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Purpose To understand from the perspectives of school professionals, parents and young people the socio-ecological factors that may facilitate and prevent e-cigarette use among young people in Perth, Western Australia. Methods Purposive sampling was used to recruit school professionals, parents and young people for one-on-one (n = 35) or joint (n = 3) interviews (in-person n = 11 or online n = 27). Data were analysed using thematic analysis and classified into four domains based on the socio-ecological model: i) individual, ii) interpersonal, iii) organizational/community and iv) societal/policy. Results Factors that were found to support vaping among young people included sensation-seeking and risk-taking behaviour; a low-risk perception of vapes; attractive characteristics of vapes; ease of access; perception vaping is a social activity; and lack of knowledge about vaping among parents and school professionals. Vaping prevention messages originating from the familial, educational and community spheres are lacking but wanted by adults and young people. Conclusions The pervasiveness of the e-cigarette trade and persistent challenges related to surveillance and enforcement need to be addressed to reduce exposure and access to e-cigarettes. A mixture of “hard” and “soft” public policy tools involving key stakeholders in a range of settings is needed to prevent e-cigarette access and uptake by young people.

IntroductionPatients with spontaneous intracranial hypotension (SIH) frequently present with several symptoms and impaired mental health. This study systematically investigates the somatic and mental symptom burden of SIH and the effect of surgical treatment.MethodsIn this single-center retrospective study, patients with surgical closure of a spinal cerebrospinal fluid leak between September 2022 and July 2023 completed the Somatic Symptom Scale (SSS-8), the Somatic Symptom Disorder – B Criteria Scale (SSD-12), and the Patient Health Questionnaire (PHQ-8) preoperatively and three and 6 months postoperatively.ResultsFifty-seven patients were included. All three scores showed clearly pathological values before surgery (SSS-8: 12 [IQR 6.5–16], SSD-12: 26 [IQR 19.5–33.5], PHQ-8: 11 [IQR 6.5–15]) representing a high somatic symptom burden and relevant current depression. After surgery, there was a significant and sustainable improvement (SSS-8: 8 [IQR 3–11.75], SSD-12: 12.5 [IQR 5–21.75], PHQ-8: 4.5 [IQR 2–9], p

Abstract Background The social media landscape is now ubiquitous in people’s everyday lives. It is a space where culture, politics, economics and sociological and public health discourses occur. There is mounting evidence that e-cigarette products are being promoted and advertised on social media, a media platform particularly popular with young people. Our research aimed to understand industry professionals’ perceptions of social media harms and potential management strategies using vaping as a case study. Methods A critical realist perspective guided reflexive thematic analysis of the qualitative in depth, semi structured interviews. Data collection occurred in January and February 2023 with 13 participants working in the areas of public health, digital media, law, governance, tobacco control and advocacy. Results Two superordinate themes emerged from the data: (1) Fathoming a complex system (social media) that contained the subordinate themes of Traversing Boundaries (crossing borders, crossing sectors) and Ungovernable (global and local landscapes, vested interests, self-regulation and opacity). (2) Addressing complexity (social media)– that contained the subordinate themes of Strengthening Institutions (global to local, policy and legislation, individuals and organisations); Defanging Industry (responsibility and transparency, moderation and algorithms, complaints); and Engaging Citizens (raising awareness, framing messaging). Conclusions There was consensus among participants that e-cigarette related social media content can be harmful and government action is urgently needed. There was an identified need for the development of government led national-level regulatory frameworks, with government led appropriate legislation; identification of an organisation or organisations with suitable levels of regulatory power and resources to monitor, enforce and penalise noncompliant social media companies; accompanied by increased community awareness raising of harmful social media content and improved digital literacy.

Introduction Mounting evidence suggests that electronic cigarettes (e-cigarettes) are extensively promoted and marketed using social media, including through user-generated content and social media influencers. This study explores how e-cigarettes are being promoted on Instagram, using a case-study approach, and the extent to which Meta’s Restricted Goods and Services Policy (Meta’s policy) is being applied and enforced. Methods We identified the accounts followed by an Australian Instagram influencer who primarily posts e-cigarette-related content. The main foci of these 855 accounts were coded and 369 vaping-focused accounts were identified. These vaping-focused accounts were then further coded by two trained coders. Results All (n=369; 100.0%) of the vape content posted by these accounts was positive in sentiment. One-third of the vape accounts (n=127; 34.4%) had a shared focus, indicating that vape content may permeate into other online communities through shared interests. A total of 64 accounts (17.3%) potentially violated Meta’s policy by attempting to purchase, sell, raffle or gift e-cigarette products. Conclusions The findings of this study suggest that pro-vaping information is available and accessible on Instagram. Much of the content identified in this study promoted the purchase or gifting of e-cigarette products and potentially violates Meta’s policy. Greater regulation and/or stronger enforcement of e-cigarette content on social media platforms such as Instagram is necessary to prevent the ongoing promotion of these harmful products.

Abstract Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary and sufficient to induce downstream open chromatin regions (dOCRs) when transcription termination is disrupted by the viral ICP27 protein. This is accompanied by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperone FACT is not sufficient to induce dOCRs in ΔICP22 infection but increases dOCR induction in wild-type HSV-1 infection. Interestingly, this is accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II in HSV-1 infection.

Abstract Previous studies provide high evidence that autotaxin (ATX)-lysophosphatidic acid (LPA) signaling through LPA receptors (LPAR) plays an important role in breast cancer initiation, progression, and invasion. However, its specific role in different breast cancer cell lines remains to be fully elucidated to offer improvements in targeted therapies. Within this study, we analyzed in vitro the effect of LPA 18:1 and the LPAR1, LPAR3 (and LPAR2) inhibitor Ki16425 on cellular functions of different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, BT-474, SKBR-3) and the human breast epithelial cell line MCF-10A, as well as Interleukin 8 (IL-8), Interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha cytokine secretion after LPA-incubation. ATX-LPA signaling showed a dose-dependent stimulatory effect especially on cellular functions of triple-negative and luminal A breast cancer cell lines. Ki16425 inhibited the LPA-induced stimulation of triple-negative breast cancer and luminal A cell lines in variable intensity depending on the functional assay, indicating the interplay of different LPAR in those assays. IL-8, IL-6 and TNF-alpha secretion was induced by LPA in MDA-MB-468 cells. This study provides further evidence about the role of the ATX-LPA axis in different breast cancer cell lines and might contribute to identify subtypes suitable for a future targeted therapy of the ATX-LPA axis.

Abstract Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates disease pathology has been a longstanding challenge. Recent studies showed that human AD neural cells, integrated into three‐dimensional (3D) hydrogel matrix, display key features of AD neuropathology. Like in the human brain, the extracellular matrix (ECM) plays a critical role in determining the rate of neuropathogenesis in hydrogel‐based 3D cellular models. Aging, the greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age‐associated changes in ECM affect accumulation of pathogenic molecules, neuroinflammation, and neurodegeneration in AD patients and in vitro models. In this review, mechanistic hypotheses is presented to address the impact of the ECM properties and their changes with aging on AD and AD‐related dementias. Altered ECM characteristics in aged brains, including matrix stiffness, pore size, and composition, will contribute to disease pathogenesis by modulating the accumulation, propagation, and spreading of pathogenic molecules of AD. Emerging hydrogel‐based disease models with differing ECM properties provide an exciting opportunity to study the impact of brain ECM aging on AD pathogenesis, providing novel mechanistic insights. Understanding the role of ECM aging in AD pathogenesis should also improve modeling AD in 3D hydrogel systems.

Background: Phase-contrast MRI of CSF and spinal cord dynamics has evolved among diseases caused by altered CSF volume (spontaneous intracranial hypotension, normal pressure hydrocephalus) and by altered CSF space (degenerative cervical myelopathy (DCM), Chiari malformation). While CSF seems to be an obvious target for possible diagnostic use, craniocaudal spinal cord motion analysis offers the benefit of fast and reliable assessments. It is driven by volume shifts between the intracranial and the intraspinal compartments (Monro-Kellie hypothesis). Despite promising initial reports, comparison of spinal cord motion data across different centers is challenged by reports of varying value, raising questions about the validity of the findings. Objective: To systematically investigate inter-center differences between phase-contrast MRI data. Methods: Age- and gender matched, retrospective, pooled-data analysis across two centers: cardiac-gated, sagittal phase-contrast MRI of the cervical spinal cord (segments C2/C3 to C7/T1) including healthy participants and DCM patients; comparison and analysis of different MRI sequences and processing techniques (manual versus fully automated). Results: A genuine craniocaudal spinal cord motion pattern and an increased focal spinal cord motion among DCM patients were depicted by both MRI sequences (p 0.86 at segments C2/C3 to C6/C7). Discussion: Craniocaudal spinal cord motion is a genuine finding. Differences between values were attributed to time-resolution of the MRI sequences. Automated processing confers the benefit of unbiased and consistent analysis, while data did not reveal any superiority.

Abstract Background Vaping is a relatively new practice, and therefore its symbolic meanings and social practices are yet to be fully understood, especially within Australia where the practice is strictly regulated. This study aimed to examine vapers motivations for use, reinforcing influences, and association with the vaper subculture. Methods Working from a constructivist epistemology and a symbolic interaction framework, in-depth interviews were conducted with a purposive sample of 37 current (89%) and former (11%) adult vapers, 70% male, mean age of 32.5. Data was analysed via thematic analysis. Results Vapers largely started vaping to quit smoking and underwent common experiences during their initiation phase. Subsequently, vapers tended to adopt one of two dominant identities, that of the ‘cloud chaser’ or the ‘substitute’, which some users moved between during different stages of their vaping career. The social and symbolic meaning of e-cigarettes and vaping varied and involved concepts of harm reduction, addiction, pleasure, stigma and community, and for some, connection to the vaper subculture. Conclusions Understanding the complexities of vaping, and the nuanced differences of ‘cloud chasers’ and ‘substitute’ vapers may have important implications for health communication, research and policy. E-cigarette users within this sample were not a homogeneous group and differed in their motivations for use, association with the vaper subculture and relationship with the vape community. These findings provide new insights into the socialisation process and subsequent identity adoption of vapers within the unique regulatory environment of Western Australia.

Abstract Background Increased spinal cord motion has been proven to be a relevant finding within spinal canal stenosis disclosed by phase-contrast MRI (PC-MRI). Adapted PC-MRI is a suitable and reliable method within the well deliberated setting. As the decision between conservative and operative treatment can be challenging in some cases, further diagnostic marker would facilitate the diagnostic process. We hypothesize that increased spinal cord motion will correlate to clinical course and functional impairment and will contribute as a new diagnostic marker. Methods A monocentric, prospective longitudinal observational trial on cervical spinal canal stenosis will be conducted at the University Medical Center Freiburg. Patients (n = 130) with relevant cervical spinal canal stenosis, being defined by at least contact to the spinal cord, will be included. Also, we will examine a control group of healthy volunteers (n = 20) as proof-of-principle. We will observe two openly assigned branches of participants undergoing conservative and surgical decompressive treatment (based on current German Guidelines) over a time course of 12 month, including a total of 4 visits. We will conduct a broad assessment of clinical parameters, standard scores and gradings, electrophysiological measurements, standard MRI, and adapted functional PC-MRI of spinal cord motion. Primary endpoint is the evaluation of an expected negative correlation of absolute spinal cord displacement to clinical impairment. Secondary endpoints are the evaluation of positive correlation of increased absolute spinal cord displacement to prolonged evoked potentials, prediction of clinical course by absolute spinal cord displacement, and demonstration of normalized spinal cord motion after decompressive surgery. Discussion With the use of adapted, non-invasive PC-MRI as a quantitative method for assessment of spinal cord motion, further objective diagnostic information can be gained, that might improve the therapeutic decision-making process. This study will offer the needed data in order to establish PC-MRI on spinal cord motion within the diagnostic work-up of patients suffering from spinal canal stenosis. Trial registration German Clinical Trials Register, ID: DRKS00012962, Register date 2018/01/17

Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy.Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10).Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate.Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.

Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.

Background: Focally increased spinal cord motion at the level of cervical spinal stenosis has been revealed by phase-contrast MRI (PC-MRI). Objective: To investigate spinal cord motion among patients suffering of degenerative cervical myelopathy (DCM) across the entire cervical spine applying automated segmentation and standardized PC-MRI post-processing protocols. Methods: Prospective, matched-pair controlled trial on 29 patients with stenosis at C5/C6. MRI-protocol covering all cervical segments: 3D T2-SPACE, prospectively ECG-triggered sagittal PC-MRI. Segmentation by trained 3D hierarchical deep convolutional neural network and data processing were conducted via in-house software pipeline. Parameters per segment: maximum velocity, peak-to-peak (PTP)-amplitude, total displacement, PTP-amplitudeHB (PTP-amplitude per duration of heartbeat), and, for characterization of intraindividual alterations, the PTP-amplitude index between the cervical segments C3/C4–C7/T1 and C2/C3. Results: Spinal cord motion was increased at C4/C5, C5/C6 and C6/C7 among patients (all parameters, p

Air quality measurements usually consist of ground-based instrumentation at fixed locations. However, vertical profiles of pollutants are of interest for understanding processes, distribution, dilution and concentration. Therefore, a multicopter system has been developed to investigate the vertical distribution of the concentration of aerosol particles, black carbon, ozone, nitrogen oxides (NOx) and carbon monoxide and the meteorological parameters of temperature and humidity. This article presents the requirements by different users, the setup of the quadrocopter system, the instrumentation and the results of first applications. The vertical distribution of particulate matter next to a highway was strongly related to atmospheric stratification, with different concentrations below and above the temperature inversion present in the morning. After the qualification phase described in this article, two identically equipped multicopters will be used upwind and downwind of line or diffuse sources such as highways or urban areas to quantify the influence of their emissions on the local air quality.

Abstract Background Breast cancer is the most common malignancy in women affecting one out of eight females throughout their lives. Autotaxin (ATX) is upregulated in breast cancer which results in increased lysophosphatidic acid (LPA) formation within the tumor. This study’s aim was to identify the role of different mammary cell populations within the ATX–LPA axis. Methods Epithelial-cell-adhesion-molecule-positive (EpCAM) and -negative cells from breast tumors, adipose-derived stem cells (ADSCs) of tumor-adjacent and tumor-distant mammary fat were isolated and compared to healthy ADSCs, mammary epithelial cells (HMECs), and mesenchymal cells (MES) of healthy mammary tissue (n = 4 each) and further to well-established breast (cancer) cell lines. Results mRNA expression analyses revealed that ADSCs and MES largely expressed LPA receptor 1 (LPAR1) while epithelial cells mainly expressed LPAR6. LPA 18:1 activated all the cell populations and cell lines by rise in cytosolic free calcium concentrations. MES and ADSCs expressed ATX whereas epithelial cells did not. ADSCs revealed the highest expression in ATX with a significant decline after adipogenic differentiation in healthy ADSCs, whereas ATX expression increased in ADSCs from tumor patients. Breast (cancer) cell lines did not express ATX. Transmigration of MES was stimulated by LPA whereas an inhibitory effect was observed in epithelial cells with no differences between tumors and healthy cells. Triple-negative breast cancer (TNBC) cell lines were also stimulated and the transmigration partly inhibited using the LPA receptor antagonist Ki16425. Conclusions We here show that each mammary cell population plays a different role in the ATX–LPA axis with ADSCs and adipocytes being the main source of ATX in tumor patients in our experimental setting. Inhibitors of this axis may therefore present a valuable target for pharmacological therapies.

Abstract Background To evaluate changes in central macular thickness (CMT) and visual outcome in patients with neovascular age-related macular degeneration (AMD) treated initially with bevacizumab and subsequently switched to either aflibercept or ranibizumab. Methods Observational clinical study was performed. We measured the structural outcome (CMT on SD-OCT; μm) and the visual outcome (best corrected visual acuity (BCVA); logMAR), as follows: before treatment (at baseline), following bevacizumab treatment (switch follow-up) and after switching from bevacizumab to aflibercept- or ranibizumab treatment (final follow-up, AG/, RG). Results From a total of 96 eyes treated with intravitreal injections of bevacizumab (10.5 ± 7.6 (mean ± SD)), 58 eyes switched to aflibercept (6.5 ± 3.9; AG) and 38 eyes switched to ranibizumab (7.1 ± 5.3; RG) (≥ 3 injections, each). In addition, these eyes were compared to 37 eyes under bevacizumab monotherapy. Primary outcome: In the AG, the CMT decreased slightly from 430 ± 220 μm at baseline to 419 ± 212 μm at switch follow-up (p = 0.86), but decreased significantly to 318 ± 159 μm at final follow-up, AG (p

Introduction The diagnosis of degenerative cervical myelopathy (DCM) is difficult in numerous patients due to the limited correlation of clinical symptoms, electrophysiology and MRI. This applies especially for early disease stages with mild symptoms or in uncertainty due to comorbidities. Conventional MRI myelopathy signs show a restricted sensitivity to clinical symptoms of at most 60%. It is desirable to select patients for surgical treatment as early as possible before irreversible neurological damage occurs. To improve treatment, a more reliable imaging is necessary. Microdiffusion imaging (MIDI) is an innovative MRI modality to depict tissue alterations within one voxel based on diffusion-weighted imaging (DWI) postprocessing. By separating the affected area into several mesoscopic compartments, pathological changes might be detected more sensitive through this subtle tissue resolution. We hypothesise, that MIDI shows myelopathic alterations more sensitive than conventional MRI and improves the correlation to functional impairment.Methods and analysis In this prospective, observational trial, 130 patients with a relevant degenerative cervical spinal stenosis receive MRI including MIDI and a standard clinical and electrophysiological assessment. Special subvoxel diffusion parameters are calculated. Clinical follow-ups are conducted after 3, 6 and with additional MRI and electrophysiology after 12 months. The primary endpoint is the sensitivity of MIDI to detect functional myelopathy defined by clinical and electrophysiological features correlated to conventional MRI myelopathy signs. Twenty healthy subjects will be included as negative control. The results will provide new insights into the development of mesoscopic spinal cord alterations in DCM associated to the clinical course. Aim is to improve the diagnostics of incipient myelopathy through this new modality.Ethics and dissemination The study protocol is approved by the Ethics Committee of the University of Freiburg (reference 261/17). The results will be published in a peer-reviewed journal.Trial registration number DRKS00012962.

Infection of cattle with chlamydiae is ubiquitous and, even in the absence of clinical sequeleae, has a quantifiable negative impact on livestock productivity. Despite recent progress, our knowledge about immune response mechanisms capable of counteracting the infection and preventing its detrimental effects is still limited. A well-established model of bovine acute respiratory Chlamydia (C.) psittaci infection was used here to characterize the kinetics of the local and systemic immune reactions in calves. In the course of two weeks following inoculation, leukocyte surface marker expression was monitored by flow cytometry in blood and bronchoalveolar lavage fluid (BALF). Immune-related protein and receptor transcription were determined by quantitative real-time reverse transcription PCR in blood, BALF and lung tissue. An early increase of IL2RA, IL10 and HSPA1A mRNA expressions was followed by a rise of lymphocytes, monocytes, and granulocytes exhibiting activated phenotypes in blood. Monocytes showed elevated expression rates of CD11b, CD14 and MHC class II. The rates of CD62L expression on CD8hi T cells in blood and on CD4+ T cells in BALF were also augmented and peaked between 2 and 4 dpi. Notably, CD25 antigen expression was significantly elevated, not only on CD8dim/CD62L+ and CD8-/CD62L+ cells in blood, but also on granulocytes in blood and BALF between 2-3 dpi. From 4 dpi onwards, changes declined and the calves recovered from the infection until 10 dpi. The findings highlight the effectiveness of rapid local and systemic immune reaction and indicate activated T cells, monocytes and granulocytes being essential for rapid eradication of the C. psittaci infection.