Using AI/ML to predict blending performance and process sensitivity for Continuous Direct Compression (CDC).

Utilising three artificial intelligence (AI)/machine learning (ML) tools, this study explores the prediction of fill level in inclined linear blenders at steady state by mapping a wide range of bulk powder characteristics to processing parameters. Predicting fill levels enables the calculation of blade passes (strain), known from existing literature to enhance content uniformity. We present and train three AI/ML models, each demonstrating unique predictive capabilities for fill level. These models collectively identify the following rank order of feature importance: RPM, Mixing Blade Region (MB) size, Wall Friction Angle (WFA), and Feed Rate (FR). Random Forest Regression, a machine learning algorithm that constructs a multitude of decision trees at training time and outputs the mode of the classes (classification) or mean prediction (regression) of the individual trees, develops a series of individually useful decision trees. but also allows the extraction of logic and breakpoints within the data. A novel tool which utilises smart optimisation and symbolic regression to model complex systems into simple, closed-form equations, is used to build an accurate reduced-order model. Finally, an Artificial Neural Network (ANN), though less interrogable emerges as the most accurate fill level predictor, with an r2 value of 0.97. Following training on single-component mixtures, the models are tested with a four-component powdered paracetamol formulation, mimicking an existing commercial drug product. The ANN predicts the fill level of this formulation at three RPMs (250, 350 and 450) with a mean absolute error of 1.4%. Ultimately, the modelling tools showcase a framework to better understand the interaction between process and formulation. The result of this allows for a first-time-right approach for formulation development whilst gaining process understanding from fewer experiments. Resulting in the ability to approach risk during product development whilst gaining a greater holistic understanding of the processing environment of the desired formulation.

Successful Formulation Window for the design of pharmaceutical tablets with required mechanical properties.

Pharmaceutical tablet formulations combine the active ingredient with processing aids and functional components. This paper evaluates compressibility based predictive models for binary and ternary formulations to establish an acceptable range of tablet compression parameters that satisfy prescribed quality target criteria for tablets including minimum tablet strength and processing constraints such as maximum ejection stress and maximum compaction pressure. The concept of Successful Formulation Window (SFW) is introduced. A methodology is proposed to determine the SFW for a given formulation based on compaction simulator data collected for individual formulation components. The methodology is validated for binary and ternary mixtures and lubricated formulations. The SFW analysis was developed to support tablet formulation design to meet mechanical requirements.

Impact of a sustained, collaborative antimicrobial stewardship programme in spinal cord injury patients.

Background: In patients with spinal cord injuries (SCIs), infections continue to be a leading cause of morbidity, mortality and hospital admission. Objectives: This study evaluated the long-term impact of a weekly, multidisciplinary Spinal/Antimicrobial Stewardship (AMS) meeting for acute-care SCI inpatients, on antimicrobial prescribing over 3 years. Methods: A retrospective, longitudinal, pre-post comparison of antimicrobial prescribing was conducted at our tertiary hospital in Melbourne. Antimicrobial prescribing was audited in 6 month blocks pre- (25 April 2017 to 24 October 2017), immediately post- (27 March 2018 to 25 September 2018) and 3 years post-implementation (2 March 2021 to 31 August 2021). Antimicrobial orders for patients admitted under the spinal unit at the meeting time were included. Results: The number of SCI patients prescribed an antimicrobial at the time of the weekly meeting decreased by 40% at 3 years post-implementation [incidence rate ratio (IRR) 0.63; 95% CI 0.51-0.79; P ≤ 0.001]. The overall number of antimicrobial orders decreased by over 22% at 3 years post-implementation (IRR 0.78; 95% CI 0.61-1.00; P = 0.052). A shorter antimicrobial order duration in the 3 year post-implementation period was observed (-28%; 95% CI -39% to -15%; P ≤ 0.001). This was most noticeable in IV orders at 3 years (-36%; 95% CI -51% to -16%; P = 0.001), and was also observed for oral orders at 3 years (-25%; 95% CI -38% to -10%; P = 0.003). Antimicrobial course duration (days) decreased for multiple indications: skin and soft tissue infections (-43%; 95% CI -67% to -1%; P = 0.045), pulmonary infections (-45%; 95% CI -67% to -9%; P = 0.022) and urinary infections (-31%; 95% CI -47% to -9%; P = 0.009). Ninety-day mortality rates were not impacted. Conclusions: This study showed that consistent, collaborative meetings between the Spinal and AMS teams can reduce antimicrobial exposure for acute-care SCI patients without adversely impacting 90 day mortality.

Application of Positron Emission Particle Tracking (PEPT) for the evaluation of powder behaviour in an incline linear blender for Continuous Direct Compression (CDC).

Positron Emission Particle Tracking (PEPT) is a non-invasive measurement technique which offers the ability to track the motion of individual particles with high temporal and spatial resolution, and thus build up an understanding of the bulk behaviour of a system from its microscopic (particle level) dynamics. Using this measurement technique, we have developed a series of novel metrics to better understand the behaviours of powders during the steady-state operation of a continuous blender system. Results are presented concerning the response of particle motion to processing parameters (mixing blade configuration and RPM), quantifying the motion in terms of predicted mixing performance. It was found that both increasing rpm and increasing hold-up mass (by selecting fewer transport blades and more mixing blades) provided improved mixing conditions. Interestingly, under specific conditions, there is evidence of convection-like mixing occurring at the interface of the transport and mixing region. This suggests the existence of a potential 'folding region' whereby powder is transported up the barrel (and away from the powder bulk bed) before being reconstituted back into the bulk mass. The results also provide valuable experimental data for the development, calibration and validation of future Discrete Element Method (DEM) simulations.

The Role of Wellness Climate in Small Business Health Promotion and Employee Wellbeing.

Wellness involves physical, emotional, behavioral, social, and spiritual dimensions. A climate for wellness exists at both the psychological and organizational levels, consisting of individual and shared perceptions of policies, structures, and managerial behavior that support or promote employee wellbeing. This study explored the associations between psychological and organizational wellness climate and the effectiveness of a team health promotion training on employees' perceived physical and mental wellbeing and substance use. Employees from 45 small businesses completed self-report measures of wellness climate, wellbeing, positive unwinding behavior, work-family conflict, job stress, drug use, and alcohol use, assessed before, and one and six months after, attending either of two types of onsite health promotion training. Team Awareness training targeted improvements in the social climate at work. Healthy Choices training targeted individual health behavior. A control group did not receive training until after the study. Businesses were randomly assigned to conditions and data were analyzed using multi-level modeling. Models that included wellness climate as a mediator fit the data significantly better than models without climate as a mediator. Team Awareness participants showed greater improvements in wellness climate and wellbeing compared to the control group. Healthy Choices participants showed no changes in climate and no mediation effects of climate. Health promotion efforts may be enhanced by including wellness climate as a target in program design at multiple levels.

Fusarioid community diversity associated with conifer seedlings in forest nurseries across the contiguous USA.

Introduction: Fusarioid fungi that cause damping-off and root diseases can result in significant losses to conifer crops produced in forest nurseries across the USA. These nurseries are vital to reforestation and forest restoration efforts. Understanding the diversity of Fusarioid fungi associated with damping-off and root diseases of conifer seedlings can provide an approach for targeted management techniques to limit seedling losses and pathogen spread to novel landscapes. Methods: This study identifies 26 Fusarium spp. (F. acuminatum, F. annulatum, F. avenaceum, F. brachygibbosum, F. clavus, F. commune, F. cugenangense, F. diversisporum, F. elaeagni, F. elaeidis, F. flocciferum, F. fredkrugeri, F. fujikuroi, F. grosmichelii, F. ipomoeae, F. lactis, F. languescens, F. luffae, F. odoratissimum, F. oxysporum, F. queenslandicum, F. redolens, F. torulosum, F. triseptatum, F. vanleeuwenii, & F. verticillioides), 15 potential species within Fusarium and Neocosmospora species complexes (two from F. fujikuroi species complex, nine from F. oxysporum species complex, three from F. tricinctum species complex, and one from Neocosmospora species complex), and four Neocosmospora spp. (N. falciforme, N. metavorans, N. pisi, & N. solani) and associated host information collected from conifer-producing nurseries across the contiguous USA. Results: Phylogenetic analyses identified Fusarioid fungi haplotypes that were associated with 1) host specificity, 2) localization to geographic regions, or 3) generalists found on multiple hosts across diverse geographic regions. Discussion: The haplotypes and novel species identified on conifer seedlings should be considered for further analysis to determine pathogenicity, pathogen spread, and assess management practices.

Decision making in next generation risk assessment for skin allergy: Using historical clinical experience to benchmark risk.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment that do not require new animal test data and better quantify uncertainties. Quantitative risk assessment for skin sensitisation uses safety assessment factors to extrapolate from the point of departure to an acceptable human exposure level. It is currently unclear whether these safety assessment factors are appropriate when using non-animal test data to derive a point-of departure. Our skin allergy risk assessment model Defined Approach uses Bayesian statistics to infer a human-relevant metric of sensitiser potency with explicit quantification of uncertainty, using any combination of human repeat insult patch test, local lymph node assay, direct peptide reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data. Here we describe the incorporation of benchmark exposures pertaining to use of consumer products with clinical data supporting a high/low risk categorisation for skin sensitisation. Margins-of-exposure (potency estimate to consumer exposure level ratio) are regressed against the benchmark risk classifications, enabling derivation of a risk metric defined as the probability that an exposure is low risk. This approach circumvents the use of safety assessment factors and provides a simple and transparent mechanism whereby clinical experience can directly feed-back into risk assessment decisions.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Key predictors and burden of meticillin-resistant Staphylococcus aureus infection in comparison with meticillin-susceptible S. aureus infection in an Australian hospital setting.

BACKGROUND: Staphylococcus aureus is associated with significant mortality and increased burden on the healthcare system. Relatively few reliable estimates are available regarding the impact of meticillin-resistant S. aureus (MRSA) infection compared with meticillin-susceptible S. aureus (MSSA) infection. AIMS: To compare patients with MRSA infection and MSSA infection to identify differences in inpatient mortality, length of stay and costs of hospital services, and identify predictors of MRSA as a cause of S. aureus infection. METHODS: An analytical, retrospective, longitudinal study using non-identifiable linked data on adults admitted to hospitals of a health district in Australia with a diagnosis of S. aureus infection over a 10-year period. The main outcome measure was 30-day inpatient mortality. Secondary endpoints included total overnight stays, all-cause inpatient mortality, and hospitalization costs within 1 year of index admission. FINDINGS: Inpatient mortality at 30, 100 and 365 days was estimated to be significantly greater for patients with MRSA infection. The mean additional cost of MRSA infection when controlling for additional factors was $5988 and 4 nights of additional hospital stay per patient within 1 year of index admission. Key predictors of MRSA infection were: date of index admission; higher comorbidity score; greater socio-economic disadvantage; admission to hospital other than via the emergency department; older age; and prior admission to hospital within 28 days of index admission. CONCLUSIONS: MRSA infection is associated with increased inpatient mortality, costs and hospital length of stay compared with MSSA infection. Efforts are required to alleviate the additional burden of MRSA infection on patients and healthcare systems.

Next generation risk assessment for skin allergy: Decision making using new approach methodologies.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment (SARA) that do not require new animal test data and better quantify uncertainties. Significant progress has been made in the development of New Approach Methodologies (NAMs), non-animal test methods, for assessment of skin sensitisation and there is now focus on their application to derive potency information for use in Next Generation Risk Assessment (NGRA). The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data. Here we have applied the SARA model within our weight of evidence NGRA framework for skin allergy to three case study materials in four consumer products. Highlighting how to structure the risk assessment, apply NAMs to derive a point of departure and conclude on consumer safety risk. NGRA based upon NAMs were, for these exposures, at least as protective as the historical risk assessment approaches. Through such case studies we are building our confidence in using NAMs for skin allergy risk assessment.

A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.

Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model. SARA uses Bayesian statistics to provide a human relevant point of departure and risk metric for a given chemical exposure based upon input data that can include both NAMs and historical in vivo studies. Regardless of whether NAM or in vivo inputs were used, the model predicted that the face cream and deodorant exposures were low and high risk respectively. Using only NAM data resulted in a minor underestimation of risk relative to in vivo. Coumarin is a predicted pro-hapten and consequently, when applying this mechanistic understanding to the selection of NAMs the discordance in relative risk could be minimized. This case study demonstrates how integrating a computational model and generating bespoke NAM data in a weight of evidence framework can build confidence in safety decision making.

Genomic Evidence of In-Flight Transmission of SARS-CoV-2 Despite Predeparture Testing.

Since the first wave of coronavirus disease in March 2020, citizens and permanent residents returning to New Zealand have been required to undergo managed isolation and quarantine (MIQ) for 14 days and mandatory testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of October 20, 2020, of 62,698 arrivals, testing of persons in MIQ had identified 215 cases of SARS-CoV-2 infection. Among 86 passengers on a flight from Dubai, United Arab Emirates, that arrived in New Zealand on September 29, test results were positive for 7 persons in MIQ. These passengers originated from 5 different countries before a layover in Dubai; 5 had negative predeparture SARS-CoV-2 test results. To assess possible points of infection, we analyzed information about their journeys, disease progression, and virus genomic data. All 7 SARS-CoV-2 genomes were genetically identical, except for a single mutation in 1 sample. Despite predeparture testing, multiple instances of in-flight SARS-CoV-2 transmission are likely.

Hemagglutinin and Neuraminidase Antibodies Are Induced in an Age- and Subtype-Dependent Manner after Influenza Virus Infection.

Despite evidence that antibodies targeting the influenza virus neuraminidase (NA) protein can be protective and are broadly cross-reactive, the immune response to NA during infection is poorly understood compared to the response to hemagglutinin (HA) protein. As such, we compared the antibody profile to HA and NA in two naturally infected human cohorts in Auckland, New Zealand: (i) a serosurvey cohort, consisting of pre- and post-influenza season sera from PCR-confirmed influenza cases (n = 50), and (ii) an immunology cohort, consisting of paired sera collected after PCR-confirmation of infection (n = 94). The induction of both HA and NA antibodies in these cohorts was influenced by age and subtype. Seroconversion to HA was more frequent in those <20 years old (yo) for influenza A (serosurvey, P = 0.01; immunology, P = 0.02) but not influenza B virus infection. Seroconversion to NA was not influenced by age or virus type. Adults ≥20 yo infected with influenza A viruses were more likely to show NA-only seroconversion compared to children (56% versus 14% [5 to 19 yo] and 0% [0 to 4 yo], respectively). Conversely, children infected with influenza B viruses were more likely than adults to show NA-only seroconversion (88% [0 to 4 yo] and 75% [5 to 19 yo] versus 40% [≥20 yo]). These data indicate a potential role for immunological memory in the dynamics of HA and NA antibody responses. A better mechanistic understanding of this phenomenon will be critical for any future vaccines aimed at eliciting NA immunity.IMPORTANCE Data on the immunologic responses to neuraminidase (NA) is lacking compared to what is available on hemagglutinin (HA) responses, despite growing evidence that NA immunity can be protective and broadly cross-reactive. Understanding these NA responses during natural infection is key to exploiting these properties for improving influenza vaccines. Using two community-acquired influenza cohorts, we showed that the induction of both HA and NA antibodies after infection is influenced by age and subtypes. Such response dynamics suggest the influence of immunological memory, and understanding how this process is regulated will be critical to any vaccine effort targeting NA immunity.

A Brief Measure of Organizational Wellness Climate: Initial Validation and Focus on Small Businesses and Substance Misuse.

OBJECTIVE: Organizations with fewer than 100 employees comprise most businesses in the United States. Since small businesses lack comparable resources, they may benefit from a simple valid tool for broadly assessing positive wellness climate, especially because climate contributes to employee wellbeing. METHODS: Using an ethnically and occupationally diverse sample of 45 businesses (n = 1512), the current study developed and tested a brief self-report measure of organizational wellness climate. RESULTS: Confirmatory factor analysis shows that a 9-item measure has good model fit (RMSEA = 0.06, CFI = 0.91), inter-item consistency of 0.74, and mean Rwg(j) of 0.87. The new measure is significantly positively correlated with physical health and wellbeing, and negatively correlated with substance use behavior. CONCLUSIONS: Findings indicate that a 9-item measure has good reliability, construct, and criterion validity. Implications for practical use of the measure are discussed.

Feasibility of Collecting Saliva for Biological Verification of Tobacco Use Status in Dental Practices and Patients' Homes: Results from the National Dental PBRN.

OBJECTIVE: To evaluate the feasibility of collecting and analyzing saliva samples from dental practices and patients' homes for biochemical verification of tobacco use status. BASIC RESEARCH DESIGN: Sub-study within single-arm, multi-center, longitudinal clinical study. CLINICAL SETTING: Dental practices in the South Central region of the United States National Dental Practice-Based Research Network and patients' homes. PARTICIPANTS: Fifty-five patients recruited from 30 dental practices. INTERVENTIONS: Participants in the sub-study were instructed on saliva collection for cotinine analysis in dental practices where they enrolled in the primary study. Saliva was collected at the practices and then from patients' homes. MAIN OUTCOME MEASURES: Feasibility for dental practice collection was define as 80% of enrolled participants having analyzable samples. For patients' home collection, feasibility was defined as 70%. RESULTS: Forty-seven samples (i.e., 86% of those enrolled) collected in dental practices were analyzable. Twenty-one samples (i.e. 38% of those enrolled) collected in patients' homes were analyzable. CONCLUSIONS: Collecting saliva samples for cotinine analysis from dental practices, but not from patients' homes, was feasible. Dental practices may provide an advantageous setting for biochemically verifying tobacco use status as part of clinical trials for tobacco cessation.

Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Methodology to estimate the break force of pharmaceutical tablets with curved faces under diametrical compression.

This paper develops a methodology to estimate the break force of curved faced tablets under diametrical compression. Common excipients used in pharmaceutical tablet formulations, including microcrystalline cellulose, calcium phosphate and mannitol as well as their mixtures were characterised. Compacts of different densities were manufactured and their compressive and tensile strength was measured. The break force of curved face tablets having a comprehensive range of face curvatures and thickness was measured using the diametrical compression method ("hardness" test). Equation σd=FπD2atD+bWD-1 introduced by Shang et al. (2013) was used to relate the break force (F) to tablet geometry (D, t, W) and material tensile strength (σd). Here, we propose a method to estimate the parameters a and b using data for flat faced tablets. The method was validated for four mixtures. The errors were analysed and compared with the USP29 method σd=10FπD2(2.84(t/D)-0.126t/W+3.15(W/D)+0.01)-1. The proposed method has better accuracy, however, requires additional characterisation of the compressive strength of the material.

Analysis of the Patient Information Quality and Readability on Esophagogastroduodenoscopy (EGD) on the Internet.

Objective: Patients are increasingly using the Internet to inform themselves of health-related topics and procedures, including EGD. We analyzed the quality of information and readability of websites after a search on 3 different search engines. Methods: We used an assessment tool for website quality analysis that we developed in addition to using validated instruments for website quality, Global Quality Score (GQS) and Health on Net (HON) certification. The readability was assessed using Flesch-Kincaid Reading Ease (FRE) and Flesch-Kincaid Grade level (FKG). 30 results of each search terms 'EGD' and 'Upper Endoscopy' from Google and 15 each from Bing and Yahoo were analyzed. A total of 45 websites were included from 100 URLs after removing duplicates, video links, and journal articles. Results: Only 3 websites were found to have good quality and comprehensive and authentic information. These websites were https://www.healthline.com, https://www.uptodate.com, and https://www.emedicine.medscape.com. There were additional 13 sites with moderate quality of information. The mean Flesch-Kincaid Reading Ease (FRE) score was 46.92 (range 81.6-6.5). The mean Flesch-Kincaid Grade level (FKG) was 11th grade, with a range of 6th grade to 12th grade and above making them difficult to read. Conclusions: Our study shows that there are quite a few websites with moderate quality content. We recommend 3 comprehensive and authentic websites out of 45 URLs analyzed for information on Internet for EGD. In addition, the readability of the websites was consistently at a higher level than recommended by AMA at 11th grade level. In addition, we identified 3 websites with moderate quality content written at 8th grade and below readability level. We feel that gastroenterologists can help their patients better understand this procedure by directing them to these comprehensive websites.

Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis.

BACKGROUND: Newer oral anticoagulants (NOACs) are being utilized increasingly for the treatment of venous thromboembolism (VTE). NOAC use is the standard of care for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute VTE involving extremities and pulmonary embolism. In contrast, most guidelines in the literature support the treatment of acute portal vein thrombosis (PVT) with low molecular weight heparin (LMWH) and vitamin K antagonists (VKA). Literature evaluating NOAC use in the treatment of acute portal vein thrombosis is sparse. This review focuses on the safety and efficacy of the use of NOACs in the treatment of acute PVT in patients, with or without concomitant cirrhosis, based on the most recent data available in the current literature. METHODS: A systematic review was conducted through a series of advanced searches in the following medical databases: PubMed, BioMed Central, Cochrane, and Google Scholar. Keywords utilized were as follows: NOAC, DOAC (direct oral anticoagulants), portal vein thrombosis, rivaroxaban, apixaban, dabigatran, and edoxaban. Articles related to newer anticoagulant use in patients with portal vein thrombosis were included. RESULTS: The adverse events, including bleeding events (major and minor) and the failure of anticoagulation (propagation of thrombus or recurrence of PVT), are similar between the NOACs and traditional anticoagulants for the treatment of acute PVT, irrespective of the presence of cirrhosis. CONCLUSIONS: Newer oral anticoagulants are safe and efficacious alternatives to traditional anticoagulation with low molecular weight heparin and vitamin K antagonists in the treatment of acute portal vein thrombosis with or without cirrhosis.

S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.