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Iodine-induced cleavage at phosphorothioate DNA (PT-DNA) is characterized by extremely high sensitivity (∼1 phosphorothioate link per 106 nucleotides), which has been used for detecting and sequencing PT-DNA in bacteria. Despite its foreseeable potential for wide applications, the cleavage mechanism at the PT-modified site has not been well established, and it remains unknown as to whether or not cleavage of the bridging P-O occurs at every PT-modified site. In this work, we conducted accurate ωB97X-D calculations and high-performance liquid chromatography-mass spectrometry to investigate the process of PT-DNA cleavage at the atomic and molecular levels. We have found that iodine chemoselectively binds to the sulfur atom of the phosphorothioate link via a strong halogen-chalcogen interaction (a type of halogen bond, with binding affinity as high as 14.9 kcal/mol) and thus triggers P-O bond cleavage via phosphotriester-like hydrolysis. Additionally, aside from cleavage of the bridging P-O bond, the downstream hydrolyses lead to unwanted P-S/P-O conversions and a loss of the phosphorothioate handle. The mechanism we outline helps to explain specific selectivity at the PT-modified site but also predicts the dynamic stoichiometry of P-S and P-O bond breaking. For instance, Tris is involved in the cascade derivation of S-iodo-phosphorothioate to S-amino-phosphorothioate, suppressing the S-iodo-phosphorothioate hydrolysis to a phosphate diester. However, hydrolysis of one-third of the Tris-O-grafting phosphotriester results in unwanted P-S/P-O conversions. Our study suggests that bacterial DNA phosphorothioation may more frequently occur than previous bioinformatic estimations have predicted from iodine-induced deep sequencing data.

Background: There is a significant push to change the trajectory of youth mental ill-health and suicide globally. Ensuring that young people have access to services that meet their individual needs and are easily accessible is a priority. Genuine stakeholder engagement in mental health system design is critical to ensure that system strengthening is likely to be successful within these complex environments. There is limited literature describing engagement processes undertaken by research teams in mental health program implementation and planning. This protocol describes the methods that will be used to engage local communities using systems science methods to mobilize knowledge and action to strengthen youth mental health services., Methods: Using participatory action research principles, the research team will actively engage with local communities to ensure genuine user-led participatory systems modelling processes and enhance knowledge mobilisation within research sites. Ensuring that culturally diverse and Aboriginal and Torres Strait Islander community voices are included will support this process. A rigorous site selection process will be undertaken to ensure that the community is committed and has capacity to actively engage in the research activities. Stakeholder engagement commences from the site selection process with the aim to build trust between researchers and key stakeholders. The research team will establish a variety of engagement resources and make opportunities available to each site depending on their local context, needs and audiences they wish to target during the process., Discussion: This protocol describes the inclusive community engagement and knowledge mobilization process for the Right care, first time, where you live research Program. This Program will use an iterative and adaptive approach that considers the social, economic, and political context of each community and attempts to maximise research engagement. A theoretical framework for applying systems approaches to knowledge mobilization that is flexible will enable the implementation of a participatory action research approach. This protocol commits to a rigorous and genuine stakeholder engagement process that can be applied in mental health research implementation., (© 2022. The Author(s).)

Introduction: Systems modelling and simulation can improve understanding of complex systems to support decision making, better managing system challenges. Advances in technology have facilitated accessibility of modelling by diverse stakeholders, allowing them to engage with and contribute to the development of systems models (participatory modelling). However, despite its increasing applications across a range of disciplines, there is a growing need to improve evaluation efforts to effectively report on the quality, importance, and value of participatory modelling. This paper aims to identify and assess evaluation frameworks, criteria, and/or processes, as well as to synthesize the findings into a comprehensive multi-scale framework for participatory modelling programs., Materials and Methods: A scoping review approach was utilized, which involved a systematic literature search via Scopus in consultation with experts to identify and appraise records that described an evaluation framework, criteria, and/or process in the context of participatory modelling. This scoping review is registered with the Open Science Framework., Results: The review identified 11 studies, which varied in evaluation purposes, terminologies, levels of examination, and time points. The review of studies highlighted areas of overlap and opportunities for further development, which prompted the development of a comprehensive multi-scale evaluation framework to assess participatory modelling programs across disciplines and systems modelling methods. The framework consists of four categories (Feasibility, Value, Change/Action, Sustainability) with 30 evaluation criteria, broken down across project-, individual-, group- and system-level impacts., Discussion & Conclusion: The presented novel framework brings together a significant knowledge base into a flexible, cross-sectoral evaluation effort that considers the whole participatory modelling process. Developed through the rigorous synthesis of multidisciplinary expertise from existing studies, the application of the framework can provide the opportunity to understand practical future implications such as which aspects are particularly important for policy decisions, community learning, and the ongoing improvement of participatory modelling methods., Competing Interests: Dr Louise Freebairn is currently employed part-time by the Brain and Mind Centre, University of Sydney; ACT Health as Director of Knowledge Translation and Health Outcomes, Epidemiology Section, ACT Health & CSART as Director of Policy Applications & Translational Science. A/Professor Jo-An Occhipinti is both Head of Systems Modelling, Simulation & Data Science at the University of Sydney’s Brain and Mind Centre and Managing Director of Computer Simulation & Advanced Research Technologies (CSART). Professor Ian Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies.

Vertically paired electrodes (VPEs) with multiple electrode pairs were developed for the enhancement of capacitive measurements by optimizing the electrode gap and number of electrode pairs. The electrode was fabricated using a conductive polymer layer of PEDOT:PSS instead of Ag and Pt metal electrodes to increase the VPE fabrication yield because the PEDOT:PSS layer could be effectively etched using a reactive dry etching process. In this study, sensitivity enhancement was realized by decreasing the electrode gap and increasing the number of VPE electrode pairs. Such an increase in sensitivity according to the electrode gap and the number of electrode pairs was estimated using a model analyte for an immunoassay. Additionally, a computer simulation was performed using VPEs with different electrode gaps and numbers of VPE electrode pairs. Finally, VPEs with multiple electrode pairs were applied for SARS-CoV-2 nucleoprotein (NP) detection. The capacitive biosensor based on the VPE with immobilized anti-SARS-CoV-2 NP was applied for the specific detection of SARS-CoV-2 in viral cultures. Using viral cultures of SARS-CoV-2, SARS-CoV, MERS-CoV, and CoV-strain 229E, the limit of detection (LOD) was estimated to satisfy the cutoff value (dilution factor of 1/800) for the medical diagnosis of COVID-19, and the assay results from the capacitive biosensor were compared with commercial rapid kit based on a lateral flow immunoassay., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We report the first complete mitochondrial genome of Odontobutis obscurus , which consists of 17,038 bp harboring 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and a control region (D-loop). The overall base composition of the complete genome is A (30.63%), C (28.72%), T (25.70%), G (14.95%). The complete mitogenome of Odontobutis obscurus , most closely related to congeners in the Bayesian inference and maximum likelihood tree, provides a better understanding of the phylogeny of the genus Odontobutis ., Competing Interests: The authors report no conflicts of interests. The authors alone are responsible for the content and writing of this article., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The youth mental health sector is persistently challenged by issues such as service fragmentation and inefficient resource allocation. Systems modelling and simulation, particularly utilizing participatory approaches, is offering promise in supporting evidence-informed decision making with limited resources by testing alternative strategies in safe virtual environments before implementing them in the real world. However, improved evaluation efforts are needed to understand the critical elements involved in and to improve methods for implementing participatory modelling for youth mental health system and service delivery. An evaluation protocol is described to evaluate the feasibility, value, impact, and sustainability of participatory systems modelling in delivering advanced decision support capabilities for youth mental health. This study applies a comprehensive multi-scale evaluation framework, drawing on participatory action research principles as well as formative, summative, process, and outcome evaluation techniques. Novel data collection procedures are presented, including online surveys that incorporate gamification to enable social network analysis and patient journey mapping. The evaluation approach also explores the experiences of diverse stakeholders, including young people with lived (or living) experience of mental illness. Social and technical opportunities will be uncovered, as well as challenges implementing these interdisciplinary methods in complex settings to improve youth mental health policy, planning, and outcomes. This study protocol can also be adapted for broader international applications, disciplines, and contexts.

Objective: This study aimed to determine the real-world effectiveness of bi- or quadrivalent human papillomavirus (HPV) vaccines in Thai adult women ≥5 years post-vaccination in reducing HPV 16/18-associated low-grade squamous intraepithelial lesions or worse (LSIL+), atypical squamous cells of undetermined significance or worse (ASC-US+), and HPV 16/18 positivity., Methods: A retrospective cohort study was conducted among Thai women aged 20-45 years in Bangkok. The vaccinated and unvaccinated groups were matched according to baseline years. HPV/Pap test results were collected from the medical records and/or obtained by cervical sample collection at the study sites. Adjusted hazard ratios were measured using multivariable Cox regression analyses., Results: A total of 993 participants (493 vaccinated and 500 unvaccinated) were enrolled from 2018 to 2019. The median ages at baseline of the vaccinated and unvaccinated groups were 33 years (interquartile range [IQR] 27-38) and 34 years (IQR 30-38), respectively. The median follow-up periods were 7.3 years (IQR 6.1-8.6) and 7.2 years (IQR 5.8-8.9) for the vaccinated group and the unvaccinated group, respectively. More women in the vaccinated group were single (29.2% vs. 13.2%, P < 0.001) and university graduates (83.2% vs. 75.4%, P = 0.009). The vaccinated and unvaccinated groups had similar personal monthly incomes (>20,000 THB/month, 63.9% vs. 62.4%, respectively, P = 0.685). There were no cases of HPV 16/18-associated LSIL+ in the vaccinated group, whereas there were four cases in the unvaccinated group. HPV vaccine effectiveness was 88.0% (95% CI 2.0-98.5) in the reduction of HPV 16/18-associated ASC-US+, and 84.6% (95% CI 43.5-95.8) in the reduction of HPV 16/18 positivity., Conclusions: HPV vaccine effectiveness was high in adult women in a real-world scenario in a developing country. Free HPV vaccination in adult women in this age group should be further explored when vaccine supplies are not limited. (HPV: human papillomavirus. LSIL+: low-grade squamous intraepithelial lesion or worse. ASC-US+: atypical squamous cells of undetermined significance or worse)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ability to accurately predict the early progression of hemorrhagic fever with renal syndrome (HFRS) is crucial for reducing morbidity and mortality rates in severely affected patients. However, the utility of biomarkers for predicting clinical outcomes remains elusive in HFRS. The aims of the current study were to analyze the serum levels of immune function-related proteins and identify novel biomarkers that may help ascertain clinical outcomes of HFRS. Enzyme-linked immunosorbent assay, Luminex, and bioanalyzer assays were used to quantitatively detect 15 biomarkers in 49 serum samples of 26 patients with HFRS. High hemoglobin (HGB) and low urine output (UO) levels were identified as potential biomarkers associated with the acute HFRS. The serum soluble urokinase plasminogen activator receptor (suPAR) and C-X-C motif chemokine ligand 10 (CXCL10) values increased in the early phase of diseases. Elevated suPAR, interleukin-10 (IL-10), CXCL10, and decreased transforming growth factor-beta 3 (TGF-β3) were representative predictors of the disease severity. Upregulation of the HGB showed a significant correlation with high levels of suPAR and CXCL10. Reduced UO positively correlated with increased suPAR, CXCL10, and TGF-β2, and decreased vascular endothelial growth factor and TGF-β3. The changing HGB and UO criteria, high suPAR, IL-10, CXCL10, and low TGF-β3 of HFRS raise significant awareness for physicians regarding prospective biomarkers for monitoring early warning signs of HFRS. This study provides critical insights into the clinical and immunological biomarkers for disease severity and progression in patients with HFRS to identify early predictions of fatal outcomes.

Background: Globally, there are fundamental shortcomings in mental health care systems, including restricted access, siloed services, interventions that are poorly matched to service users' needs, underuse of personal outcome monitoring to track progress, exclusion of family and carers, and suboptimal experiences of care. Health information technologies (HITs) hold great potential to improve these aspects that underpin the enhanced quality of mental health care., Objective: Project Synergy aimed to co-design, implement, and evaluate novel HITs, as exemplified by the InnoWell Platform, to work with standard health care organizations. The goals were to deliver improved outcomes for specific populations under focus and support organizations to enact significant system-level reforms., Methods: Participating health care organizations included the following: Open Arms-Veterans & Families Counselling (in Sydney and Lismore, New South Wales [NSW]); NSW North Coast headspace centers for youth (Port Macquarie, Coffs Harbour, Grafton, Lismore, and Tweed Heads); the Butterfly Foundation's National Helpline for eating disorders; Kildare Road Medical Centre for enhanced primary care; and Connect to Wellbeing North Coast NSW (administered by Neami National), for population-based intake and assessment. Service users, families and carers, health professionals, and administrators of services across Australia were actively engaged in the configuration of the InnoWell Platform to meet service needs, identify barriers to and facilitators of quality mental health care, and highlight potentially the best points in the service pathway to integrate the InnoWell Platform. The locally configured InnoWell Platform was then implemented within the respective services. A mixed methods approach, including surveys, semistructured interviews, and workshops, was used to evaluate the impact of the InnoWell Platform. A participatory systems modeling approach involving co-design with local stakeholders was also undertaken to simulate the likely impact of the platform in combination with other services being considered for implementation within the North Coast Primary Health Network to explore resulting impacts on mental health outcomes, including suicide prevention., Results: Despite overwhelming support for integrating digital health solutions into mental health service settings and promising impacts of the platform simulated under idealized implementation conditions, our results emphasized that successful implementation is dependent on health professional and service readiness for change, leadership at the local service level, the appropriateness and responsiveness of the technology for the target end users, and, critically, funding models being available to support implementation. The key places of interoperability of digital solutions and a willingness to use technology to coordinate health care system use were also highlighted., Conclusions: Although the COVID-19 pandemic has resulted in the widespread acceptance of very basic digital health solutions, Project Synergy highlights the critical need to support equity of access to HITs, provide funding for digital infrastructure and digital mental health care, and actively promote the use of technology-enabled, coordinated systems of care., (©Haley M LaMonica, Frank Iorfino, Grace Yeeun Lee, Sarah Piper, Jo-An Occhipinti, Tracey A Davenport, Shane Cross, Alyssa Milton, Laura Ospina-Pinillos, Lisa Whittle, Shelley C Rowe, Mitchell Dowling, Elizabeth Stewart, Antonia Ottavio, Samuel Hockey, Vanessa Wan Sze Cheng, Jane Burns, Elizabeth M Scott, Ian B Hickie. Originally published in JMIR Mental Health (https://mental.jmir.org), 09.03.2022.)

Since octopuses are similar in appearance and can be processed into various forms, seafood fraud has been reported. In this study, we developed the PCR assay to simultaneously detect three octopuses (big blue octopus, giant Pacific octopus, and common octopus). Specific primer sets were designed based on COI gene. We observed that the specific PCR amplicon sizes were 84 bp for big blue octopus, 117 bp for giant Pacific octopus, and 166 bp for common octopus, respectively. This assay was then used to test for specificity and did not show cross-reactivity with 15 cephalopods families. The limit of detection of the multiplex PCR assay was 0.1 pg. Subsequently, 30 commercial food products were then monitored to evaluate the applicability of this assay. All products were specifically amplified, and three octopus species of interest were distinguished. Therefore, this assay can be used as an octopus authentication tool in the seafood industry., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interest., (© The Korean Society of Food Science and Technology 2022.)

As commensal colonizers in livestock, there has been little attention on staphylococci, especially non- aureus staphylococci (NAS), contaminating meat production chain. To assess prevalence of staphylococci in retail pork and slaughterhouse carcass samples in Korea, we collected 578 samples from Korean slaughterhouses (n=311) and retail markets (n=267) for isolation of staphylococci and determined antimicrobial resistance phenotypes in all the isolates. The presence of and prevalence of fusB -family genes ( fusB , fusC , fusD , and fusF ) and mutations in fusA genes were examined in fusidic acid resistant isolates. A total of 47 staphylococcal isolates of 4 different species ( Staphylococcus aureus, n=4; S. hyicus , n=1; S. epidermidis , n=10; Mammaliicoccus sciuri , n=32) were isolated. Fusidic acid resistance were confirmed in 9/10 S. epidermidis and all of the 32 M. sciuri (previously S. sciuri ) isolates. Acquired fusidic acid resistance genes were detected in all the resistant strains; fusB and fusC in S. epidermidis and fusB/C in M. sciuri . Multi-locus sequence type analysis revealed that ST63 (n=10, 31%) and ST30 (n=8, 25%) genotypes were most prevalent among fusidic acid resistant M. sciuri isolates. In conclusion, the high prevalence of fusB -family genes in S. epidermidis and M. sciuri strains isolated from pork indicated that NAS might act as a reservoir for fusidic acid resistance gene transmissions in pork production chains., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 10 5  µm 3 ) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy 1,2 imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets 3 and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Linezolid resistance, mediated by the cfr gene, which confers resistant phenotypes to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antimicrobials, has emerged in S. aureus and non-aureus staphylococci (NAS). Moreover, due to the transferable potential via plasmids, the spread of cfr among staphylococci is of great concern. In the present study, we investigated the prevalence of cfr-mediated linezolid resistance in ST398 methicillin-resistant S. aureus (MRSA) and NAS strains isolated from a pig farm. Among the 26 staphylococci isolates collected from a pig farm, 14 cfr-harboring ST398 MRSA and NAS (S. epidermidis, S. pasteuri, S. cohnii, and S. rostri) strains were resistant to linezolid and also carried the fexA gene. Comparative genome analysis of cfr-carrying linezolid-resistant ST398 MRSA and NAS (S. pasteuri, S. cohnii, and S. epidermidis) strains revealed that the segments harboring cfr in different staphylococcal strains showed ≥ 99 % sequence identity and the corresponding region containing the cfr, fexA, and Tn558 elements were located in a 38-kb plasmid, designated pSA12 of ST398 MRSA. These observations indicate that the cfr-carrying plasmids and/or fragments may be disseminated among staphylococci in a pig farm and possibly transmitted to staphylococci of human origin, subsequently posing a threat to public health. This is the first report of the co-existence of cfr in linezolid-resistant ST398 MRSA and NAS isolated from a pig farm in South Korea., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Glycans are expressed on the surface of nearly all host and bacterial cells. Not surprisingly, glycan-mediated molecular interactions play a vital role in bacterial pathogenesis and host responses against pathogens. Glycan-mediated host-pathogen interactions can benefit the pathogen, host, or both. Here, we discuss (i) bacterial glycans that play a critical role in bacterial colonization and/or immune evasion, (ii) host glycans that are utilized by bacteria for pathogenesis, and (iii) bacterial and host glycans involved in immune responses against pathogens. We further discuss (iv) opportunities and challenges for transforming these research findings into more effective antibacterial strategies, and (v) technological advances in glycoscience that have helped to accelerate progress in research. These studies collectively offer valuable insights into new perspectives on antibacterial strategies that may effectively tackle the drug-resistant pathogens that are rapidly spreading globally., Competing Interests: Declaration of interests There are no interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Despite significant investment, mental health issues remain a leading cause of death among young people globally. Sophisticated decision analysis methods are needed to better understand the dynamic and multisector drivers of youth mental health. System modeling can help explore complex issues such as youth mental health and inform strategies to effectively respond to local needs and achieve lasting improvements. The advantages of engaging stakeholders in model development processes have long been recognized; however, the methods for doing so are often not well-described., Objective: This paper aims to describe the participatory procedures that will be used to support systems modeling for national multisite implementation. The Right Care, First Time, Where You Live research program will focus on regional youth mental health applications of systems modeling in 8 different sites across Australia., Methods: The participatory model development approach involves an iterative process of engaging with a range of participants, including people with lived experience of mental health issues. Their knowledge of the local systems, pathways, and drivers is combined with the academic literature and data to populate the models and validate their structure. The process centers around 3 workshops where participants interact and actively engage in group model-building activities to define, refine, and validate the systems models. This paper provides a detailed blueprint for the implementation of this process for mental health applications., Results: The participatory modeling methods described in this paper will be implemented at 2 sites per year from 2022 to 2025. The 8 selected sites have been chosen to capture variations in important factors, including determinants of mental health issues and access to services. Site engagement commenced in August 2021, and the first modeling workshops are scheduled to commence in February 2022., Conclusions: Mental health system decision makers require tools to help navigate complex environments and leverage interdisciplinary problem-solving. Systems modeling can mobilize data from diverse sources to explore a range of scenarios, including the impact of interventions in different combinations and contexts. Involving stakeholders in the model development process ensures that the model findings are context-relevant and fit-for-purpose to inform decision-making., International Registered Report Identifier (irrid): PRR1-10.2196/32988., (©Louise Freebairn, Jo-An Occhipinti, Yun Ju C Song, Adam Skinner, Kenny Lawson, Grace Yeeun Lee, Samuel J Hockey, Samantha Huntley, Ian B Hickie. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.02.2022.)

Obesity is associated with the dysregulation of vitamin D metabolism and altered immune responses in bone marrow-derived dendritic cells (BMDCs). Vitamin D can affect the differentiation, maturation, and activation of dendritic cells (DCs) and regulate autophagy via vitamin D receptor signaling. Autophagy was shown to be involved in the functions of DCs. We investigated the effects of dietary vitamin D supplementation and in vitro 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) treatment on autophagy in BMDCs from control diet (CON)-fed lean and high-fat diet (HFD)-induced obese mice. C57BL/6 male mice were fed CON or HFD with 10% or 45% kcal fat, respectively, supplemented with 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS) for 12 weeks. BMDCs were generated by culturing bone marrow cells from the mice with 20 ng/mL rmGM-CSF and treated with 1 nM 1,25(OH) 2 D 3 . Maturation of BMDCs was induced by lipopolysaccharide (50 ng/mL) stimulation. Treatment with 1,25(OH) 2 D 3 inhibited the expression of phenotypes related to DC function (MHC class Ⅱ, CD86, CD80) and production of IL-12p70 by BMDCs from control and obese mice, regardless of dietary vitamin D supplementation. LC3Ⅱ/Ⅰ and VPS34 protein levels increased, and p62 expression decreased, after 1,25(OH) 2 D 3 treatment of the BMDCs in CON-vDC only. Vdr mRNA levels decreased following 1,25(OH) 2 D 3 treatment of BMDCs in the HFD-vDC. In conclusion, autophagy flux was increased by 1,25(OH) 2 D 3 treatment of the BMDCs in CON-vDC but not in the HFD-vDC group. This suggests that the decreased expression of Vdr following 1,25(OH) 2 D 3 treatment might have affected autophagy flux in BMDCs from obese mice., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Chemoresistance of leukemic cells has largely been attributed to clonal evolution secondary to accumulating mutations. Here, we show that a subset of leukemic blasts in contact with the mesenchymal stroma undergo cellular conversion into a distinct cell type that exhibits a stem cell-like phenotype and chemoresistance. These stroma-induced changes occur in a reversible and stochastic manner driven by cross-talk, whereby stromal contact induces interleukin-4 in leukemic cells that in turn targets the mesenchymal stroma to facilitate the development of new subset. This mechanism was dependent on interleukin-4-mediated upregulation of vascular cell adhesion molecule- 1 in mesenchymal stroma, causing tight adherence of leukemic cells to mesenchymal progenitors for generation of new subsets. Together, our study reveals another class of chemoresistance in leukemic blasts via functional evolution through stromal cross-talk, and demonstrates dynamic switching of leukemic cell fates that could cause a non-homologous response to chemotherapy in concert with the patient-specific microenvironment.

Background: Spine-hip discordance (SHD) increases fracture risk. However, its prevalence and clinical implications have not been investigated in patients with hip fractures. This study determined the prevalence and association of SHD with mortality and investigated the cause of SHD in patients with hip fractures., Methods: This study included patients admitted for fragility hip fractures between 2011 and 2020. All patients underwent dual energy X-ray absorptiometry and anteroposterior and lateral views of the lumbosacral spine during admission. Data on demographics, diagnosis, American Society of Anesthesiologists score, and mortality were collected. A T-score difference of more than 1.5 between L1-4 and the femur neck was considered discordant, and 3 groups (lumbar low [LL] discordance, no discordance [ND], and femur neck low [FL] discordance) were compared. In the discordance group, lumbar radiographs were reviewed to determine the cause of discordance., Results: Among 1,220 eligible patients, 130 were excluded due to patient refusal or bilateral hip implantation; therefore, this study included 1,090 patients (271 male and 819 female). The prevalence of LL, ND, and FL was 4.4%, 66.4% and 29.2% in men and 3.9%, 76.1%, and 20.0% women. Mortality was not associated with discordance. The most common causes of discordance were physiological in the LL group and pathological in the FL group for both sexes., Conclusions: Patients with hip fractures showed lower rates of ND and higher rates of FL compared to the general population. True discordance should be carefully judged for pathological and artifact reasons. The clinical implications of SHD require further investigation.

There is a need to identify the species of similar types of fish, especially those that are commercially sold. Particularly, the price of tuna varies depending on its type, which is difficult to determine as they are sold in cut or processed forms. This study developed a multiplex polymerase chain reaction (PCR) assay to identify the five most common tuna species: bigeye, skipjack, Atlantic bluefin, albacore, and yellowfin tunas. Newly designed species-specific primer sets for these five tuna species were created. Subsequently, the amplicon sizes obtained were 270, 238, 200, 178, and 127 base pairs for bigeye, skipjack, Atlantic bluefin, albacore, and yellowfin tunas, respectively. Each primer's specificity was further tested using 15 other fish species, and no cross-reactivity was observed. To identify multiple targets in a single reaction, multiplex PCR was optimized to increase its resolution and accuracy. The detection levels of the multiplex PCR assay were confirmed to be 1 pg for all the five tunas. Additionally, it was successfully applied to 32 types of commercial tuna products. Therefore, this multiplex PCR assay could be an efficient identification method for various tuna species.

Hepatitis A virus (HAV) is a serious threat to public health worldwide. We used multiplex polymerase chain reaction (PCR)-based next-generation sequencing (NGS) to derive information on viral genetic diversity and conduct precise phylogenetic analysis. Four HAV genome sequences were obtained using multiplex PCR-based NGS. HAV whole-genome sequence of one sample was obtained by conventional Sanger sequencing. The HAV strains demonstrated a geographic cluster with sub-genotype IA strains in the Republic of Korea. The phylogenetic pattern of HAV viral protein (VP) 3 region showed no phylogenetic conflict between the whole-genome and partial-genome sequences. The VP3 region in serum and stool samples showed sensitive detection of HAV with differences of quantification that did not exceed <10 copies/μL than the consensus VP4 region using quantitative PCR (qPCR). In conclusion, multiplex PCR-based NGS was implemented to define HAV genotypes using nearly whole-genome sequences obtained directly from hepatitis A patients. The VP3 region might be a potential candidate for tracking the genotypic origin of emerging HAV outbreaks. VP3-specific qPCR was developed for the molecular diagnosis of HAV infection. This study may be useful to predict for the disease management and subsequent development of hepatitis A infection at high risk of severe illness.

Background: Remifentanil reduces cough during extubation. Ramosetron, a 5-HT 3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients., Methods: Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC 50 ) and 95% of patients (EC 95 ) were assessed using Dixon's up-and-down or isotonic regression method with a bootstrapping approach., Results: Using Dixon's up-and-down method, the EC 50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC 50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC 95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL)., Conclusion: Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease., Study Question: Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function?, Study Design and Methods: Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits., Results: Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function., Interpretation: sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease., (Published by Elsevier Inc.)

A new heteroleptic complex series of tin was synthesized by the salt metathesis reaction of SnX 2 (X = Cl, Br, and I) with aminoalkoxide and various N -alkoxy-functionalized carboxamide ligands. The complexes, [ClSn(dmamp)] 2 ( 1 ), [BrSn(dmamp)] 2 ( 2 ), and [ISn(dmamp)] 2 ( 3 ), were prepared from the salt metathesis reaction of SnX 2 with one equivalent of dmamp; [Sn(dmamp)(empa)] 2 ( 4 ), [Sn(dmamp)(mdpa)] 2 ( 5 ), and [Sn(dmamp)(edpa)] 2 ( 6 ) were prepared via the salt metathesis reaction using complex 2 with one equivalent of N -alkoxy-functionalized carboxamide ligand. Complexes 1 - 5 displayed dimeric molecular structures with tin metal centers interconnected by μ 2 -O bonding via the alkoxy oxygen atom. The molecular structures of complexes 1 - 5 showed distorted trigonal bipyramidal geometries with lone pair electrons in the equatorial position. Using complex 6 as a tin precursor, SnO x films were deposited by chemical solution deposition (CSD) and subsequent post-deposition annealing (PDA) at high temperatures. SnO and SnO 2 films were selectively obtained under controlled PDA atmospheres of argon and oxygen, respectively. The SnO films featured a tetragonal romarchite structure with high crystallinity and a preferred growth orientation along the (101) plane. They also exhibited a lower transmittance of >52% at 400 nm due to an optical band gap of 2.9 eV. In contrast, the SnO 2 films exhibited a tetragonal cassiterite crystal structure and an extremely high transmittance of >97% at 400 nm was observed with an optical band gap of 3.6 eV., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

This study evaluated the association of the serum total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) with mortality in incident peritoneal dialysis (PD) patients. We performed a multi-center, prospective cohort study of 630 incident PD patients from 2008 to 2015 in Korea. Participants were stratified into quintiles according to baseline TC, HDL-C, LDL-C and TC/HDL-C. The association between mortality and each lipid profile was evaluated using multivariate Cox regression analysis. During a median follow-up period of 70.3 ± 25.2 months, 185 deaths were recorded. The highest TC/HDL-C group had the highest body mass index, percentage of diabetes and serum albumin level. Multivariate analysis demonstrated that the highest quintile of TC/HDL-C was associated with increased risk of all-cause mortality (hazard ratio 1.69, 95% confidence interval 1.04-2.76; p = 0.036), whereas TC, HDL-C and LDL-C were not associated with mortality. Linear regression analysis showed a positive correlation between TC/HDL-C and body mass index. Increased serum TC/HDL-C was an independent risk factor for mortality in the subgroup of old age, female, cardiovascular disease and low HDL-C. The single lipid marker of TC or HDL-C was not able to predict mortality in PD patients. However, increased serum TC/HDL-C was independently associated with all-cause mortality in PD patients.

Based on electron backscatter diffraction (EBSD), hollow structures of Ni foam struts fabricated by electroplating on a chemically removable template were observed. Three-dimensional (3D) pore structures of Ni foams were also obtained using X-ray computed tomography (CT), and microstructural features such as porosity, pore size and strut thickness were statistically quantified. Evolution of microstructure and mechanical properties during ex situ compression of open-cell Ni-foams was investigated based on X-ray CT, and experimental results were compared with predictions by the finite element method (FEM). 3D microstructures obtained by X-ray CT revealed that the stress drop started with the buckling of struts at the center of the Ni-foams. The flow stress increased after the buckling of the struts spreads to most of the regions. For effective simulation of the compressive deformation and determination of the microstructural evolution, small domains of interest were selected from the entire set of observed 3D microstructures based on X-ray CT, and struts of Ni foams with a hollow structure were simplified with relevant thin-solid struts. Numerical 3D modeling comprehensively disclosed that compression caused the transverse buckling of the struts, with the bending and buckling of struts thus reducing the stress. Thickness variation of the struts causes a change in the porosity of Ni-foams without a change in pore shape or connectivity. The overall range of strut thickness was from 59 to 133 μm, and the range of porosity values was from 80% to 93.7%. A stress drop was predicted with a decrease in the strut thickness or an increase in the porosity, as measured experimentally. It was also found that the stress drop contributed to an increase in the calculated energy absorption efficiency.

Crohn's disease (CD) and ulcerative colitis (UC) can be difficult to differentiate. As differential diagnosis is important in establishing a long-term treatment plan for patients, we aimed to develop a machine learning model for the differential diagnosis of the two diseases using RNA sequencing (RNA-seq) data from endoscopic biopsy tissue from patients with inflammatory bowel disease ( n = 127; CD, 94; UC, 33). Biopsy samples were taken from inflammatory lesions or normal tissues. The RNA-seq dataset was processed via mapping to the human reference genome (GRCh38) and quantifying the corresponding gene models that comprised 19,596 protein-coding genes. An unsupervised learning model showed distinct clusters of four classes: CD inflammatory, CD normal, UC inflammatory, and UC normal. A supervised learning model based on partial least squares discriminant analysis was able to distinguish inflammatory CD from inflammatory UC after pruning the strong classifiers of normal CD vs. normal UC. The error rate was minimal and affected only two components: 20 and 50 genes for the first and second components, respectively. The corresponding overall error rate was 0.147. RNA-seq analysis of tissue and the two components revealed in this study may be helpful for distinguishing CD from UC.

Chronic metabolic inflammation is a key feature of obesity, insulin resistance, and diabetes. Here, we showed that altered regulation of the Ca 2+ channel inositol trisphosphate receptor (IP 3 R) was an adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation induced by cytokine exposure in vitro or by obesity in vivo led to increases in the abundance and activity of IP 3 Rs and in the phosphorylation of the Ca 2+ -dependent kinase CaMKII in adipocytes in a manner dependent on the kinase JNK. In mice, adipocyte-specific loss of IP 3 R1/2 protected against adipose tissue inflammation and insulin resistance, despite the mice exhibiting substantial diet-induced weight gain. Thus, this work suggests that increased IP 3 R activity is a key link between obesity, inflammation, and insulin resistance. These data also suggest that approaches to target IP 3 R-mediated Ca 2+ homeostasis in adipocytes may offer new therapeutic opportunities against metabolic diseases, especially because GWAS studies also implicate this locus in human obesity.

This paper describes the synthesis of eight novel zirconium and hafnium complexes containing N -alkoxy carboxamidate-type ligands, as potential precursors for metal oxides and atomic layer deposition (ALD) for HfO 2 . A series of ligands, viz., N -ethoxy-2,2-dimethylpropanamide (edpaH), N -ethoxy-2-methylpropanamide (empaH), and N -methoxy-2,2-dimethylpropanamide (mdpaH), were used to afford complexes Zr(edpa) 4 ( 1 ), Hf(edpa) 4 ( 2 ), Zr(empa) 4 ( 3 ), Hf(empa) 4 ( 4 ), Zr(mdpa) 4 ( 5 ), Hf(mdpa) 4 ( 6 ), ZrCp(edpa) 3 ( 7 ), and HfCp(edpa) 3 ( 8 ). Thermogravimetric analysis curves assessed for the evaporation characteristics of complexes 1 - 8 revealed single-step weight losses with low residues, except for the mdpa-containing complexes. Single-crystal X-ray diffraction studies of 1 , 2 , 5 , and 6 revealed that all the complexes have monomeric molecular structures, with the central metal ion surrounded by eight oxygen atoms from the four bidentate alkoxyalkoxide ligands. Among the complexes prepared, 8 exhibited a low melting point (64 °C), good volatility (1 Torr at 112 °C), high thermal stability, and excellent endurance over 6 weeks at 120 °C. Therefore, an ALD process for the growth of HfO 2 was developed using HfCp(edpa) 3 ( 8 ) as a novel precursor. Furthermore, the HfO 2 film exhibited a low capacitance equivalent oxide thickness of ∼1.5 nm, with J g as low as ∼3 × 10 -4 A/cm 2 at V g -1 V in a metal-insulator-semiconductor capacitor (Au/HfO 2 / p -Si).

Background: During the coronavirus disease 2019 (COVID-19) pandemic, various adverse skin reactions to long-term mask wearing have been reported., Aim: To assess the clinical features of mask-induced dermatoses and to recommend prevention and treatment options., Methods: From April to August 2020, questionnaires including topics such as demographic information, pre-existing skin disorders, reported mask-related symptoms, daily mask-wearing duration and frequency, types of masks used and whether the participant was a healthcare worker, were distributed to patients in 12 hospitals. Dermatologists assessed skin lesions, confirmed diagnosis and recorded treatments., Results: Itchiness was the most frequent symptom, mostly affecting the cheeks. The most common skin disease was new-onset contact dermatitis (33.94%), followed by new-onset acne (16.97%) and worsening of pre-existing acne (16.97%). Daily wearing of masks was significantly (P = 0.02) associated with new-onset contact dermatitis. More than half of patients with pre-existing skin problems experienced disease worsening while wearing masks. Longer duration of wearing (> 6 h/day, P = 0.04) and use of cotton masks (P < 0.001) significantly increased acne flare-up. Healthcare workers had a higher incidence of skin disease. Skin lesions were generally mild and well tolerated with topical treatment. The study had some limitations: the effect of seasonal characteristics and other risk factors were not assessed, and the patients were visiting dermatological clinics and had interest in their skin status, thus, there may have been selection bias., Conclusion: Mask-induced/-triggered dermatoses contribute to increase the dermatological burden during the pandemic., (© 2021 British Association of Dermatologists.)

The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis 1,2 . Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4) 3 . Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans 4-7 , no mechanism of action has yet been described 8-10 . Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Background/objectives: Obesity is associated with the impaired regulation of T cells characterized by increased numbers of Th1 and Th17 cells and the dysregulation of vitamin D metabolism. Both obesity and vitamin D have been reported to affect autophagy; however, a limited number of studies have investigated the effects of vitamin D on T cell autophagy in obese mice. Therefore, we aimed to determine whether in vitro treatment with vitamin D affects the proliferation, function, and autophagy of T cells from obese and control mice., Materials/methods: Five-week-old male C57BL/6 mice were fed control or high-fat diets (10% or 45% kcal fat: CON or HFDs, respectively) for 12 weeks. Purified T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either 10 nM 1,25(OH) 2 D 3 or 0.1% ethanol (vehicle control). The proliferative response; expression of CD25, Foxp3, RORγt, and autophagy-related proteins (LC3A/B, SQSTM1/P62, BECLIN-1, ATG12); and the production of interferon (IFN)-γ, interleukin (IL)-4, IL-17A, and IL-10 by T cells were measured., Results: Compared with the CON group, T cell proliferation tended to be lower, and the production of IFN-γ was higher in the HFD group. IL-17A production was reduced by 1,25(OH)2D 3 treatment in both groups. The LC3 II/I ratio was higher in the HFD group than the CON group, but P62 did not differ. We observed no effect of vitamin D treatment on T cell autophagy., Conclusions: Our findings suggest that diet-induced obesity may impair the function and inhibit autophagy of T cells, possibly leading to the dysregulation of T cell homeostasis, which may be behind the aggravation of inflammation commonly observed in obesity., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2021 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

To identify the vulnerability of recovery sleep, this study investigated the occurrence of obstructive sleep apnea during daytime sleep following overnight flights in healthy airline pilots. We conducted daytime polysomnography following a long-haul night-time flight in 103 pilots. The following variables were assessed: apnea-hypopnea index, respiratory disturbance index and oxygen desaturation index. Moderate-to-severe obstructive sleep apnea was defined as an apnea-hypopnea index ≥15. Seventy-three pilots (70.9%) with no known history of obstructive sleep apnea presented with moderate-to-severe obstructive sleep apnea. Pilots showed high mean apnea-hypopnea, respiratory disturbance and oxygen desaturation indices. The body mass index, Berlin questionnaire score and cumulative flight time contributed to these indices, with both body mass index and cumulative flight time remaining significant at an apnea-hypopnea index ≥15. We found that pilots are vulnerable to obstructive sleep apnea during daytime sleep after night-time flights, which may deteriorate their health, increase fatigue and impair overall flight safety. Further research is needed to ensure flight safety, as daytime recovery sleep is unavoidable for night-time flight pilots. The pilots' normal and recovery sleep patterns should both be studied to develop an effective sleep management protocol., (© 2021 European Sleep Research Society.)

MLC1 is a membrane protein mainly expressed in astrocytes, and genetic mutations lead to the development of a leukodystrophy, megalencephalic leukoencephalopathy with subcortical cysts disease. Currently, the biochemical properties of the MLC1 protein are largely unknown. In this study, we aimed to characterize the transmembrane (TM) topology and oligomeric nature of the MLC1 protein. Systematic immunofluorescence staining data revealed that the MLC1 protein has eight TM domains and that both the N- and C-terminus face the cytoplasm. We found that MLC1 can be purified as an oligomer and could form a trimeric complex in both detergent micelles and reconstituted proteoliposomes. Additionally, a single-molecule photobleaching experiment showed that MLC1 protein complexes could consist of three MLC1 monomers in the reconstituted proteoliposomes. These results can provide a basis for both the high-resolution structural determination and functional characterization of the MLC1 protein.

Aims: Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage., Methods and Results: We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity., Conclusions: NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Since the animal test ban on cosmetics in the EU in 2013, alternative in vitro safety tests have been actively researched to replace in vivo animal tests. For the development and evaluation of a new test method, reference chemicals with quality in vivo data are essential to assess the predictive capacity and applicability domain. Here, we compiled a reference chemical database (ChemSkin DB) for the development and evaluation of new in vitro skin irritation tests. The first candidates were selected from 317 chemicals (source data n = 1567) searched from the literature from the last 20 years, including previous validation study reports, ECETOC, and published papers. Chemicals showing inconsistent classification or those that were commercially unavailable, difficult or dangerous to handle, prohibitively expensive, or without quality in vivo or in vitro data were removed, leaving a total of 100 chemicals. Supporting references, in vivo Draize scores, UN GHS/EU CLP classifications and commercial sources were compiled. Test results produced by the approved methods of OECD Test No. 439 were included and compared using the classification table, scatter plot, and Pearson correlation analysis to identify the false predictions and differences between in vitro skin irritation tests. These results may provide an insight into the future development of new in vitro skin irritation tests.

Enhanced care coordination is essential to improving access to and navigation between youth mental health services. By facilitating better communication and coordination within and between youth mental health services, the goal is to guide young people quickly to the level of care they need and reduce instances of those receiving inappropriate care (too much or too little), or no care at all. Yet, it is often unclear how this goal can be achieved in a scalable way in local regions. We recommend using technology-enabled care coordination to facilitate streamlined transitions for young people across primary, secondary, more specialised or hospital-based care. First, we describe how technology-enabled care coordination could be achieved through two fundamental shifts in current service provisions; a model of care which puts the person at the centre of their care; and a technology infrastructure that facilitates this model. Second, we detail how dynamic simulation modelling can be used to rapidly test the operational features of implementation and the likely impacts of technology-enabled care coordination in a local service environment. Combined with traditional implementation research, dynamic simulation modelling can facilitate the transformation of real-world services. This work demonstrates the benefits of creating a smart health service infrastructure with embedded dynamic simulation modelling to improve operational efficiency and clinical outcomes through participatory and data driven health service planning., Competing Interests: IH was an inaugural Commissioner on Australia's National Mental Health Commission (2012–18). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017–20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. ES was the Medical Director, Young Adult Mental Health Unit, St Vincent's Hospital Darlinghurst, Discipline Leader of Adult Mental Health, School of Medicine, University of Notre Dame, Principal Research Fellow, Brain and Mind Centre, The University of Sydney and Consultant Psychiatrist. She has received honoraria for educational seminars related to the clinical management of depressive disorders supported by Servier and Eli-Lilly pharmaceuticals. She has participated in a national advisory board for the antidepressant compound Pristiq, manufactured by Pfizer. She was the National Coordinator of an antidepressant trial sponsored by Servier. TD is now Director (Research and Evaluation), Design and Strategy Division, Australian Digital Health Agency. J-AO is Head of Systems Modelling, Simulation & Data Science, Brain and Mind Centre, University of Sydney, as well as Managing Director of Computer Simulation & Advanced Research Technologies (CSART). 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 © 2021 Iorfino, Piper, Prodan, LaMonica, Davenport, Lee, Capon, Scott, Occhipinti and Hickie.)

Background: While recent reports have suggested that hip corticosteroid injections can hasten joint degeneration, there are few published data on the topic. The purpose of the present study was to evaluate for an association between corticosteroid injection and rapidly destructive hip disease (RDHD) and to determine the rate of, and risk factors for, occurrence., Methods: This study was conducted in 2 parts. First, to assess for a potential association between hip corticosteroid injection and RDHD, a case-control analysis was performed. Patients who developed RDHD between 2013 and 2016 served as cases, whereas those who underwent total hip arthroplasty for diagnoses other than RDHD during the same period served as controls, and the exposure of interest was prior intra-articular hip corticosteroid injection. Second, in a retrospective cohort analysis, we analyzed all patients who received a fluoroscopically guided intra-articular hip corticosteroid injection at our institution from 2013 to 2016. The rate of post-injection RDHD was determined, and logistic regression was used to identify risk factors for occurrence., Results: In the case-control analysis, hip corticosteroid injection was associated with the development of RDHD (adjusted odds ratio, 8.56 [95% confidence interval, 3.29 to 22.3], p < 0.0001). There was evidence of a dose-response curve, with the risk of RDHD increasing with injection dosage as well as with the number of injections received. In the retrospective cohort analysis, the rate of post-injection RDHD was 5.4% (37 of 688). Cases of post-injection RDHD were diagnosed at an average of 5.1 months following injection and were characterized by rapidly progressive joint-space narrowing, osteolysis, and collapse of the femoral head., Conclusions: This study documents an association between hip corticosteroid injection and RDHD. While the risk of RDHD following a single low-dose (≤40 mg) triamcinolone injection is low, the risk is higher following high-dose (≥80 mg) injection and multiple injections. These findings provide information that can be used to counsel patients about the risks associated with this common procedure. In addition, caution should be taken with intra-articular hip injections utilizing ≥80 mg of corticosteroid and multiple injections., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G684)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

In recent years, as all actions of Internet users become information, the importance of personal information is emphasized, but in reality, the management of personal information is still insufficient. With the advent of the concept of sharing systems such as the sharing economy, the numbers of IoT application services (for example, a healthcare service using sharing IoT devices, or a vehicle sharing system with IoT devices) using users' personal information are increasing, but the risk of using personal information is not managed. To solve this issue, the European GDPR stipulates the content of personal information protection. In this paper, we present a method to securely manage personal information in IoT devices in IoT application environments in accordance with the GDPR. We first describe the lifecycle stages of personal information occurring in IoT application services and propose a method to securely manage personal information at each stage of the lifecycle according to the flow of personal information in IoT devices. We also evaluated the usefulness and applicability of the proposed scheme through two service scenarios. Since the proposed method satisfies the requirements for personal information management in IoT application environments, it is expected to contribute to the development of the IoT business field that handles personal information.

As the shelf life of platelets collected from donated blood is very short, approximately 5 days, the determination of bacterial contamination in platelets has become necessary. In this study, rapid analysis of Gram-positive and Gram-negative bacterial contamination in platelet samples was presented without pre-enrichment using pig serum-derived antibodies against the outer membrane proteins (OMP) of Gram-negative bacteria and antibodies against lipoteichoic acid (LTA) on the surface of Gram-positive bacteria. The anti-OMP antibodies against Gram-negative bacteria were isolated using sequential incubation with (1) the modified Gram-negative bacteria ClearColi, which lacks lipopolysaccharide (LPS) on the outer membrane, and (2) the Gram-positive bacteria Bacillus subtilis to filter away nonspecifically bound proteins from ClearColi. The anti-lipoteichoic acid (LTA) antibodies against Gram-positive bacteria were isolated using sequential incubation with (1) the Gram-positive bacteria B. subtilis and (2) the Gram-negative bacteria Escherichia coli BL21 to filter away nonspecifically bound proteins from B. subtilis . The feasibility of using the antibodies isolated from pig serum against Gram-negative and Gram-positive bacteria was demonstrated using flow cytometry. Finally, detection of the contamination of platelets with Gram-negative and Gram-positive bacteria using the impedance immunosensor based on these isolated antibodies was successfully demonstrated.

Aim: This study aimed to determine whether the peer attachment of adolescents, mediated by career-related self-efficacy and having parents with positive attitudes, influences health risk behaviours., Design: A cross-sectional questionnaire survey., Methods: This study adopted the secondary data analysis method, using the 2010 Korean Children and Youth Panel Survey (KCYPS). The 7th-wave panel data of 1,932 first graders in high schools were analysed using structural equation modelling., Results: The final model provided a good fit for the data. Having a close relationship with peers had a direct effect on adolescents' health risk behaviours. High peer attachment also had an indirect effect on health risk behaviours, mediated by career-related self-efficacy and having parents with positive attitudes. Though adolescents with broad and intimate peer relationships may be exposed to more temptations towards health risk behaviours and tend to make riskier decisions, these influences are reduced by being exposed to positive parenting attitudes and having clear, conscious career goals., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Direct-to-consumer genetic testing (DTC-GT) provides a means for consumers to gain insights into their genetic background and how it relates to their health without the involvement of medical institutions. In Korea, DTC-GT was introduced in 2016 in accordance with the legislation on Paragraph (3) 2 of Article 50 of the Bioethics and Safety Act. Only 12 genetic test items involving 46 genes were approved at first, but the approved items were expanded to 70 in November 2020. However, the genetic test items of DTC-GT services in Korea are still restricted to the wellness area, and access to disease risk related information is only permitted to medical institutions. Further, studies revealing the relationship between genotype differences and responses to nutrients, food components, or nutritional status are increasing, and this association appears to be robust for some genes. This strong association between genetic variations and nutrition suggests that DTC-GT can be used as an important tool by clinical nutritionists to gain insights into an individual's genetic susceptibilities and provide guidance on nutritional counseling and meal planning based on the patient's genetic information. This review summarized the history and current status of DTC-GT and investigated the relationship between genetic variations with associated phenotypic traits to clarify further the importance of DTC-GT in the field of clinical nutrition., Competing Interests: Conflict of Interest: The authors declare that they have no competing interests., (Copyright © 2021. The Korean Society of Clinical Nutrition.)

Context: Whether proton pump inhibitors (PPI) can improve glycemic control among individuals with diabetes or decrease the risk of incident diabetes in the general population is unclear., Objective: To evaluate the impact of PPI therapy on glycemic control among individuals with diabetes and the risk of diabetes among those without diabetes., Results: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. We included studies comparing glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) among individuals with diabetes treated with and without PPI therapy as an add-on to standard therapy. Studies evaluating the risk of incident diabetes among individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences between groups or relative risks were imputed using random-effects models., Results: Seven studies (n = 342) for glycemic control and 5 studies (n = 244 439) for risk of incident diabetes were included. Compared with standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD, -0.36 %; 95% CI, -0.68 to -0.05; P = 0.025) and FBG (WMD, -10.0 mg/dL; 95% CI, -19.4 to -0.6; P = 0.037). PPI use did not reduce the risk of incident diabetes (pooled RR, 1.10; 95% CI, 0.89 to 1.34; P = 0.385)., Conclusion: Add-on PPI improved glycemic indices among individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when prescribing antacids to patients with diabetes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Salmonella enterica serovar Typhi ISP2825, isolated in 1983 from a Chilean patient, is one of the major S. Typhi strains used for research, along with strains Ty2, CT18, and H58. The complete genome sequence of ISP2825, consisting of a 4,774,014-bp circular chromosome, will help us understand typhoid pathogenesis and evolution.

Background: Current global challenges are generating extensive social disruption and uncertainty that have the potential to undermine the mental health, wellbeing, and futures of young people. The scale and complexity of challenges call for engagement with systems science-based decision analytic tools that can capture the dynamics and interrelationships between physical, social, economic, and health systems, and support effective national and regional responses. At the outset of the pandemic mental health-related systems models were developed for the Australian context, however, the extent to which findings are generalisable across diverse regions remains unknown. This study aims to explore the context dependency of systems modelling insights. Methods: This study will employ a comparative case study design, applying participatory system dynamics modelling across eight diverse regions of Australia to answer three primary research questions: (i) Will current regional differences in key youth mental health outcomes be exacerbated in forward projections due to the social and economic impacts of COVID-19?; (ii) What combination of social policies and health system strengthening initiatives will deliver the greatest impacts within each region?; (iii) To what extent are optimal strategic responses consistent across the diverse regions? We provide a detailed technical blueprint as a potential springboard for more timely construction and deployment of systems models in international contexts to facilitate a broader examination of the question of generalisability and inform investments in the mental health and wellbeing of young people in the post COVID-19 recovery. Discussion: Computer simulation is known as the third pillar of science (after theory and experiment). Simulation allows researchers and decision makers to move beyond what can be manipulated within the scale, time, and ethical limits of the experimental approach. Such learning when achieved collectively, has the potential to enhance regional self-determination, help move beyond incremental adjustments to the status quo, and catalyze transformational change. This research seeks to advance efforts to establish regional decision support infrastructure and empower communities to effectively respond. In addition, this research seeks to move towards an understanding of the extent to which systems modelling insights may be relevant to the global mental health response by encouraging researchers to use, challenge, and advance the existing work for scientific and societal progress., Competing Interests: J-AO is both Head of Systems Modelling, Simulation & Data Science at the University of Sydney's Brain and Mind Centre and Managing Director of Computer Simulation & Advanced Research Technologies (CSART). IH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017–20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. LF is Senior Research Fellow with the Brain and Mind Centre, University of Sydney; Director of Knowledge Translation and Health Outcomes, Epidemiology Section, ACT Health; & Director of Policy Applications & Translational Science of CSART. The remaining authors declare that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Occhipinti, Skinner, Freebairn, Song, Ho, Lawson, Lee and Hickie.)

Paramyxoviruses, negative-sense single-stranded RNA viruses, pose a critical threat to human public health. Currently, 78 species, 17 genera, and 4 subfamilies of paramyxoviruses are harbored by multiple natural reservoirs, including rodents, bats, birds, reptiles, and fish. Henipaviruses are critical zoonotic pathogens that cause severe acute respiratory distress and neurological diseases in humans. Using reverse transcription-polymerase chain reaction, 115 Crocidura species individuals were examined for the prevalence of paramyxovirus infections. Paramyxovirus RNA was observed in 26 (22.6%) shrews collected at five trapping sites, Republic of Korea. Herein, we report two genetically distinct novel paramyxoviruses (genus: Henipavirus ): Gamak virus (GAKV) and Daeryong virus (DARV) isolated from C. lasiura and C. shantungensis , respectively. Two GAKVs and one DARV were nearly completely sequenced using next-generation sequencing. GAKV and DARV contain six genes (3'-N-P-M-F-G-L-5') with genome sizes of 18,460 nucleotides and 19,471 nucleotides, respectively. The phylogenetic inference demonstrated that GAKV and DARV form independent genetic lineages of Henipavirus in Crocidura species. GAKV-infected human lung epithelial cells elicited the induction of type I/III interferons, interferon-stimulated genes, and proinflammatory cytokines. In conclusion, this study contributes further understandings of the molecular prevalence, genetic characteristics and diversity, and zoonotic potential of novel paramyxoviruses in shrews.