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Aeration of the middle turbinate, termed 'Concha bullosa', is one of the most common, obstructive, anatomic variants seen in patients with sinusitis. The present study was carried out on 150 patients of chronic sinusitis, who underwent CT scan paranasal sinuses, coronal section prior to Functional Endoscopic Sinus Surgery (FESS). The CT Scans were evaluated to detect the incidence of Concha bullosa and its types, the significance of Concha bullosa in genesis of osteomeatal complex disease and relation between type of Concha bullosa and osteomeatal complex disease. Later the patients were subjected to FESS. In this study we found that the overall incidence of inflammatory disease in the osteomeatal complex in these symptomatic patients was no different between with and without Concha bullosa and osteomeatal complex disease is found to be more frequent if peumatization is localized to inferior part of middle turbinate. Concha bullosa requires specific endoscopic surgical techniques. [ABSTRACT FROM AUTHOR]

Abstract: Selenization growth of phase-separation-free polycrystalline CuIn1– x Ga x Se2 films was demonstrated using a less-hazardous organometallic Se source, diethylselenide [(C2H5)2Se: DESe], and stacked structure of Se-premixed Cu–In–Ga metals called ‘precursors’. Distinct from the case of using Se vapor or H2Se gas, single-phase CuInGaSe2 films were obtained without thermal annealing using a combination of DESe and Se-premixed precursors. Photoluminescence spectra of the films at 77K were dominated by the defect-related donor–acceptor pair and free electron to acceptor recombination emissions, which are particular to the CuInGaSe2 films exhibiting high-conversion efficiency. [Copyright &y& Elsevier]

Worldwide, nearly 45 million children under the age of 5 years were affected by wasting in 2022. Ethiopia has been challenged by disasters increasing the caseload of children with wasting. This study aimed to determine the effect of a simplified approach on recovery of children with acute malnutrition as compared with the standard protocol. A cluster randomized, controlled, noninferiority trial was carried out in three regions of Ethiopia from December 4, 2021, to July 30, 2022. A total of 58 clusters (health posts) were randomized into intervention and control groups. Children with SAM in the intervention groups received two sachets of Ready-to-Use Therapeutic Food (RUTF), whereas children in the control groups received RUTF based on their body weight. Children with moderate acute malnutrition (MAM) received one sachet of RUTF and one sachet of Ready-to-Use Supplementary Food (RUSF) daily in the intervention and control groups, respectively. Per protocol (PP) and intention-to-treat analysis were used to compare recovery at a noninferiority margin of 15%. Data were collected from 55 health posts and 1032 children. In the PP analysis, the recovery rate of children with wasting among the simplified group (97.8%) was noninferior to the standard protocol group (97.7%), p = 0.399. The RUTF cost per treatment of child with SAM was 56.55 USD for the standard versus 42.78 USD for the simplified approach. The simplified approach is noninferior to the standard protocol in terms of recovery and has a lower cost of RUTF. Further study is recommended to assess the effectiveness of the simplified approach in emergency contexts., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."

Introduction: Wasting occurs when the body's nutritional needs are unmet due to insufficient intake or illness. It represents a significant global challenge, with approximately 45 million infants and children under 5 years of age suffering from wasting in 2022., Methods: A cluster-randomized, controlled, non-inferiority trial was conducted in three regions of Ethiopia. A non-inferiority margin of 15%, along with a recovery rate of 90% and a minimum acceptable recovery rate of 75%, were considered alongside an intra-cluster correlation coefficient of 0.05 and an anticipated loss to follow-up of 10% in determining the total sample size of 1,052 children. Children with severe acute malnutrition (SAM) in the simplified group received two sachets of ready-to-use therapeutic food (RUTF) daily, while the standard group received RUTF based on their body weight. For moderate acute malnutrition (MAM) cases, the simplified group received one sachet of RUTF, whereas the standard group received one sachet of ready-to-use supplementary food daily. A non-parametric Kaplan-Meir curve was utilized to compare the survival time to recovery., Results: A total of 1,032 data points were gathered. For SAM cases, the average length of stay was 8.86 (±3.91) weeks for the simplified protocol and 8.26 (±4.18) weeks for the standard protocol ( P  = 0.13). For MAM cases, the average length of stay was 8.18 (±2.96) weeks for the simplified approach and 8.32 (±3.55) weeks for the standard protocol ( P  = 0.61). There was no significant difference ( P  = 0.502) observed between the simplified protocol [8 weeks, interquartile range (IQR): 7.06-8.94] and the standard protocol [9 weeks (IQR: 8.17-9.83)] among children with SAM on the median time to cure. There was no significant difference ( P  = 0.502) in the time to cure between the simplified approach [8 weeks (IQR: 7.53-8.47)] and the standard protocol [8 weeks (IQR: 7.66-8.34)] among children with MAM. The survival curves displayed similarity, with the log-rank test not showing significance ( P  > 0.5), indicating the non-inferiority of the simplified approach for cure time., Conclusion: The findings showed that the simplified and standard protocols demonstrated no significant differences in terms of the average duration of stay and time required for recovery., Clinical Trial Registration: https://pactr.samrc.ac.za/, Identifier (PACTR202202496481398)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Maru, Tamiru, Baye, Chitekwe, Kifle, Lailou and Belachew.)

Patient-derived organoids (PDOs) retain the original tumor's characteristics to a large degree and allow direct evaluation of the drug sensitivity, thereby emerging as a valuable resource for both basic and preclinical researches. Whereas most past studies stereotypically adopted a single PDO as an avatar of the patient, it remains to be investigated whether this assumption can be justified even for the tumor with spatial diversity. To address this issue, we established and characterized multiple PDOs originating from various sites of a patient with advanced uterine carcinosarcoma (UCS). Specifically, cancer cells were separately sampled from three sites; resected UCS tumor tissue, the peritoneal lavage fluid, and an intra-uterine brushing of the tumor. The three derived PDOs were morphologically undistinguishable, displaying typical carcinoma organoids-like appearance, but two of them proliferated at a faster rate. The primary tumor harbored mutations in TP53 and STK11 along with amplifications in CCNE1, ERBB2, and KRAS. These two mutations and the CCNE1 amplification were detected in all PDOs, while either KRAS or ERBB2 amplification was selectively observed in each PDO in a mutually exclusive manner. Observed intra-tumor heterogeneity in HER2 expression was differentially reproduced in the PDOs, which mirrored each PDO's sensitivity to HER2 inhibitors. Inter-PDO heterogeneity was also evident in sensitivity to standard cytotoxic agents. Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Animal health surveillance is crucial for early detection of emergency animal diseases and effective responses. However, surveillance systems are complex and rely on the contributions of many animal health stakeholders. Veterinarians are key stakeholders in this system, given their role and skills in investigating, diagnosing, and reporting notifiable diseases. This study investigated the contribution of the veterinary workforce to the Australian animal health surveillance system and opportunities for future involvement. To achieve the aims of the study, an online cross-sectional survey among the veterinary profession was conducted. Descriptive statistics and regression analyses were used to provide an overview and investigate drivers of attitudes and practices of veterinarians in relation to animal health surveillance. A total of 311 usable responses were obtained, with 191 being from veterinarians who worked in private practice in the previous 12 months. Among private practitioners, 58.6% worked with companion animals, 34.0% were mixed practice veterinarians and 7.3% were equine veterinarians. Over half (56.6%) of all participants considered themselves active participants in the local animal disease management system. The level of confidence in understanding the reporting system and knowing and identifying signs of endemic and exotic diseases was moderate among those working in private practice, with companion animal veterinarians reporting the lowest levels of confidence (p < 0.05). Approximately 40% of veterinarians had taken samples for diagnosis for notifiable diseases in the last year, with just over 20% reporting a notifiable disease. Awareness of and participation in training and surveillance programs for animal diseases by veterinarians was low, with those working in private practice having lower levels of both awareness and participation for most programs. In relation to potential future contribution to the surveillance system, over half of participants reported being interested and available to undertake surveillance work on behalf of the government, with those in mixed practice reporting higher levels of interest (69.6%) compared to those in companion (49.5%) and equine practice (30.8%). However, key challenges identified were related to perceived conflict of interest, and tensions between client needs and government agenda, followed by profitability and suitability of the business. This study provides evidence of a significant existing contribution by the veterinary profession to the surveillance system, and the capacity and willingness to increase this contribution. However, there are gaps in awareness, confidence and participation, as well as financial and veterinary-client relationship challenges that should be considered in any future planning to strengthen the Australian surveillance system., Competing Interests: Declaration of Competing Interest At the time of the study, Dr Emma Davis was employed by Global Veterinary Solutions Pty. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: HIV/AIDS poses a significant health challenge in sub-Saharan African countries, with a disproportionate impact on women of reproductive age. The disparities in knowledge, attitudes, and practices related to family planning among women living with HIV can be intricate and multi-faceted. This study aimed to assess the knowledge, attitude, practice, and associated factors regarding family planning among the women living with HIV at the University of Gondar specialized hospital, Gondar, Ethiopia., Method: A cross-sectional study was carried out at the University of Gondar Teaching Referral Hospital, focusing on HIV-positive women of reproductive age who visited the ART unit from July 8-28, 2022. Data collection involved the use of pre-tested, structured questionnaires administered through interviews. The gathered data were entered into the electronic Kobo Collect platform and subsequently exported for analysis using SPSS version 26. Descriptive summaries, including frequencies, means, and percentages, were presented through tables and figures. Logistic regression was employed to identify potential predictors, presenting adjusted odds ratios with a 95% confidence interval and a significance level set at a P-value of 0.05., Results: A total of 328 study participants were included. About 93% of the study population had good knowledge about modern contraceptives, and about 94% of the study population had good knowledge about safer conception. Only 30.2% of the study population had knowledge of the dual contraceptive method. The attitude and practice of women towards family planning (FP) were 71.0% and 55.8%, respectively. The study revealed that the most commonly employed contraceptive method was injectable contraceptives, constituting 34.2% of usage. Having one and a greater number of children (AOR = 2.25, 95% CI: 1.10, 4.49), having discussions on fertility plans with healthcare providers (AOR = 2.20, 95% CI: 1.02, 4.761), and having good family planning practices (AOR = 2.15, 95% CI: 1.19, 3.87) were significantly associated with the attitude toward family planning. Married women (AOR = 1.88, 95% CI = 1.11, 3.1), able to read and write (AOR = 2.12, 95% CI:1.04,4.32), college and above educational level (AOR = 4.51, 95% CI:1.93,10.87), had discussion on fertility plan with healthcare providers (AOR = 5.09, 95% CI: 1.96, 13.24), knowledge about dual method (AOR = 1.95, CI: 1.08, 3.50), and knowledge about modern contraceptive methods (AOR = 7.24, 95% CI: 1.56, 33.58) were significantly associated with good practice of family planning., Conclusion: Women living with HIV exhibited notably high levels of knowledge regarding modern contraceptive methods and safer conception. The knowledge of the dual method was low. More than half of the study population had good practice in family planning. More than two-thirds of HIV-positive reproductive-age women had a good attitude about family planning. Having one or a greater number of children, having a discussion on a fertility plan with a healthcare provider, and having a good practice of family planning were significantly associated with a good attitude toward family planning. Married women, education status, discussions on fertility plans with healthcare providers, knowledge about dual methods, and knowledge about modern contraceptive methods were significantly associated with good family planning practices. The stakeholders should design interventions based on the aforementioned factors to improve the attitude and practice of family planning., (© 2024. The Author(s).)

The tumor-elicited inflammation is closely related to tumor microenvironment during tumor progression. S100A8, an endogenous ligand of Toll-like receptor 4 (TLR4), is known as a key molecule in the tumor microenvironment and premetastatic niche formation. We firstly generated a novel multivalent S100A8 competitive inhibitory peptide (divalent peptide3A5) against TLR4/MD-2, using the alanine scanning. Divalent peptide3A5 suppressed S100A8-mediated interleukin-8 and vascular endothelial growth factor production in human colorectal tumor SW480 cells. Using SW480-transplanted xenograft models, divalent peptide3A5 suppressed tumor progression in a dose-dependent manner. We demonstrated that combination therapy with divalent peptide3A5 and bevacizumab synergistically suppressed tumor growth in SW480 xenograft models. Using syngeneic mouse models, we found that divalent peptide3A5 improved the efficacy of anti-programmed death (PD)1 antibody, and lung metastasis. In addition, by using multivalent peptide library screening based on peptide3A5, we then isolated two more candidates; divalent ILVIK, and tetravalent ILVIK. Of note, multivalent ILVIK, but not monovalent ILVIK showed competitive inhibitory activity against TLR4/MD-2 complex, and anti-tumoral activity in SW480 xenograft models. As most tumor cells including SW480 cells also express TLR4, S100A8 inhibitory peptides would target both the tumor microenvironment and tumor cells. Thus, multivalent S100A8 inhibitory peptides would provide new pharmaceutical options for aggressive cancers., (© 2023. The Author(s).)

Hereditary stomatocytosis (HSt) is a type of congenital hemolytic anemia caused by abnormally increased cation permeability of erythrocyte membranes. Dehydrated HSt (DHSt) is the most common subtype of HSt and is diagnosed based on clinical and laboratory findings related to erythrocytes. PIEZO1 and KCNN4 have been recognized as causative genes, and many related variants have been reported. We analyzed the genomic background of 23 patients from 20 Japanese families suspected of having DHSt using a target capture sequence and identified pathogenic/likely pathogenic variants of PIEZO1 or KCNN4 in 12 families., (© 2023. The Author(s).)

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cervical cancer remains a major threat to women's health, especially in countries with limited medical resources, and new drugs are needed to improve patient survival and minimize adverse effects. Here, we examine the effects of a triphenylphosphonium (TPP)-conjugated pyrrole-imidazole polyamide (CCC-h1005) targeting the common homoplasmic mitochondrial DNA (mtDNA) cancer risk variant (ATP6 8860A>G) on the survival of cervical cancer cell lines, cisplatin-resistant HeLa cells and patient-derived cervical clear cell carcinoma cells as models of cervical cancer treatment. We found that CCC-h1005 induced death in these cells and suppressed the growth of xenografted HeLa tumors with no severe adverse effects. These results suggest that PIP-TPP designed to target mtDNA cancer risk variants can be used to treat many cervical cancers harboring high copies of the target variant, providing a foundation for clinical trials of this class of molecules for treating cervical cancer and other types of cancers., (© 2022 UICC.)

Bovine viral diarrhoea virus (BVDV) is a disease of global importance, affecting the production and welfare of cattle enterprises through poor reproductive performance and calf mortality. In Australia, the prevention of BVDV introduction and spread is primarily achieved with on-farm biosecurity; however, the use of these practices can vary amongst producers. Economic utility is commonly identified as a contributor to the uptake of on-farm biosecurity, but other factors such as animal welfare, producer priorities and introduction risk also influence farmer behaviour. This study uses an individual-based, stochastic simulation model to examine the economic and non-economic value of 23 on-farm biosecurity combinations for the control of BVDV in Australian beef farms without (N0) and with (N1) a neighbouring population of persistently infected (PI) cattle. Combinations of quarantine of purchased bulls (Q), hygiene during herd health events (H), double-fencing adjacent boundaries with neighbouring farms (F) and vaccination against BVDV (V) were tested. This study is the first to simulate the use of strategic PI exposure (PI) as an alternative to V, a contentious practice performed by some Australian beef farmers. Introduction of BVDV into a naïve 300-breeder self-replacing beef herd was achieved through the purchase of PI bulls (N0 and N1 herds) and over-the-fence contact with neighbouring PI animals (N1 herds only). The predicted median cumulative loss due to BVDV over a 15-year period was AUD$172/breeder and AUD$453/breeder for an N0 and N1 herd, respectively. Early establishment of BVDV in the simulation period was found to be the primary factor contributing to economic loss. Consequently, the Q and QF combinations resulted in the highest predicted average annual cost-benefit for BVDV-free N0 and N1 herds. In the five years following establishment of BVDV, use of QP (N0 herds) and V (N1 herds) combinations were most cost-effective. Combinations that involved V and P (in conjunction with F in N1 herds) also resulted in the lowest number of PI animals sold to other farms or feedlots over the simulation period. However, in both N0 and N1 herds, P resulted in the highest number of infected cattle, which has implications for poor animal welfare and increased antimicrobial use on Australian beef farms. The outcomes reported in this study can guide decisions to prevent BVDV introduction and spread on extensive beef farms using on-farm biosecurity, based on the risk of BVDV exposure and the priorities of the individual farmer., Competing Interests: Declaration of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Emerging evidence suggests that neural activity contributes to tumor initiation and its acquisition of metastatic properties. More specifically, it has been reported that the sympathetic nervous system regulates tumor angiogenesis, tumor growth, and metastasis. The function of the sympathetic nervous system in primary tumors has been gradually elucidated. However, its functions in pre-metastatic environments and/or the preparation of metastatic environments far from the primary sites are still unknown. To investigate the role of the sympathetic nervous system in pre-metastatic environments, we performed chemical sympathectomy using 6-OHDA in mice and observed a decrease in lung metastasis by attenuating the recruitment of myeloid-derived suppressor cells. Furthermore, we note that neuro-immune cell interactions could be observed in tumor-bearing mouse lungs in conjunction with the decreased expression of Sema3A. These data indicate that the sympathetic nervous system contributes to the preparation of pre-metastatic microenvironments in the lungs, which are mediated by neuro-immune cell interactions.

This study investigated the involvement of private veterinarians in surveillance activities and the veterinary workforce's contribution to the Australian animal health surveillance system. The perception that there is overall a decreased engagement by veterinarians in surveillance outcomes at a time when there is increased need for bolstering of surveillance systems was investigated. Three key questions were considered: (1) What is the current contribution of private veterinarians to the Australian surveillance system? (2) What is the veterinary professions capacity to assume a more prominent role in surveillance? (3) What is the interest and ability of the veterinary profession in Australia to undertake this surveillance role now and into the future? Semi-structured telephone interviews were conducted with 17 private veterinarians with data analyzed qualitatively to identify key themes. Results demonstrate that private veterinarians are aware of their responsibilities and are engaged in surveillance activities at both formal and informal levels. The key challenges associated with current and future contributions were related to workload, remuneration, conflicts of interest and clarity over how responsibility for surveillance is shared amongst those involved in the system. The study has demonstrated that even amongst an engaged population, barriers do need to be addressed if private veterinarians are to be tasked with increasing their involvement in animal health surveillance activities., Competing Interests: Author ED was employed by Global Veterinary Solutions Pty. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hayes, Manyweathers, Maru, Davis, Woodgate and Hernandez-Jover.)

In this paper, we report the case of a 71-year-old man with an 8-year history of melanonychia on the right little finger, who referred to our hospital because the color of pigmented area had gradually darkened and the width had expanded. Physical examination revealed longitudinal melanonychia with brown color (4 mm in width). Dermoscopic examination revealed multiple white round clods and splinter hemorrhages. No micro-Hutchinson sign was observed. We performed a punch biopsy (diameter 3 mm) of the nail matrix for diagnosis. Histopathological examination revealed irregular acanthosis of epithelium of the nail bed and distal matrix, which consisted of basaloid cells without nuclear atypia. Several zones exhibited cell whorls reminiscent of squamous eddies. The whorls were composed of large pink cells arranged in an onion peel-like fashion. The basaloid cells tested negative for human papillomavirus in situ hybridization and p16 staining. The morphology of white round clods (milia-like cysts in metaphoric term) observed in dermoscopic analysis corresponded to squamous eddies in histopathology. Considering these features, ungual seborrheic keratosis (SK) with longitudinal melanonychia was diagnosed, which is an atypical site for SK. We suggest that the dermoscopic finding of milia-like cysts may be useful for the diagnosis of ungual SK., (© 2022 Japanese Dermatological Association.)

Metastasis remains the leading cause of cancer-related death. In 1889, Stephen Paget originally proposed the theory "seed-and-soil." Both cancer cell-intrinsic properties ("seed") and fertile microenvironment ("soil") are essential for metastasis formation. To date, accumulating evidences supported the theory using mouse models. The formation of a premetastatic niche has been widely accepted as an accel for metastasis. Similar to tumor microenvironment, various types of cells, such as immune cells, endothelial cells, and fibroblasts are involved in premetastatic niche formation. We have discovered that primary tumors hijack Toll-like receptor 4 (TLR4) signaling to establish a premetastatic niche in the lung by utilizing the endogenous ligands. In this review, we discuss the mechanisms that underlie inflammation-associated premetastatic niche formation upon metastasis, focusing especially on myeloid cells and macrophages as the cells executing and mediating complicated processes., (© 2022. The Author(s).)

To explore Australian sheep and beef producer vulnerability to an emergency animal disease outbreak, Bayesian Network models have been developed, with the ultimate goal of creating risk management tool for outbreak preparedness. These models were developed using multiple stakeholder elicitation including modelling experts, epidemiologists and on-farm stakeholders, including on-farm/survey data. An evaluation of the model's predictive capacity was conducted, using independent, blinded on-farm vulnerability assessments. Nine properties were visited, four each with sheep and beef enterprises, and one mixed enterprise. There were some discrepancies between the model predictions and on-farm assessment in the beef enterprises, with greater disparity with the sheep properties. Discrepancies between the model predictions and on-farm assessments have created opportunities for examination of the data collection process for the model development, the model itself and the on-farm assessment process. Bayesian Network approaches that allow for the inclusion of both continuous and discrete variables may improve the usefulness of these models, avoiding the loss of nuanced data by the need for discretisation of continuous variables, as will the inclusion of input from on-farm stakeholders in model development. Future work includes more data collection to improve the sensitivity of the model predictions, and a deeper, systemic exploration of the factors that may impact Australian producers' vulnerability to an emergency animal disease outbreak., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Recently, we introduced an organoid-based chemical carcinogenesis model using mouse normal tissue-derived organoids. In the present review article, the histopathological and immunohistochemical characteristics of mouse normal tissue-derived organoids and tumors derived from these organoids after their in vitro treatment with genotoxic carcinogens and injection into nude mouse are reviewed. In organoids treated in vitro with genotoxic carcinogens, we confirmed macroscopic tumorigenicity and histopathological findings, including neoplastic characteristics, such as multilayered epithelia and/or invasion of epithelia into the surrounding interstitium. In contrast glandular/cystic structures with monolayered epithelia were clearly demarcated from the surrounding Matrigel/interstitium in the untreated control groups. In addition to macroscopic tumorigenicity, these microscopic epithelial changes, which are characteristic of the early stages of carcinogenesis, are included in the requirements for carcinogenicity-positive judgement of the organoid-based carcinogenesis model. Immunohistochemistry of cytokeratins (CKs), used to determine the origin of epithelia and distribution of extraductal invasive lesions, or oncogenic kinases, which reflect molecular activation in epithelia following chemical treatment, is helpful for accurate diagnosis and molecular evaluation in the early stages of carcinogenesis. This information improves our biological understanding of organoid-based chemical carcinogenesis models., (©2022 The Japanese Society of Toxicologic Pathology.)

Improving public understanding and acceptance are critical for promoting coronavirus (COVID-19) vaccination. However, how to promote COVID-19 vaccine programs remains controversial due to various ethical issues. This study, thus, aimed to survey the acceptance of COVID-19 vaccines among Japanese citizens and discuss relevant ethical issues. A cross-sectional survey was conducted via an online platform. An anonymous, quantitative, self-administered online questionnaire was sent to 6965 registered Japanese residents (20-79 years of age), which included questions regarding the respondent's general knowledge, experience, and opinions of vaccines, vaccine development, COVID-19, and COVID-19 vaccines. Of the 1569 respondents, 730 (46.5%) and 839 (53.5%) were categorized into the younger and older groups, respectively. Most of the respondents possessed general knowledge of COVID-19 vaccines and their features. Of the respondents, 57.8% definitely agreed (10.5%) or somewhat agreed (47.3%) to receive COVID-19 vaccines. The older group showed significantly greater willingness to receive vaccines and higher literacy regarding vaccines in general. Possible reasons for the older group's greater willingness to receive COVID-19 vaccines are a high risk of severe COVID-19 infection and their past accumulated experience of receiving various vaccinations. Although active public intervention could increase vaccination rates, most of the respondents did not agree with mandatory vaccination. Furthermore, a gap between the participants in the COVID-19 vaccine trials and the prioritized population in real-world vaccination should be adjusted in future vaccine development., Supplementary Information: The online version contains supplementary material available at 10.1007/s41649-022-00207-4., Competing Interests: Competing InterestsHaruka Nakada received a research grant from the Japan Agency for Medical Research and Development. Other authors have no relevant financial or non-financial interests to disclose., (© National University of Singapore and Springer Nature Singapore Pte Ltd. 2022.)

Bovine viral diarrhea virus (BVDV) is an economically important disease in Australian beef farming. The disease typically results in low-level production losses that can be difficult to detect for several years. Simulation modeling can be used to support the decision to control BVDV; however, current BVDV simulation models do not adequately reflect the extensive farming environment of Australian beef production. Therefore, the objective of this study was to develop a disease simulation model to explore the impact of BVDV on beef cattle production in south-east Australia. A dynamic, individual-based, stochastic, discrete-time simulation model was created to simulate within-herd transmission of BVDV in a seasonal, self-replacing beef herd. We used the model to simulate the effect of herd size and BVDV introduction time on disease transmission and assessed the short- and long-term impact of BVDV on production outputs that influence the economic performance of beef farms. We found that BVDV can become established in a herd after a single PI introduction in 60% of cases, most frequently associated with the breeding period. The initial impact of BVDV will be more severe in smaller herds, although self-elimination is more likely in small herds than in larger herds, in which there is a 23% chance that the virus can persist for >15 years following a single incursion in a herd with 800 breeders. The number and weight of steers sold was reduced in the presence of BVDV and the results demonstrated that repeat incursions exacerbate long-term production losses, even when annual losses appear marginal. This model reflects the short- and long-term production losses attributed to BVDV in beef herds in southeast Australia and provides a foundation from which the influence and economic utility of BVDV prevention in Australian beef herds can be assessed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fountain, Hernandez-Jover, Kirkeby, Halasa, Manyweathers, Maru and Brookes.)

Endometrial cancer (EC) is the most common malignancy of the female reproductive tract worldwide. Although comprehensive genomic analyses of EC have already uncovered many recurrent genetic alterations and deregulated signaling pathways, its disease model has been limited in quantity and quality. Here, we review the current status of genetic models for EC in mice, which have been developed in two distinct ways at the level of organisms and cells. Accordingly, we first describe the in vivo model using genetic engineering. This approach has been applied to only a subset of genes, with a primary focus on Pten inactivation, given that PTEN is the most frequently altered gene in human EC. In these models, the tissue specificity in genetic engineering determined by the Cre transgenic line has been insufficient. Consequently, the molecular mechanisms underlying EC development remain poorly understood, and preclinical models are still limited in number. Recently, refined Cre transgenic mice have been created to address this issue. With highly specific gene recombination in the endometrial cell lineage, acceptable in vivo modeling of EC development is warranted using these Cre lines. Second, we illustrate an emerging cell-based model. This hybrid approach comprises ex vivo genetic engineering of organoids and in vivo tumor development in immunocompromised mice. Although only a few successful cases have been reported as proof of concept, this approach allows quick and comprehensive analysis, ensuring a high potential for reconstituting carcinogenesis. Hence, ex vivo/in vivo hybrid modeling of EC development and its comparison with corresponding in vivo models may dramatically accelerate EC research. Finally, we provide perspectives on future directions of EC modeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maru and Hippo.)

Genetically engineered mice have been the gold standard in modeling tumor development. Recent studies have demonstrated that genetically engineered organoids can develop subcutaneous tumors in immunocompromised mice, at least for organs that prefer predominant driver mutations for tumorigenesis. To further substantiate this concept, the fallopian tube (FT), a major cell of origin of ovarian high-grade serous carcinoma (HGSC), which almost invariably carries TP53 mutations, was investigated for p53 inactivation-driven tumorigenesis. Murine FT organoids subjected to lentiviral Cre-mediated Trp53 deletion did not develop tumors. However, subsequent suppression of Pten and simultaneous induction of mutant Pik3ca led to the development of carcinoma in situ and HGSC-like tumors, respectively, whereas concurrent deletion of Apc resulted in the development of benign cysts, mirroring frequent activation of the PI3K/AKT axis and the marginal impact of Wnt pathway activation in HGSC. Consistent with the frequent activation of the RAS pathway in HGSC, mutant Kras cooperated with Trp53 deletion for the development of tumors, which unexpectedly contained sarcoma cells in addition to carcinoma cells, despite the epithelial origin of the inoculated organoids. This finding is in sharp contrast with the exclusive adenocarcinoma development from gastrointestinal organoids with the same genotype reported in previous studies, suggesting a tissue-specific epithelial-mesenchymal transition program. In tumor-derived organoids, the Cre-mediated recombination rate reached 100% for Trp53 but not for the other genes, highlighting the advantage of p53 inactivation in FT tumorigenesis. The Trp53 wildtype FT organoids expressing the mutant Kras developed sarcoma and carcinoma upon Cdkn2a suppression and Tgfbr2 deletion, respectively, revealing novel pro-tumorigenic genetic cooperation and critical roles of TGF-β signaling for epithelial-mesenchymal transition in FT-derived tumorigenesis. Collectively, the organoid-based approach represents a shortcut to tumorigenesis and provides novel insights into the relationships among genotype, cell type, and tumor phenotype underlying tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

KRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in Kras G12D -expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for Kras G12D . Collectively, we showed that the oncogenic potential of Kras G12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.

RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether "naked nonvesicular extracellular mRNA" (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1β (IL1β)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3'-untranslated region of nex-IL1β-mRNA and transports it to the nucleus. The nex-IL1β-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA.

To maintain and strengthen Australia's competitive international advantage in sheep meat and wool markets, the biosecurity systems that support these industries need to be robust and effective. These systems, strengthened by jurisdictional and livestock industry investments, can also be enhanced by a deeper understanding of individual producer risk of exposure to animal diseases and capacity to respond to these risks. This observational study developed a Vulnerability framework, built from current data from Australian sheep producers around behaviors and beliefs that may impact on their likelihood of Exposure and Response Capacity (willingness and ability to respond) to an emergency animal disease (EAD). Using foot and mouth disease (FMD) as a model, a cross-sectional survey gathered information on sheep producers' demographics, and their practices and beliefs around animal health management and biosecurity. Using the Vulnerability framework, a Bayesian Network (BN) model was developed as a first attempt to develop a decision making tool to inform risk based surveillance resource allocation. Populated by the data from 448 completed questionnaires, the BN model was analyzed to investigate relationships between variables and develop producer Vulnerability profiles. Respondents reported high levels of implementation of biosecurity practices that impact the likelihood of exposure to an EAD, such as the use of appropriate animal movement documentation (75.4%) and isolation of incoming stock (64.9%). However, adoption of other practices relating to feral animal control and biosecurity protocols for visitors were limited. Respondents reported a high uptake of Response Capacity practices, including identifying themselves as responsible for observing (94.6%), reporting unusual signs of disease in their animals (91.0%) and daily/weekly inspection of animals (90.0%). The BN analysis identified six Vulnerability typologies, with three levels of Exposure (high, moderate, low) and two levels of Response Capacity (high, low), as described by producer demographics and practices. The most influential Exposure variables on producer Vulnerability included adoption levels of visitor biosecurity and visitor access protocols. Findings from this study can guide decisions around resource allocation to improve Australia's readiness for EAD incursion and strengthen the country's biosecurity system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Manyweathers, Maru, Hayes, Loechel, Kruger, Mankad, Xie, Woodgate and Hernandez-Jover.)