gingival Carcinoma: A Retrospective Study.

Objective: This study aims to identify the rate of occult nodal metastasis (ONM), risk factors associated with ONM, and compare regional recurrence (RR), 2-year disease-free survival (DFS) in patients treated with elective neck dissection (END) versus expectant management (OBS) for primary T1-T2 gingival squamous cell carcinoma (GSCC) of the maxilla and mandible. Methods: A retrospective analysis was conducted and included patients from 2014 to 2021 who were treated at a tertiary referral center. Results: Twenty patients underwent END and 36 were managed expectantly, with a mean follow-up period of 28 months. ONM was observed in 26% of the study cohort with 16.7% occurring in the maxilla and 36.4% in the mandible. No specific histopathologic features were predictive for ONM. No regional recurrence occurred. Local recurrence occurred in 5% and 2.8% of END and OBS groups, respectively. Two-year DFS were comparable between the END (93.8%) versus OBS (83.9%) as well as maxilla (90.9%) versus mandible (83.4%), P > 0.05. Conclusion: ONM remains variable in cT1-T2N0 GSCC with a greater incidence occurring in the mandible when compared to the maxilla, respectively. An END should be strongly considered for mandibular GSCC. Overall, END for the N0 neck has been shown to provide significant overall and disease-free survival benefits. However, further prospective randomized studies are needed to verify risk factors for ONM and validate the disease-related survival benefit of an elective neck dissection in this patient population.

Deciphering the evolutionary landscape of severe fever with thrombocytopenia syndrome virus across East Asia.

Severe fever with thrombocytopenia syndrome virus (SFTSV) poses a significant public health challenge in East Asia, necessitating a deeper understanding of its evolutionary dynamics to effectively manage its spread and pathogenicity. This study provides a comprehensive analysis of the genetic diversity, recombination patterns, and selection pressures across the SFTSV genome, utilizing an extensive dataset of 2041 sequences from various hosts and regions up to November 2023. Employing maximum likelihood and Bayesian evolutionary analysis by sampling trees (BEAST), we elucidated the phylogenetic relationships among nine distinct SFTSV genotypes (A, B1, B2, B3, B4, C, D, E, and F), revealing intricate patterns of viral evolution and genotype distribution across China, South Korea, and Japan. Furthermore, our analysis identified 34 potential reassortments, underscoring a dynamic genetic interplay among SFTSV strains. Genetic recombination was observed most frequently in the large segment and least in the small segment, with notable recombination hotspots characterized by stem-loop hairpin structures, indicative of a structural propensity for genetic recombination. Additionally, selection pressure analysis on critical viral genes indicated a predominant trend of negative selection, with specific sites within the RNA-dependent RNA polymerase and glycoprotein genes showing positive selection. These sites suggest evolutionary adaptations to host immune responses and environmental pressures. This study sheds light on the intricate evolutionary mechanisms shaping SFTSV, offering insights into its adaptive strategies and potential implications for vaccine development and therapeutic interventions.

Improved efficacy of pembrolizumab combined with soluble EphB4-albumin in HPV-negative EphrinB2 positive head neck squamous cell carcinoma.

OBJECTIVE: Patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need. METHODS: This is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome. RESULTS: Twenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities. DISCUSSION: The combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

External validation of clinical risk prediction score for elderly treated with endovascular thrombectomy.

BACKGROUND AND AIM: The thrombectomy in the elderly prediction score (TERPS) for functional outcome after anterior circulation endovascular therapy (EVT) in patients ≥ 80 years was recently developed. The aim of this study was to assess predictors of functional outcome in the elderly and validate the prediction model. METHODS: Consecutive patients treated with EVT from the Oslo Acute Reperfusion Stroke Study were evaluated for inclusion. Clinical and radiological parameters were used to calculate the TERPS, and functional outcome were assessed at 3-month follow-up. RESULTS: Out of 1028 patients who underwent EVT for acute ischemic stroke from January 2017 to July 2022, 218 (21.2%) patients ≥ 80 years with anterior ischemic stroke were included. Fair outcome, defined as modified Rankin scale ≤ 3 (mRS), was achieved in 117 (53.7%). In bivariate analyses, male sex (p 0.035), age (p 0.025), baseline National Institute of Health Stroke Scale (NIHSS, p < 0.001), pre-stroke mRS (p 0.002) and Alberta Stroke Program Early Computed Tomography score (ASPECTS, p 0.001) were associated with fair outcome. Significant predictors for fair outcome in regression analyses were lower pre-stroke mRS, adjusted odd ratio, (aOR) 0.67 (95% CI 0.50-0.91, p 0.01), NIHSS, aOR 0.92 (95% CI 0.87-0.97, p 0.002), and higher ASPECTS, aOR 1.22 (95% CI 1.03-1.44, p 0.023). The area under the curve (AUC) using TERPS was 0.74 (95% CI 0.67-0.80). CONCLUSIONS: The risk prediction score TERPS showed moderate performance in this external validation. Other variables may still be included to improve the model and validation using other cohorts is recommended. TRIAL REGISTRATION: NCT06220981.

Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Neural Crest.

This chapter discusses the role of cardiac neural crest cells in the formation of the septum that divides the cardiac arterial pole into separate systemic and pulmonary arteries. Further, cardiac neural crest cells directly support the normal development and patterning of derivatives of the caudal pharyngeal arches, including the great arteries, thymus, thyroid, and parathyroids. Recently, cardiac neural crest cells have also been shown to indirectly influence the development of the secondary heart field, another derivative of the caudal pharynx, by modulating signaling in the pharynx. The contribution and function of the cardiac neural crest cells has been learned in avian models; most of the genes associated with cardiac neural crest function have been identified using mouse models. Together these studies show that the neural crest cells may not only critical for normal cardiovascular development but also may be involved secondarily because they represent a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Cardiac neural crest cells span from the caudal pharynx into the outflow tract, and therefore may be susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations resulting from genetic and/or environmental insults necessarily requires better understanding the role of cardiac neural crest cells in cardiac development.

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .

Analytical propagation model for underwater free-space optical communication through realistic levels of oceanic absorption and scattering.

Optical communications (OC) through water bodies is an attractive technology for a variety of applications. Thanks to current single-photon detection capabilities, OC receiver systems can reliably decode very weak transmitted signals. This is the regime where pulse position modulation is an ideal scheme. However, there has to be at least one photon that goes through the pupil of the fore optics and lands in the assigned time bin. We estimate the detectable photon budget as a function of range for propagation through ocean water, both open and coastal. We make realistic assumptions about the water's inherent optical properties, specifically, absorption and scattering coefficients, as well as the strong directionality of the scattering phase function for typical hydrosol populations. We adopt an analytical (hence very fast) path-integral small-angle solution of the radiative transfer equation for multiple forward-peaked scattering across intermediate to large optical distances. Integrals are performed both along the directly transmitted beam (whether or not it is still populated) and radially away from it. We use this modeling framework to estimate transmission of a 1 J pulse of 532 nm light through open ocean and coastal waters. Thresholds for single-photon detection per time bin are a few km and a few 100 m. These are indicative estimates that will be reduced in practice due to sensor noise, background light, turbulence, bubbles, and so on, to be included in future work.

Aqueous VEGF-A Levels as a Liquid Biopsy Biomarker of Retinoblastoma Vitreous Seed Response to Therapy.

Purpose: Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be clinically evident at first. A predictive biomarker of tumor regression and relapse could help guide real-time clinical decision making. Retinoblastoma is an oxygen-sensitive tumor; paradoxically, VS survive in the hypoxic vitreous. We hypothesized that VS elaborate pro-angiogenic cytokines. The purpose was to determine if pro-angiogenic cytokine signatures from aqueous humor could serve as a biomarker of VS response to treatment. Methods: Multiplex ELISA was performed on aqueous from rabbit eyes with human retinoblastoma VS xenografts to identify expressed proangiogenic cytokines and changes in aqueous cytokine levels during intravitreal treatment were determined. Confirmatory RNAscope in situ hybridization for VEGF-A was performed on human retinoblastoma tumor sections and VS xenografts from rabbits. For human eyes undergoing intravitreal chemotherapy, serial aqueous VEGF-A levels measured via VEGF-A-specific ELISA were compared to clinical response. Results: VEGF-A was highly expressed in human retinoblastoma VS in the xenograft model, and was the only proangiogenic cytokine that correlated with VS disease burden. In rabbits, aqueous VEGF-A levels decreased in response to therapy, consistent with quantitative VS reduction. In patients, aqueous VEGF-A levels associated with clinical changes in disease burden (regression, stability, or relapse), with changes in VEGF-A levels correlating with clinical response. Conclusions: Aqueous VEGF-A levels correlate with extent of retinoblastoma VS, suggesting that aqueous VEGF-A may serve as a predictive molecular biomarker of treatment response.

Developing a PmSLP3-based vaccine formulation that provides robust long-lasting protection against hemorrhagic septicemia-causing serogroup B and E strains of Pasteurella multocida in cattle.

Background: Pasteurella multocida is a bacterial pathogen that causes a variety of infections across diverse animal species, with one of the most devastating associated diseases being hemorrhagic septicemia. Outbreaks of hemorrhagic septicemia in cattle and buffaloes are marked by rapid progression and high mortality. These infections have particularly harmful socio-economic impacts on small holder farmers in Africa and Asia who are heavily reliant on a small number of animals kept as a means of subsistence for milk and draft power purposes. A novel vaccine target, PmSLP-3, has been identified on the surface of hemorrhagic septicemia-associated strains of P. multocida and was previously shown to elicit robust protection in cattle against lethal challenge with a serogroup B strain. Methods: Here, we further investigate the protective efficacy of this surface lipoprotein, including evaluating the immunogenicity and protection upon formulation with a variety of adjuvants in both mice and cattle. Results: PmSLP-3 formulated with Montanide ISA 61 elicited the highest level of serum and mucosal IgG, elicited long-lasting serum antibodies, and was fully protective against serogroup B challenge. Studies were then performed to identify the minimum number of doses required and the needed protein quantity to maintain protection. Duration studies were performed in cattle, demonstrating sustained serum IgG titres for 3 years after two doses of vaccine and full protection against lethal serogroup B challenge at 7 months after a single vaccine dose. Finally, a serogroup E challenge study was performed, demonstrating that PmSLP-3 vaccine can provide protection against challenge by the two serogroups responsible for hemorrhagic septicemia. Conclusion: Together, these data indicate that PmSLP-3 formulated with Montanide ISA 61 is an immunogenic and protective vaccine against hemorrhagic septicemia-causing P. multocida strains in cattle.

An unusual presentation of unifocal Rosai-Dorfman disease and surgical treatment.

Rosai-Dorfman disease (RDD) is a rare histiocytic disorder with an unclear aetiology, and commonly presents with painless, bilateral cervical lymphadenopathy. Extranodal presentation in the absence of nodal involvement has been reported to have a predilection for the head and neck with less than 20 cases involving the jaw bones and sinuses. We present an interesting case of unifocal RDD of the infratemporal space in the absence of nodal involvement in a 61-year-old female treated with surgical excision and adjuvant radiation therapy.

Is the Use of Dexmedetomidine Upon Emergence From Anesthesia Associated With Neck Hematoma Formation Following Head and Neck Microvascular Reconstruction?

BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha-2-receptor agonist, and its use has not been well studied in major microvascular reconstructive surgery of the head and neck. PURPOSE: The purpose is to measure the association between DEX and neck hematoma formation in subjects undergoing head and neck microvascular reconstructive surgery. STUDY DESIGN, SETTING, SAMPLE: The investigators implemented a retrospective cohort study on subjects undergoing microvascular head and neck reconstruction for benign and malignant pathology at the University of Alabama at Birmingham from 2014 to 2021. Patients with unresectable tumors were excluded. PREDICTOR VARIABLE: The predictor variable was the intraoperative use of DEX upon emergence from general anesthesia. Subjects received standard anesthetic drugs and DEX, while control subjects received only standard anesthetic drugs. MAIN OUTCOME VARIABLE(S): The primary outcome was postoperative neck hematoma formation necessitating a return to the operating theater. The secondary outcome was the length of stay (LOS). COVARIATES: The covariates were demographic, operative, and oral morphine equivalents of anesthesia drugs. ANALYSES: Bivariate analyses were performed using the Student's t-test and the χ2 test for continuous and categorical variables. Multivariate regression analyses were conducted to assess for associations between DEX and the outcomes adjusted for confounding variables when present. P values of < .05 were regarded as statistically significant. RESULTS: A total of 297 subjects (mean age, 59.6 years, and standard deviation [SD], 14.9) with 61.6% male received DEX, and 304 subjects (mean age, 58.9 years, and SD, 14.6) with 60.2% male served as controls (P > .5). A total of 11 postoperative neck hematoma occurred in the control group when compared to 2 in the DEX (relative risk = 5.4, 95% confidence interval [CI], 1.2 to 24, P = .02). The mean LOS was 7.7 (SD, 4.3) and 9.4 (SD, 8.1) for the DEX and control groups (95% CI, 0.7 to 2.8, P < .01). After adjusting for tobacco history, tracheostomy, and neck dissection, DEX (Beta coefficient (B) = -1.7, 95% CI -2.7 to -0.7, P < .01) and neck dissection (B = 2.2, 95% CI 1.0 to 3.4, P < .01) were statistically associated with LOS. CONCLUSION AND RELEVANCE: The use of intraoperative DEX upon emergence from general anesthesia was associated with lower postoperative neck hematoma formation and a shorter length of stay following microvascular head and neck reconstruction.

Validation and clinical discovery demonstration of breast cancer data from a real-world data extraction platform.

Objective: To validate and demonstrate the clinical discovery utility of a novel patient-mediated, medical record collection and data extraction platform developed to improve access and utilization of real-world clinical data. Materials and Methods: Clinical variables were extracted from the medical records of 1011 consented patients with breast cancer. To validate the extracted data, case report forms completed using the structured data output of the platform were compared to manual chart review for 50 randomly-selected patients with metastatic breast cancer. To demonstrate the platform's clinical discovery utility, we identified 194 patients with early-stage clinical data who went on to develop distant metastases and utilized the platform-extracted data to assess associations between time to distant metastasis (TDM) and early-stage tumor histology, molecular type, and germline BRCA status. Results: The platform-extracted data for the validation cohort had 97.6% precision (91.98%-100% by variable type) and 81.48% recall (58.15%-95.00% by variable type) compared to manual chart review. In our discovery cohort, the shortest TDM was significantly associated with metaplastic (739.0 days) and inflammatory histologies (1005.8 days), HR-/HER2- molecular types (1187.4 days), and positive BRCA status (1042.5 days) as compared to other histologies, molecular types, and negative BRCA status, respectively. Multivariable analyses did not produce statistically significant results. Discussion: The precision and recall of platform-extracted clinical data are reported, although specificity could not be assessed. The data can generate clinically-relevant insights. Conclusion: The structured real-world data produced by a novel patient-mediated, medical record-extraction platform are reliable and can power clinical discovery.

A Retrospective Analysis of 129 Ameloblastoma Cases: Clinical and Demographical Trends from a Single Institution.

Ameloblastomas are benign neoplasms of the jaw, but frequently require extensive surgery. The aim of the study was to analyze the demographic and clinicopathological features of ameloblastoma cases at a single Oral and Maxillofacial Surgery group in the United States. STUDY DESIGN: A retrospective chart review of patients evaluated for ameloblastoma between 2010 and 2020 at a single tertiary care center. Age, race, sex, tumor size, tumor location, and histological subtypes were recorded. RESULTS: A total of 129 cases of ameloblastoma were recorded with a mean patient age of 42 ± 18.6 years (range 9-91 years old), male to female ratio 1.08:1. Ameloblastoma presenting in the mandible outnumbered maxilla in primary (118 to 8, respectively) and recurrent cases (8 to 1, respectively). There was a higher prevalence of ameloblastoma in Black patients (61.3%) with mean age of Black patients occurring at 40.5 years and the mean age of White patients occurring at 47.8 years and mean tumor size trended larger in the Black patients (15.7 cm2) compared to White patients (11.8 cm2). CONCLUSION: Data suggests a strong influence of racial factors on the incidence of ameloblastoma, with regards to size, Black patients with ameloblastoma trended higher and more data is needed to clearly elucidate any relationship between the tumor size and race, as other factors may influence the size (such as time to discovery).

Generative large language models are all-purpose text analytics engines: text-to-text learning is all your need.

OBJECTIVE: To solve major clinical natural language processing (NLP) tasks using a unified text-to-text learning architecture based on a generative large language model (LLM) via prompt tuning. METHODS: We formulated 7 key clinical NLP tasks as text-to-text learning and solved them using one unified generative clinical LLM, GatorTronGPT, developed using GPT-3 architecture and trained with up to 20 billion parameters. We adopted soft prompts (ie, trainable vectors) with frozen LLM, where the LLM parameters were not updated (ie, frozen) and only the vectors of soft prompts were updated, known as prompt tuning. We added additional soft prompts as a prefix to the input layer, which were optimized during the prompt tuning. We evaluated the proposed method using 7 clinical NLP tasks and compared them with previous task-specific solutions based on Transformer models. RESULTS AND CONCLUSION: The proposed approach achieved state-of-the-art performance for 5 out of 7 major clinical NLP tasks using one unified generative LLM. Our approach outperformed previous task-specific transformer models by ∼3% for concept extraction and 7% for relation extraction applied to social determinants of health, 3.4% for clinical concept normalization, 3.4%-10% for clinical abbreviation disambiguation, and 5.5%-9% for natural language inference. Our approach also outperformed a previously developed prompt-based machine reading comprehension (MRC) model, GatorTron-MRC, for clinical concept and relation extraction. The proposed approach can deliver the "one model for all" promise from training to deployment using a unified generative LLM.

Thinking Twice about the Cervical Mass: A Case Report of Primary Vaginal Leiomyosarcoma and Review of the Literature.

Primary vaginal leiomyosarcoma (LMS) is an unusual cause of aggressive gynecologic cancer which requires prompt surgical treatment for favorable outcomes. Definitive diagnosis and treatment render unique challenges to clinicians based on vague presentation and limited evidence for management. Here, we describe a case of vaginal LMS in a middle-aged woman with a history of cervical dysplasia found to have a proximal vaginal mass after presenting with vaginal discharge and cramping pain. The patient was diagnosed on pathologic surgical specimen and subsequently underwent definitive surgical treatment. She remains with no evidence of disease 20 months later. In our report, we emphasize the nuances of surgical management including localized source control in those desiring future fertility. Ultimately, we make recommendations for surgical treatment and surveillance based on the available published literature.

Differential beta-coronavirus infection dynamics in human bronchial epithelial organoids.

The lower respiratory system serves as the target and barrier for beta-coronavirus (beta-CoV) infections. In this study, we explored beta-CoV infection dynamics in human bronchial epithelial (HBE) organoids, focusing on HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2. Utilizing advanced organoid culture techniques, we observed robust replication for all beta-CoVs, particularly noting that SARS-CoV-2 reached peak viral RNA levels at 72 h postinfection. Through comprehensive transcriptomic analysis, we identified significant shifts in cell population dynamics, marked by an increase in goblet cells and a concurrent decrease in ciliated cells. Furthermore, our cell tropism analysis unveiled distinct preferences in viral targeting: HCoV-OC43 predominantly infected club cells, while SARS-CoV had a dual tropism for goblet and ciliated cells. In contrast, SARS-CoV-2 primarily infected ciliated cells, and MERS-CoV showed a marked affinity for goblet cells. Host factor analysis revealed the upregulation of genes encoding viral receptors and proteases. Notably, HCoV-OC43 induced the unfolded protein response pathway, which may facilitate viral replication. Our study also reveals a complex interplay between inflammatory pathways and the suppression of interferon responses during beta-CoV infections. These findings provide insights into host-virus interactions and antiviral defense mechanisms, contributing to our understanding of beta-CoV infections in the respiratory tract.

The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice.

Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.

High frequencies of alpha common cold coronavirus/SARS-CoV-2 cross-reactive functional CD4+ and CD8+ memory T cells are associated with protection from symptomatic and fatal SARS-CoV-2 infections in unvaccinated COVID-19 patients.

Background: Cross-reactive SARS-CoV-2-specific memory CD4+ and CD8+ T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4+ and CD8+ T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated. Methods: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4+ and CD8+ T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms. Results: Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134+CD137+CD4+ and CD134+CD137+CD8+ T cells that cross-recognized conserved epitopes from α-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs/SARS-CoV-2 cross-reactive exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells, detected both ex vivo and in vitro. Conclusions: These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4+ and CD8+ T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4+, and CD8+ T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.