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Current coronavirus disease 2019 vaccines face limitations including waning immunity, immune escape by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, limited cellular response, and poor mucosal immunity. We engineered a Clec9A-receptor binding domain (RBD) antibody construct that delivers the SARS-CoV-2 RBD to conventional type 1 dendritic cells. Compared with non-targeting approaches, single dose immunization in mice with Clec9A-RBD induced far higher RBD-specific antibody titers that were sustained for up to 21 months after vaccination. Uniquely, increasing neutralizing and antibody-dependent cytotoxicity activities across the sarbecovirus family was observed, suggesting antibody affinity maturation over time. Consistently and remarkably, RBD-specific follicular T helper cells and germinal center B cells persisted up to 12 months after immunization. Furthermore, Clec9A-RBD immunization induced a durable mono- and poly-functional T-helper 1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants of concern, including Omicron subvariants, and with a robust CD8 + T cell signature. Uniquely, Clec9A-RBD single-shot systemic immunization effectively primed RBD-specific cellular and humoral immunity in lung and resulted in significant protection against homologous SARS-CoV-2 challenge as evidenced by limited body weight loss and approximately 2 log 10 decrease in lung viral loads compared with non-immunized controls. Therefore, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal protective immunity against rapidly evolving SARS-CoV2 variants., Competing Interests: Declaration of interests M.H.L., I.C., and K.M.T. are listed as inventors on patents relating to Clec9A antibodies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy., Aim: To evaluate the use of serum biomarkers to predict HBeAg loss., Methods: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated., Results: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm., Conclusions: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon., 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.Daniel Q. Huang Advisory board: Eisai, Gilead. Liang Shen nil; Wah Phyo nil; Gavin Cloherty Employee of Abbott Diagnostics; Emily K. Butler Employee of Abbott Diagnostics; Mary C. Kuhns Employee of Abbott Diagnostics; Anne L. McNamara Employee of Abbott Diagnostics; Vera Holzmayer Employee of Abbott Diagnostics; Jeffrey Gersch Employee of Abbott Diagnostics; Mark Anderson Employee of Abbott Diagnostics; Wei Lyn Yang: Advisory board: Gilead, Abbie, Bristol Myers Squibb, MSD; Jing Hieng Ngu Advisory Board: Gilead Sciences; Speakers Bureau: Abbvie; Jason Chang nil; Jessica Tan nil; Taufique Ahmed nil; Yock Young Dan Advisory Board: BMS, Gilead, Novartis, Abbvie, MSD; Speaker's Bureau: Sanofi Aventis, Siemens; Research grants: BMS, Novartis and Johnson & Johnson; Yin Mei Lee nil; Guan Huei Lee nil; Poh Seng Tan nil; Htet Toe Wai Khine nil; Amy Tay nil; Seng Gee Lim: Advisory Board: Gilead Sciences, Roche, GSK, Janssen, Grifols, Assembly, Arbutus, Abbott, Sysmex. Speakers Bureau: Gilead Sciences, Abbott, Sysmex, Roche, GSK. Educational/research funding: Abbott, Gilead Sciences., (Copyright © 2024. Published by Elsevier B.V.)

Background: The National Institute for Health and Care Excellence (NICE) recommends that people aged 60+ years with newly diagnosed diabetes and weight loss undergo abdominal imaging to assess for pancreatic cancer. More nuanced stratification could lead to enrichment of these referral pathways., Methods: Population-based cohort study of adults aged 30-85 years at type 2 diabetes diagnosis (2010-2021) using the QResearch primary care database in England linked to secondary care data, the national cancer registry and mortality registers. Clinical prediction models were developed to estimate risks of pancreatic cancer diagnosis within 2 years and evaluated using internal-external cross-validation., Results: Seven hundred and sixty-seven of 253,766 individuals were diagnosed with pancreatic cancer within 2 years. Models included age, sex, BMI, prior venous thromboembolism, digoxin prescription, HbA1c, ALT, creatinine, haemoglobin, platelet count; and the presence of abdominal pain, weight loss, jaundice, heartburn, indigestion or nausea (previous 6 months). The Cox model had the highest discrimination (Harrell's C-index 0.802 (95% CI: 0.797-0.817)), the highest clinical utility, and was well calibrated. The model's highest 1% of predicted risks captured 12.51% of pancreatic cancer cases. NICE guidance had 3.95% sensitivity., Discussion: A new prediction model could have clinical utility in identifying individuals with recent onset diabetes suitable for fast-track abdominal imaging., (© 2024. The Author(s).)

The generation of bone-marrow-derived dendritic cells is a widely used approach in immunological research to study antigen processing and presentation, as well as T-cell activation responses. However, the initial step of isolating the bone marrow can be time-consuming, especially when larger numbers of precursor cells are required. Here, we assessed whether an accelerated bone marrow isolation method using centrifugation is suitable for the differentiation of FMS-like tyrosine kinase 3 ligand-driven dendritic cells. Compared to the conventional flushing method, the centrifugation-based isolation method resulted in a similar bone marrow cell yield on Day 0, increased cell numbers by Day 8, similar proportions of dendritic cell subsets, and consequently a higher number of type 1 conventional dendritic cells (cDC1) from the culture. Although the primary purpose of this method of optimization was to improve experimental efficiency and increase the output of cDC1s, the protocol is also compatible with the differentiation of other dendritic cell subsets such as cDC2 and plasmacytoid dendritic cells, with an improved output cell count and a consistent phenotype.

Introduction: This study aimed to determine the prevalence and association between the severity of COVID-19 and short and long-term neuropsychiatric symptoms, as well as the risk factors for the development of these symptoms., Materials and Methods: A prospective observational study was conducted between 1st October 2021 till September 2022 in the state of Johor, Malaysia. 300 patients with confirmed SARS-CoV-2 infection were randomly selected and followed up for six months. Data were analysed by using Chi-square test, Fisher's Exact test, Paired t test and Multiple logistic regression., Results: The prevalence of short-term neuropsychiatric symptoms was 78%, with anosmia being the most prevalent symptom. Long-term symptoms were found in 22.75% of patients, with headache being the most prevalent (p= 0.001). COVID-19 Stage 2 and 3 infections were associated with a higher risk of short-term neuropsychiatric symptoms, OR for Stage 2 infection was 5.18 (95% CI: 1.48-16.97; p=0.009) and for Stage 3 infection was 4.52 (95% CI: 1.76-11.59; p=0.002). Complete vaccination was a significant predictor of longterm symptoms with adjusted OR 3.65 (95% CI 1.22-10.91; p=0.021)., Conclusion: This study demonstrated that neuropsychiatric symptoms were common among COVID-19 patients in Johor, Malaysia and the risk of these symptoms was associated with the severity of the infection. Additionally, complete vaccination does not completely protect against long-term neuropsychiatric deficits. This is crucial for continuous monitoring and addressing neuropsychiatric symptoms in COVID-19 survivors.

Objectives: The aim of the study was to describe injuries related to electric scooter at a Major-Trauma-Centre in the UK, We reviewed data from January 2020-December 2020., Methods: All patient-records mentioning electric-scooter at a major-MTC. Records were reviewed, and data were stratified according to two groups: electric scooter riders and other road users. A predefined survey was completed in all cases where 'e-scooter or electric scooter' was present. This contained variables such as patient demographics, mechanism of injury (including head and body protection), acuity, intoxication, treatment facility and clinical utilisation. Among incidents involving electric scooters, summary statistics on continuous and categorical variables of interest were reported. Healthcare modelling utilising time driven activity-based costing and Patient-Level-Activity-Costing used to conduct a post hoc analysis of health provider costs., Results: 202 e-scooter injuries were identified. Riders were more likely to be young males aged 18-35, a minority of reported cases being associated with the influence of alcohol or drugs (7.4%). They fall independently involving no other party (87%); sustaining both minor and major injuries; with a significant proportion requiring urgent and emergent surgery 23.7% (n = 40) with 60.1% (n = 121) requiring further secondary care follow-up; whilst 16% require immediate admission with a mean LOS of 5.9 days, including 8-ITU admissions. The overall mortality rate was 0.5% (n = 1), and cost per patient was £1482.46/patient, reducing to £927.25/patient if immediate surgery (<12 h s) was not required., Conclusion: Due to an emphasis on social distancing, changes in UK law, e-scooters injuries have increased. Most injuries are reported in riders, and are minor, however the mean health episode cost was over £1000.00/patient due to the minority of serious injuries. Research on interventions to prevent e-scooter injuries including protective clothing like helmet wearing is needed to address this growing area of concern, and unnecessary costly healthcare utilisation., Competing Interests: Conflicts of interest None., (Copyright © 2022 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. All rights reserved.)

In multi-objective optimization, it becomes prohibitively difficult to cover the Pareto front (PF) as the number of points scales exponentially with the dimensionality of the objective space. The challenge is exacerbated in expensive optimization domains where evaluation data is at a premium. To overcome insufficient representations of PFs, Pareto estimation (PE) invokes inverse machine learning to map preferred but unexplored regions along the front to the Pareto set in decision space. However, the accuracy of the inverse model depends on the training data, which is inherently scarce/small given high-dimensional/expensive objectives. To alleviate this small data challenge, this paper marks a first study on multi-source inverse transfer learning for PE. A method to maximally utilize experiential source tasks to augment PE in the target optimization task is proposed. Information transfers between heterogeneous source-target pairs is uniquely enabled in the inverse setting through the unification provided by common objective spaces. Our approach is tested experimentally on benchmark functions as well as on high-fidelity, multidisciplinary simulation data of composite materials manufacturing processes, revealing significant gains to the predictive accuracy and PF approximation capacity of Pareto set learning. With such accurate inverse models made feasible, a future of on-demand human-machine interaction facilitating multi-objective decisions is envisioned., (© 2023. The Author(s).)

The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between the nucleus and cytosol 1 . The central channel of the NPC is filled with hundreds of intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs) 2,3 . Although the structure of the NPC scaffold has been resolved in remarkable detail, the actual transport machinery built up by FG-NUPs-about 50 MDa-is depicted as an approximately 60-nm hole in even highly resolved tomograms and/or structures computed with artificial intelligence 4-11 . Here we directly probed conformations of the vital FG-NUP98 inside NPCs in live cells and in permeabilized cells with an intact transport machinery by using a synthetic biology-enabled site-specific small-molecule labelling approach paired with highly time-resolved fluorescence microscopy. Single permeabilized cell measurements of the distance distribution of FG-NUP98 segments combined with coarse-grained molecular simulations of the NPC allowed us to map the uncharted molecular environment inside the nanosized transport channel. We determined that the channel provides-in the terminology of the Flory polymer theory 12 -a 'good solvent' environment. This enables the FG domain to adopt expanded conformations and thus control transport between the nucleus and cytoplasm. With more than 30% of the proteome being formed from IDPs, our study opens a window into resolving disorder-function relationships of IDPs in situ, which are important in various processes, such as cellular signalling, phase separation, ageing and viral entry., (© 2023. The Author(s).)

Single-molecule Förster-resonance energy transfer (smFRET) experiments allow the study of biomolecular structure and dynamics in vitro and in vivo. We performed an international blind study involving 19 laboratories to assess the uncertainty of FRET experiments for proteins with respect to the measured FRET efficiency histograms, determination of distances, and the detection and quantification of structural dynamics. Using two protein systems with distinct conformational changes and dynamics, we obtained an uncertainty of the FRET efficiency ≤0.06, corresponding to an interdye distance precision of ≤2 Å and accuracy of ≤5 Å. We further discuss the limits for detecting fluctuations in this distance range and how to identify dye perturbations. Our work demonstrates the ability of smFRET experiments to simultaneously measure distances and avoid the averaging of conformational dynamics for realistic protein systems, highlighting its importance in the expanding toolbox of integrative structural biology., (© 2023. The Author(s).)

Objectives: Uptake of influenza, pneumococcal and shingles vaccines in older adults vary across regions and socioeconomic backgrounds. In this study, we study the coverage and factors associated with vaccination uptake, as well as refusal in the unvaccinated population and their associations with ethnicity, deprivation, household size and health conditions., Design, Setting and Participants: This is a cross-sectional study of adults aged 65 years or older in England, using a large primary care database. Associations of vaccine uptake and refusal in the unvaccinated with ethnicity, deprivation, household size and health conditions were modelled using multivariable logistic regression., Outcome Measure: Influenza, pneumococcal and shingles vaccine uptake and refusal (in the unvaccinated)., Results: This study included 2 054 463 patients from 1318 general practices. 1 711 465 (83.3%) received at least one influenza vaccine, 1 391 228 (67.7%) pneumococcal vaccine and 690 783 (53.4%) shingles vaccine. Compared with White ethnicity, influenza vaccine uptake was lower in Chinese (OR 0.49; 95% CI 0.45 to 0.53), 'Other ethnic' groups (0.63; 95% CI 0.60 to 0.65), black Caribbean (0.68; 95% CI 0.64 to 0.71) and black African (0.72; 95% CI 0.68 to 0.77). There was generally lower vaccination uptake among more deprived individuals, people living in larger household sizes (three or more persons) and those with fewer health conditions. Among those who were unvaccinated, higher odds of refusal were associated with the black Caribbean ethnic group and marginally with increased deprivation, but not associated with higher refusal in those living in large households or those with lesser health conditions., Conclusion: Certain ethnic minority groups, deprived populations, large households and 'healthier' individuals were less likely to receive a vaccine, although higher refusal was only associated with ethnicity and deprivation but not larger households nor healthier individuals. Understanding these may inform tailored public health messaging to different communities for equitable implementation of vaccination programmes., Competing Interests: Competing interests: PST reports previous consultation with AstraZeneca and Duke-NUS outside the submitted work. KK is a Member of the Scientific Advisory Group for Emergencies (SAGE), Member of Independent SAGE, Director of the University of Leicester Centre for Black Minority Health and Trustee of the south Asian Health Foundation. JH-C is a member of several SAGE committees and chair of the risk stratification subgroup of the NERVTAG. She is an unpaid director of QResearch and founder and former medical director of ClinRisk Ltd (outside the submitted work). MP, AKC, HD-M, DS, TAR, FZ, BRS, SJG, CC, CG have no interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk ., Design: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression., Results: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC., Conclusion: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis., Competing Interests: Competing interests: JH-C reports grants from National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford, grants from John Fell Oxford University Press Research Fund, grants from Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre, grants from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z) and other research councils, during the conduct of the study. JH-C is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work. JH-C is a founder and shareholder of ClinRisk ltd and was its medical director until 31st May 2019. ClinRisk Ltd produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems. AC reports consulting fees from Mendelian, outside the scope of the current work. RB-R is a cofounder of Alchemab Therapeutics and consultant for Alchemab Therapeutics and GSK. PST reports previous consultation with AstraZeneca and Duke-NUS outside the current work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Heterogeneous studies have demonstrated ethnic inequalities in the risk of SARS-CoV-2 infection and adverse COVID-19 outcomes. This study evaluates the association between ethnicity and COVID-19 outcomes in two large population-based cohorts from England and Canada and investigates potential explanatory factors for ethnic patterning of severe outcomes., Methods: We identified adults aged 18 to 99 years in the QResearch primary care (England) and Ontario (Canada) healthcare administrative population-based datasets (start of follow-up: 24th and 25th Jan 2020 in England and Canada, respectively; end of follow-up: 31st Oct and 30th Sept 2020, respectively). We harmonised the definitions and the design of two cohorts to investigate associations between ethnicity and COVID-19-related death, hospitalisation, and intensive care (ICU) admission, adjusted for confounders, and combined the estimates obtained from survival analyses. We calculated the 'percentage of excess risk mediated' by these risk factors in the QResearch cohort., Results: There were 9.83 million adults in the QResearch cohort (11,597 deaths; 21,917 hospitalisations; 2932 ICU admissions) and 10.27 million adults in the Ontario cohort (951 deaths; 5132 hospitalisations; 1191 ICU admissions). Compared to the general population, pooled random-effects estimates showed that South Asian ethnicity was associated with an increased risk of COVID-19 death (hazard ratio: 1.63, 95% CI: 1.09-2.44), hospitalisation (1.53; 1.32-1.76), and ICU admission (1.67; 1.23-2.28). Associations with ethnic groups were consistent across levels of deprivation. In QResearch, sociodemographic, lifestyle, and clinical factors accounted for 42.9% (South Asian) and 39.4% (Black) of the excess risk of COVID-19 death., Conclusion: International population-level analyses demonstrate clear ethnic inequalities in COVID-19 risks. Policymakers should be cognisant of the increased risks in some ethnic populations and design equitable health policy as the pandemic continues., (© 2023. The Author(s).)

Tissue resident memory T cells (T RM cells) can provide effective tissue surveillance and can respond rapidly to infection. Vaccination strategies aimed at generating T RM cells have shown promise against a range of pathogens. We have previously shown that the choice of adjuvant critically influences CD8 + T RM cell formation in the liver. However, the range of adjuvants tested was limited. Here, we assessed the ability of a broad range of adjuvants stimulating membrane (TLR4), endosomal (TLR3, TLR7 and TLR9) and cytosolic (cGAS, RIG-I) pathogen recognition receptors for their capacity to induce CD8 + T RM formation in a subunit vaccination model. We show that CpG oligodeoxynucleotides (ODN) remain the most efficient inducers of liver T RM cells among all adjuvants tested. Moreover, their combination with the cationic liposome DOTAP further enhances the potency, particularly of the class B ODN CpG 1668 and the human TLR9 ligand CpG 2006 (CpG 7909). This study informs the design of efficient liver T RM -based vaccines for their potential translation., 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 Elsevier Ltd. All rights reserved.)

Acute ischaemic strokes occur despite the use of direct oral anticoagulants (DOACs). A retrospective review was conducted at a high-volume primary stroke centre over a 3-year period to assess the acute management of stroke presentations in patients prescribed DOACs. During the time period of the study, 103 of 195 anticoagulated stroke patients presented within the timeframe for thrombolysis and only 15 patients had DOAC plasma level assays performed. Of these 103, 5 received thrombolysis; however, DOAC level was not a factor in these cases., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Measuring the three-dimensional motion of trees at every position remains challenging as it requires dynamic measurement technology with sufficient spatial and temporal resolution. Consequently, this study explores the use of a novel multi-beam flash light detection and ranging (LiDAR) sensor to tackle such a sensing barrier. A framework is proposed to record tree vibrations, to construct the motions of tree skeletons from the point-cloud frames recorded by the LiDAR sensor and to derive the dynamic properties of trees. The feasibility of the framework is justified through measurement on a Ficus microcarpa under pull-and-release tests. The relative differences for the first two modal frequencies between the LiDAR and linear variable differential transformer measurements in the displacement Fourier spectra are 0.1% and 2.5%, respectively. The framework is further adopted to study the dynamic response of different trees subjected to typhoons, including a Liquidambar formosana , three Araucaria heterophylla trees, a Sterculia lanceolata , a Celtis sinensis , a Tabebuia chrysantha and a Cinnamomum camphora . Results suggest that broadleaved trees might exhibit vibration in a wide frequency band, whereas the coniferous trees could follow a distinct dominant frequency.

SignificanceAlthough the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24-amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.

Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes., Competing Interests: HH is an employee of Bavarian Nordic GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pang, Daraj, Balka, De Nardo, Macri, Hochrein, Masterman, Tan, Shoppee, Magill, Jahan, Bafit, Zhan, Kile, Lawlor, Radford, Wright and O’Keeffe.)

Background & Aims: The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA., Methods: We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT)., Results: A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy)., Conclusions: ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity., Methods: We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase)., Results: There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72)., Interpretation: Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19., Competing Interests: Competing interests: PST reports personal fees from AstraZeneca, and personal fees from Duke-NUS, outside the submitted work. CACC reports receiving personal fees from ClinRisk, outside this work. MRM reports grants from Pfizer and Rusan, outside the submitted work. JHC is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health. JHC is a founder and shareholder of ClinRisk Ltd and was its medical director until 31 May 2019; ClinRisk produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems. AvE and JCH work at the Clinical Trial Service Unit and Epidemiological Studies Unit, which receives research grants from industry that are governed by University of Oxford contracts that protect its independence, and has a staff policy of not taking personal payments from industry; further details can be found at https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf. AKC, HMS, NL and PA have no conflicts to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The application of intra-operative blood salvage autotransfusion(IBSA) in liver transplantation(LT) for hepatocellular carcinoma(HCC) remains controversial due to the theoretical risk of tumour cell(TC) reintroduction. Current studies evaluating for presence of TC are limited by suboptimal detection techniques. This study aims to analyze the presence of TC in HCC LT autologous blood using microfluidics technology., Methods: A prospective study of HCC patients who underwent LT from February 2018-April 2019 was conducted. Blood samples were collected peri-operatively. TCs were isolated using microfluidics technology and stained with antibody cocktails for confirmation., Results: A total of 15 HCC LT patients were recruited. All recipients had tumour characteristics within the University of California, San Francisco(UCSF) criteria pre-operatively. TC was detected in all of the autologous blood samples collected from the surgical field. After IOCS wash, five patients had no detectable TC, while 10 patients had detectable TC; of these two remained positive for TC after Leukocyte Depletion Filter(LDF) filtration., Conclusion: The risk of tumour cell reintroduction using IBSA in HCC LT patients can be reduced with a single LDF. Future studies should evaluate the proliferation capacity and tumorigenicity of HCC TC in IBSA samples, and the effects of TC reintroduction in patients with pre-existing HCC TCs., (Copyright © 2021. Published by Elsevier Ltd.)

Background: A more transmissible variant of SARS-CoV-2, the variant of concern 202012/01 or lineage B.1.1.7, has emerged in the UK. We aimed to estimate the risk of critical care admission, mortality in patients who are critically ill, and overall mortality associated with lineage B.1.1.7 compared with non-B.1.1.7. We also compared clinical outcomes between these two groups., Methods: For this observational cohort study, we linked large primary care (QResearch), national critical care (Intensive Care National Audit & Research Centre Case Mix Programme), and national COVID-19 testing (Public Health England) databases. We used SARS-CoV-2 positive samples with S-gene molecular diagnostic assay failure (SGTF) as a proxy for the presence of lineage B.1.1.7. We extracted two cohorts from the data: the primary care cohort, comprising patients in primary care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 26, 2021, and known SGTF status; and the critical care cohort, comprising patients admitted for critical care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 27, 2021, and known SGTF status. We explored the associations between SARS-CoV-2 infection with and without lineage B.1.1.7 and admission to a critical care unit (CCU), 28-day mortality, and 28-day mortality following CCU admission. We used Royston-Parmar models adjusted for age, sex, geographical region, other sociodemographic factors (deprivation index, ethnicity, household housing category, and smoking status for the primary care cohort; and ethnicity, body-mass index, deprivation index, and dependency before admission to acute hospital for the CCU cohort), and comorbidities (asthma, chronic obstructive pulmonary disease, type 1 and 2 diabetes, and hypertension for the primary care cohort; and cardiovascular disease, respiratory disease, metastatic disease, and immunocompromised conditions for the CCU cohort). We reported information on types and duration of organ support for the B.1.1.7 and non-B.1.1.7 groups., Findings: The primary care cohort included 198 420 patients with SARS-CoV-2 infection. Of these, 117 926 (59·4%) had lineage B.1.1.7, 836 (0·4%) were admitted to CCU, and 899 (0·4%) died within 28 days. The critical care cohort included 4272 patients admitted to CCU. Of these, 2685 (62·8%) had lineage B.1.1.7 and 662 (15·5%) died at the end of critical care. In the primary care cohort, we estimated adjusted hazard ratios (HRs) of 2·15 (95% CI 1·75-2·65) for CCU admission and 1·65 (1·36-2·01) for 28-day mortality for patients with lineage B.1.1.7 compared with the non-B.1.1.7 group. The adjusted HR for mortality in critical care, estimated with the critical care cohort, was 0·91 (0·76-1·09) for patients with lineage B.1.1.7 compared with those with non-B.1.1.7 infection., Interpretation: Patients with lineage B.1.1.7 were at increased risk of CCU admission and 28-day mortality compared with patients with non-B.1.1.7 SARS-CoV-2. For patients receiving critical care, mortality appeared to be independent of virus strain. Our findings emphasise the importance of measures to control exposure to and infection with COVID-19., Funding: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, and the Medical Sciences Division of the University of Oxford., Competing Interests: Competing interests JH-C reports receiving grants from the Wellcome trust, Health Data Research-UK, National Institute for Health Research (NIHR) Biomedical Research Centre (Oxford), John Fell Oxford University Press Research Fund, Cancer Research UK, and Oxford Wellcome Institutional Strategic Support Fund; being a member of SAGE subgroups on ethnicity and chair of the NERVTAG risk stratification subgroup; being an unpaid director of QResearch; and being a founder and former director of ClinRisk, outside the submitted work. PST reports previous consultations with AstraZeneca and Duke-National University of Singapore, outside the submitted work. PW was Chief Medical Officer for Sensyne Health, his department received research funding from Sensyne Health, and he holds shares in the company; and he received grant funding from the National Institute for Health Research and Wellcome Trust., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Availability of transient elastography (TE) limits the application of Baveno-VI criteria. In a derivation study, the ABP criteria (Albumin >40 g/l, Bilirubin <22 μmol/l and Platelet >114,000/μl) had been shown to perform well in identifying compensated advanced chronic liver disease (cACLD) patients without high-risk varices (HRV). We aim to externally validate this novel ABP criteria for the exclusion of HRVs among cACLD patients., Methods: Data was retrospectively collected from consecutive cACLD patients with paired TE and esophagogastroduodenoscopy (EGD) performed between 2011 and 2017 in Changi General Hospital, Singapore. We estimate the discriminative ability of ABP criteria in validation cohort using AUROC and calibration-in-the-large. We subsequently compare the performance between ABP and Baveno-VI criteria in the validation cohort., Results: Among 314 patients included in our validation cohort, 32 (10.2%) had HRV on screening EGD. Application of ABP criteria within this validation cohort has increased discriminative ability than the derivation cohort. The AUROC of validation and derivation cohort were 0.68 (0.60-0.76) and 0.66 (0.60-0.76), respectively. The mean and standard error for calibration-in-the-large and calibration slope were -0.08 (0.22) and 0.93 (0.26) respectively. The ABP criteria had excellent performance in excluding HRV and will spare more screening EGDs than the Baveno-VI criteria (39.2% vs 27.4%, p < 0.001), without missing more HRVs., Conclusion: We validated the performance of ABP criteria for the exclusion of HRVs in cACLD patients. ABP criteria is superior to Baveno-VI criteria by sparing more screening EGD without the need of TE., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: COVID-19 pandemic has affected healthcare services around the globe as hospitals were turned into designated hospitals to accommodate high risk groups of patients with COVID-19 infection including end stage kidney disease (ESKD) patients. In Malaysia, there was insufficient data on COVID-19 infection among ESKD patients. This study aims to determine factors and survival outcomes associated with COVID-19 infection among ESKD patients in a designated COVID-19 hospital in Malaysia., Methods and Materials: A retrospective cross-sectional study involving 80 haemodialysis (HD) patients recruited from March 2020 till March 2021. Patients' information and results was retrieved and evaluated. Risk factors affecting the COVID-19 mortality were analysed using a one-way analysis of variance (ANOVA) and binary logistic regression., Results: The mean age of the patients was 54 years who were predominantly Malays (87.5%) and living in rural areas. Majority of them had comorbidities such as diabetes mellitus (71%) and hypertension (90%). The most common presentations were fever (46%) and cough (54%) with chest radiographs showing bilateral lower zone ground glass opacities (45%). A quarter of the study population were admitted to the intensive care unit, necessitating mechanical ventilation. This study found that 51% of the patients were given steroids and 45% required oxygen supplementation. The COVID-19 infection mortality among the study population was 12.5%. Simple logistic regression analysis showed that albumin, Odd Ratio, OR=0.85 (95% Confidence Interval, 95%CI: 0.73, 0.98)) and absolute lymphocyte count OR=0.08 (95%CI: 0.11, 0.56) have inverse association with COVID-19 mortality. C-reactive protein OR=1.02 (95%CI: 1.01, 1.04), lactate dehydrogenase OR=1.01 (95%CI: 1.00, 1.01), mechanical ventilation OR=17.21 (95%CI: 3.03, 97.67) and high dose steroids OR=15.71 (95%CI: 1.80, 137.42) were directly associated with COVID-19 mortality., Conclusion: The high mortality rate among ESKD patients receiving HD was alarming. This warrants additional infection control measures to prevent the spread of COVID- 19 infection among this vulnerable group of patients. Expediting vaccination efforts in this group of patients should be advocated to reduce the incidence of complications from COVID-19 infection.

Importance: Although children mainly experience mild COVID-19 disease, hospitalization rates are increasing, with limited understanding of underlying factors. There is an established association between race and severe COVID-19 outcomes in adults in England; however, whether a similar association exists in children is unclear., Objective: To investigate the association between race and childhood COVID-19 testing and hospital outcomes., Design, Setting, Participants: In this cohort study, children (0-18 years of age) from participating family practices in England were identified in the QResearch database between January 24 and November 30, 2020. The QResearch database has individually linked patients with national SARS-CoV-2 testing, hospital admission, and mortality data., Exposures: The main characteristic of interest is self-reported race. Other exposures were age, sex, deprivation level, geographic region, household size, and comorbidities (asthma; diabetes; and cardiac, neurologic, and hematologic conditions)., Main Outcomes and Measures: The primary outcome was hospital admission with confirmed COVID-19. Secondary outcomes were SARS-CoV-2-positive test result and any hospital attendance with confirmed COVID-19 and intensive care admission., Results: Of 2 576 353 children (mean [SD] age, 9.23 [5.24] years; 48.8% female), 410 726 (15.9%) were tested for SARS-CoV-2 and 26 322 (6.4%) tested positive. A total of 1853 children (0.07%) with confirmed COVID-19 attended hospital, 343 (0.01%) were admitted to the hospital, and 73 (0.002%) required intensive care. Testing varied across race. White children had the highest proportion of SARS-CoV-2 tests (223 701/1 311 041 [17.1%]), whereas Asian children (33 213/243 545 [13.6%]), Black children (7727/93 620 [8.3%]), and children of mixed or other races (18 971/147 529 [12.9%]) had lower proportions. Compared with White children, Asian children were more likely to have COVID-19 hospital admissions (adjusted odds ratio [OR], 1.62; 95% CI, 1.12-2.36), whereas Black children (adjusted OR, 1.44; 95% CI, 0.90-2.31) and children of mixed or other races (adjusted OR, 1.40; 95% CI, 0.93-2.10) had comparable hospital admissions. Asian children were more likely to be admitted to intensive care (adjusted OR, 2.11; 95% CI, 1.07-4.14), and Black children (adjusted OR, 2.31; 95% CI, 1.08-4.94) and children of mixed or other races (adjusted OR, 2.14; 95% CI, 1.25-3.65) had longer hospital admissions (≥36 hours)., Conclusions and Relevance: In this large population-based study exploring the association between race and childhood COVID-19 testing and hospital outcomes, several race-specific disparities were observed in severe COVID-19 outcomes. However, ascertainment bias and residual confounding in this cohort study should be considered before drawing any further conclusions. Overall, findings of this study have important public health implications internationally.

Interleukin-6 (IL-6) is an important immuno-modulating cytokine playing a pivotal role in inflammatory processes in disease induction and progression. As IL-6 serves as an important indicator of disease state, it is of paramount importance to develop low cost, fast and sensitive improved methods of detection. Here we present an electrochemical immunosensor platform based on the use of highly porous graphitic carbon electrodes fabricated by direct laser writing of commercial polyimide tapes and chemically modified with capture IL-6 antibodies. The unique porous and 3D morphology, as well as the high density of edge planes of the graphitic carbon electrodes, resulted in a fast heterogeneous electron transfer (HET) rate, k 0 = 0.13 cm/s. The resulting immunosensor showed a linear response to log of concentration in the working range of 10 to 500 pg/mL, and low limit of detection (LOD) of 5.1 pg/mL IL-6 in phosphate buffer saline. The total test time was approximately 90 min, faster than the time required for ELISA testing. Moreover, the assay did not require additional sample pre-concentration or labelling steps. The immunosensor shelf-life was long, with stable results obtained after 6 weeks of storage at 4 °C, and the selectivity was high, as no response was obtained in the presence of another inflammatory cytokine, Interlukin-4. These results show that laser-fabricated graphitic carbon electrodes can be used as selective and sensitive electrochemical immunosensors and offer a viable option for rapid and low-cost biomarker detection for point-of-care analysis.

Introduction: Hormone replacement therapy (HRT) can help women experiencing menopausal symptoms, but usage has declined due to uncertainty around risks of cancer and some cardiovascular diseases (CVD). Moreover, improved cancer survival rates mean that more women who survive cancer go on to experience menopausal symptoms. Understanding these relationships is important so that women and their clinicians can make informed decisions around the risks and benefits of HRT. This study's primary aim is to determine the association between HRT use after cancer diagnosis and the risk of cancer-specific mortality. The secondary aims are to investigate the risks of HRT on subsequent cancer, all-cause mortality and CVD., Methods and Analysis: We will conduct a population-based longitudinal cohort study of 18-79 year-old women diagnosed with cancer between 1998 and 2020, using the QResearch database. The main exposure is HRT use, categorised based on compound, dose and route of administration, and modelled as a time-varying covariate. Analysis of HRT use precancer and postcancer diagnosis will be conducted separately. The primary outcome is cancer-specific mortality, which will be stratified by cancer site. Secondary outcomes include subsequent cancer diagnosis, CVD (including venous thrombo-embolism) and all-cause mortality. Adjustment will be made for key confounders such as age, body mass index, ethnicity, deprivation index, comorbidities, and cancer grade, stage and treatment. Statistical analysis will include descriptive statistics and Cox proportional hazards models to calculate HRs and 95% CIs., Ethics and Dissemination: Ethical approval for this project was obtained from the QResearch Scientific Committee (Ref: OX24, project title 'Use of hormone replacement therapy and survival from cancer'). This project has been, and will continue to be, supported by patient and public involvement panels. We intend to the submit the findings for peer-reviewed publication in an academic journal and disseminate them to the public through Cancer Research UK., Competing Interests: Competing interests: JH-C is an unpaid director of the Qresearch database (partnership between the University of Oxford and EMIS, commercial supplier of GP computer systems). She is shareholder and former director of ClinRisk Ltd outside the submitted work. PST reports consulting with AstraZeneca and Duke-NUS outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Previous studies suggested that the prevalence of chronic respiratory disease in patients hospitalised with COVID-19 was lower than its prevalence in the general population. The aim of this study was to assess whether chronic lung disease or use of inhaled corticosteroids (ICS) affects the risk of contracting severe COVID-19., Methods: In this population cohort study, records from 1205 general practices in England that contribute to the QResearch database were linked to Public Health England's database of SARS-CoV-2 testing and English hospital admissions, intensive care unit (ICU) admissions, and deaths for COVID-19. All patients aged 20 years and older who were registered with one of the 1205 general practices on Jan 24, 2020, were included in this study. With Cox regression, we examined the risks of COVID-19-related hospitalisation, admission to ICU, and death in relation to respiratory disease and use of ICS, adjusting for demographic and socioeconomic status and comorbidities associated with severe COVID-19., Findings: Between Jan 24 and April 30, 2020, 8 256 161 people were included in the cohort and observed, of whom 14 479 (0·2%) were admitted to hospital with COVID-19, 1542 (<0·1%) were admitted to ICU, and 5956 (0·1%) died. People with some respiratory diseases were at an increased risk of hospitalisation (chronic obstructive pulmonary disease [COPD] hazard ratio [HR] 1·54 [95% CI 1·45-1·63], asthma 1·18 [1·13-1·24], severe asthma 1·29 [1·22-1·37; people on three or more current asthma medications], bronchiectasis 1·34 [1·20-1·50], sarcoidosis 1·36 [1·10-1·68], extrinsic allergic alveolitis 1·35 [0·82-2·21], idiopathic pulmonary fibrosis 1·59 [1·30-1·95], other interstitial lung disease 1·66 [1·30-2·12], and lung cancer 2·24 [1·89-2·65]) and death (COPD 1·54 [1·42-1·67], asthma 0·99 [0·91-1·07], severe asthma 1·08 [0·98-1·19], bronchiectasis 1·12 [0·94-1·33], sarcoidosis 1·41 [0·99-1·99), extrinsic allergic alveolitis 1·56 [0·78-3·13], idiopathic pulmonary fibrosis 1·47 [1·12-1·92], other interstitial lung disease 2·05 [1·49-2·81], and lung cancer 1·77 [1·37-2·29]) due to COVID-19 compared with those without these diseases. Admission to ICU was rare, but the HR for people with asthma was 1·08 (0·93-1·25) and severe asthma was 1·30 (1·08-1·58). In a post-hoc analysis, relative risks of severe COVID-19 in people with respiratory disease were similar before and after shielding was introduced on March 23, 2020. In another post-hoc analysis, people with two or more prescriptions for ICS in the 150 days before study start were at a slightly higher risk of severe COVID-19 compared with all other individuals (ie, no or one ICS prescription): HR 1·13 (1·03-1·23) for hospitalisation, 1·63 (1·18-2·24) for ICU admission, and 1·15 (1·01-1·31) for death., Interpretation: The risk of severe COVID-19 in people with asthma is relatively small. People with COPD and interstitial lung disease appear to have a modestly increased risk of severe disease, but their risk of death from COVID-19 at the height of the epidemic was mostly far lower than the ordinary risk of death from any cause. Use of inhaled steroids might be associated with a modestly increased risk of severe COVID-19., Funding: National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: Hepatocellular carcinoma (HCC) is a significant global problem. With advances in HCC diagnosis and therapy, our hypothesis is that there are significant differences in the clinical characteristics and treatment of HCC over the years., Methods: Patients with HCC between 1980 and 2018 from three major tertiary hospitals in Singapore were enrolled into a Research Electronic Data Capture database. Clinical characteristics and treatment of HCC were compared between those diagnosed before 2008 (cohort A) and during the current decade (ie from 2008 onwards) (cohort B)., Results: There were 3013 patients. Mean age of HCC diagnosis was significantly older in cohort B (68.6 vs 61.2 years, P  < 0.001). The most common etiology remained as chronic hepatitis B infection but the proportion due to hepatitis B was significantly lower in cohort B (46.6% vs 57.2%, P  < 0.0001). The prevalence of cryptogenic/non-alcoholic steatohepatitis was significantly higher in cohort B than cohort A (27.1% vs 18.6%, P  < 0.0001). More patients received curative therapy in cohort B (43.7% vs 27.1%, P  < 0.0001., Conclusion: In this largest collection of HCC patients in Singapore, patients are diagnosed with HCC at an older age and cryptogenic/non-alcoholic steatohepatitis is becoming more important as an etiology of HCC in the current decade. More patients also received curative therapy in the current decade., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of Plasmodium -derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed PbT-II, that produces CD4 + T cells specific for an MHC class II (I-A b )-restricted Plasmodium epitope and is responsive to both sporozoites and blood-stage P. berghei . Here, we identify a peptide within the P. berghei heat shock protein 90 as the cognate epitope recognised by PbT-II cells. We show that C57BL/6 mice infected with P. berghei blood-stage induce an endogenous CD4 T cell response specific for this epitope, indicating cells of similar specificity to PbT-II cells are present in the naïve repertoire. Adoptive transfer of in vitro activated T H 1-, or particularly T H 2-polarised PbT-II cells improved control of P. berghei parasitemia in C57BL/6 mice and drastically reduced the onset of experimental cerebral malaria. Our results identify a versatile, potentially protective MHC-II restricted epitope useful for exploration of CD4 T cell-mediated immunity and vaccination strategies against malaria., Competing Interests: 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., (© 2021 The Authors.)

Introduction: Recent evidence suggests that ethnic minority groups are disproportionately at increased risk of hospitalisation and death from SARS-CoV-2 infection. Population-based evidence on potential explanatory factors across minority groups and within subgroups is lacking. This study aims to quantify the association between ethnicity and the risk of hospitalisation and mortality due to COVID-19., Methods and Analysis: This is a retrospective cohort study of adults registered across a representative and anonymised national primary care database (QResearch) that includes data on 10 million people in England. Sociodemographic, deprivation, clinical and domicile characteristics will be summarised and compared across ethnic subgroups (categorised as per 2011 census). Cox models will be used to calculate HR for hospitalisation and COVID-19 mortality associated with ethnic group. Potential confounding and explanatory factors (such as demographic, socioeconomic and clinical) will be adjusted for within regression models. The percentage contribution of distinct risk factor classes to the excess risks seen in ethnic groups/subgroups will be calculated., Ethics and Dissemination: The study has undergone ethics review in accordance with the QResearch agreement (reference OX102). Findings will be disseminated through peer-reviewed manuscripts, presentations at scientific meetings and conferences with national and international stakeholders., Competing Interests: Competing interests: JH-C is founder and director of QResearch database, which is a not-for-profit organisation with EMIS (leading commercial supplier of IT for 55% of general practices in the UK). JH-C is co-owner of ClinRisk and was a paid director until June 2019. ClinRisk develops open and closed source software to ensure the reliable and updatable implementation of clinical risk equations within clinical computer systems to help improve patient care, outside the submitted work. KK is national lead for NIHR ARC ethnicity and diversity, Director for the University of Leicester Centre for BME Health, Trustee of the South Asian Health Foundation and member of the Independent SAGE. The authors declare that no support from any organisation and no financial relationships have influenced the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Humans have the ability to identify recurring patterns in diverse situations encountered over a lifetime, constantly understanding relationships between tasks and efficiently solving them through knowledge reuse. The capacity of artificial intelligence systems to mimic such cognitive behaviors for effective problem solving is deemed invaluable, particularly when tackling real-world problems where speed and accuracy are critical. Recently, the notion of evolutionary multitasking has been explored as a means of solving multiple optimization tasks simultaneously using a single population of evolving individuals. In the presence of similarities (or even partial overlaps) between high-quality solutions of related optimization problems, the resulting scope for intertask genetic transfer often leads to significant performance speedup-as the cost of re-exploring overlapping regions of the search space is reduced. While multitasking solvers have led to recent success stories, a known shortcoming of existing methods is their inability to adapt the extent of transfer in a principled manner. Thus, in the absence of any prior knowledge about the relationships between optimization functions, a threat of predominantly negative (harmful) transfer prevails. With this in mind, this article presents a realization of a cognizant evolutionary multitasking engine within the domain of multiobjective optimization. Our proposed algorithm learns intertask relationships based on overlaps in the probabilistic search distributions derived from data generated during the course of multitasking-and accordingly adapts the extent of genetic transfers online. The efficacy of the method is substantiated on multiobjective benchmark problems as well as a practical case study of knowledge transfers from low-fidelity optimization tasks to substantially reduce the cost of high-fidelity optimization.

Current breast cancer risk models identify mostly less aggressive tumors, although only women developing fatal breast cancer will greatly benefit from early identification. Here, we evaluated the use of mammography features (microcalcification clusters, computer-generated Breast Imaging Reporting and Data System [cBIRADS] density and lack of breast density reduction) as early markers of aggressive subtypes and tumor characteristics. Mammograms were retrieved from a population-based cohort of women that were diagnosed with breast cancer from 2001 to 2008 in Stockholm-Gotland County, Sweden. Tumor and patient characteristics were obtained from Stockholm Breast Cancer Quality Register and the Swedish Cancer Registry. Multinomial logistic regression was used to individually model each mammographic feature as a function of molecular subtypes, tumor characteristics and detection mode. A total of 4546 women with invasive breast cancer were included in the study. Women with microcalcification clusters in the affected breast were more likely to have human epidermal growth factor receptor 2 subtype (odds ratio [OR] 1.78; 95% confidence interval [CI] 1.24-2.54) and potentially less likely to have basal subtype (OR 0.54; 0.30-0.96) compared to Luminal A subtype. High mammographic cBIRADS showed association with larger tumor size and interval vs screen-detected cancers. Lack of density reduction was associated with interval vs screen-detected cancers (OR 1.43; 1.11-1.83) and potentially of Luminal B subtype vs Luminal A subtype (OR 1.76; 1.04-2.99). In conclusion, microcalcification clusters, cBIRADS density and lack of breast density reduction could serve as early markers of particular subtypes and tumor characteristics of breast cancer. This information has the potential to be integrated into risk models to identify women at risk for developing aggressive breast cancer in need of supplemental screening., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)