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Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance. [ABSTRACT FROM AUTHOR]

• Contact X-ray brachytherapy (CXB) and external beam radiation (EBRT) are rectal cancer treatment options. • The ideal sequence of treatment for rectal cancer (≤3 cm) has not been validated. • Propensity-scored methods were used to assess efficacy of upfront CXB treatment. • Increased overall survival was observed in patients who received CXB-first. • These findings support using CXB before EBRT in rectal cancers (≤3 cm). External Beam Radiotherapy (EBRT) followed by Contact X-ray Brachytherapy (CXB) and vice versa are viable alternatives to surgery for selected rectal cancer patients who have small tumours (≤3 cm). However, the optimal sequence of treatment needs to be established. We compared two approaches using Propensity Score (PS) matching and inverse probability treatment weighting (IPTW) analyses to investigate whether the sequence of treatment affected patient outcomes. This retrospective analysis (2008–2019) included patients with rectal adenocarcinoma (cT1-3,N0-1,M0, grade 1–2, size ≤ 3 cm) who received both EBRT and CXB, irrespective of treatment sequence. PS matching and IPTW were conducted to balance covariate standardised mean differences between groups. Oncological outcomes and rate of post-treatment rectal bleeding were assessed. Following PS matching and IPTW analyses from 251 eligible patients; 103 starting with EBRT (median follow-up: 37 [IQR:18–56] months) and 148 with CXB (median follow-up: 32 [IQR:16–54] months, a significant improvement in 3-year overall survival (77% vs 85%, p = 0.02, [HR:0.58 (95% CI:0.37–0.91)]) and a higher risk of post-treatment rectal bleeding (grade 1 (26%) and grade 2 (6%)) were found in patients who started with CXB (p = 0.08). No significant differences were observed in local regrowth (18% vs 12%, p = 0.47), distant relapse (10% vs 6%, p = 0.53), 3-year organ preservation rates (70% vs 75%, p = 0.20, [HR:0.66 (95% CI: 0.35–1.26)]), or disease-free survival (78% vs 82%, p = 0.17, [HR: 0.47 (95% CI: 0.16–1.38)]) In patients with rectal cancer (≤3 cm), commencing with CXB rather than EBRT, was associated with improved overall survival, but had a higher risk of G1/2 rectal bleeding. No statistically significant differences were observed in other oncological outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction‐associated steatotic liver disease (MASLD) versus other chronic liver diseases. Methods: A dataset of HCC patients from a UK hospital (2007–2022) was analyzed. The Mann–Whitney U‐test compared continuous variables. The χ2 and two‐tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival. Results: A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non‐MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3‐mm (95% confidence interval [CI] 10.8–14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43–0.91) of receiving curative treatment compared to non‐MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non‐MASLD HCC (hazard ratio 1.03, 95% CI 0.85–1.25, P = 0.748). Conclusion: Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non‐cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment. [ABSTRACT FROM AUTHOR]

Background: Covid-19 healthcare worker testing, isolation and quarantine policies had to balance risks to patients from the virus and from staff absence. The emergence of the Omicron variant led to dangerous levels of key-worker absence globally. We evaluated whether using two manufacturers' lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection significantly and was acceptable to hospital staff. In a nested study, to understand risks of return to work after a 5-day isolation/quarantine period, we examined virus culture 5–7 days after positive test or significant exposure. Methods: Fully-vaccinated Liverpool (UK) University Hospitals staff participated (February-May 2022) in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV-2 detection, and whether dual swabbing was acceptable to users. Participants used nose-throat swab Innova and nose-only swab Orient Gene LFTs in daily randomised order for 10 days. A user-experience questionnaire was administered on exit. Selected participants gave swabs for viral culture on days 5–7 after symptom onset or first positive test. Cultures were considered positive if cytopathic effect was apparent or SARS-CoV-2 N gene sub-genomic RNA was detected. Results: Two hundred and twenty-six individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49; OR: 2.1, 1.1–4.1; P = 0.03) to be positive. If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (OR: 2.7, 1.3–5.2; P = 0.005); swabbing first with Innova made no significant difference (OR: 1.1, 0.5–2.3; P = 0.85). Orient Gene positive Innova negative result-pairs became more frequent over time (OR: 1.2, 1.1–1.3; P < 0.001). Of individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual versus single test results. Viral cultures from days 5–7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious. Conclusions: Dual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work ~ 5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics. Trial registration: https://www.isrctn.com/ISRCTN47058442 (26 January 2022). [ABSTRACT FROM AUTHOR]

Whisky, as a high value product, is often adulterated, with adverse economic effects for both producers and consumers as well as potential public health impacts. Here we report the use of DAPCI-MS to analyse and chemically profile both genuine and counterfeit whisky samples employing a novel 'direct from the bottle' methodology with zero sample pre-treatment, zero solvent requirement and almost no sample usage. 25 samples have been analysed from a collection of blended Scotch whisky (n = 15) and known counterfeit whisky products (n = 10). Principal component analysis has been applied to dimensionally reduce the data and discriminate between sample groups. Additional chemometric modelling, a partial least squares regression, has correctly classified samples with 92% success rate. DAPCI-MS shows promise for simple, fast and accurate counterfeit detection with potential for generic aroma profiling and process quality monitoring applications. [ABSTRACT FROM AUTHOR]

Background Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets. Objectives To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods. Methods Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach. Results Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [ n  = 74 (6.4%) versus n  = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug–pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%. Conclusions Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess the utility of the Ages and Stages Questionnaire–3rd Edition (ASQ‐3) and the Vineland Adaptive Behavior Scales–2nd Edition (VABS‐II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large‐population signal generation initiatives. Methods: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development–3rd Edition (BSID‐III), the VABS‐II, and the ASQ‐3 (n = 223). The sensitivity and specificity of the ASQ‐3 and VABS‐II to identify developmental delay at 24 months were examined, using the BSID‐III to define cases. Results: The ASQ‐3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ‐3 and BSID‐III at 24 months, the ASQ‐3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut‐points resulted in improved properties and may be preferred in certain contexts. The VABS‐II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID‐III referral data (sensitivity = 100.0%, specificity = 96.6%). Significance: Both the ASQ‐3 and VABS‐II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at‐risk groups. These findings identify the ASQ‐3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS‐II has excellent psychometric properties, it is more labor‐intensive for both the research team and participants and is available in fewer languages than the ASQ‐3. [ABSTRACT FROM AUTHOR]

Abstract: Compliance with the Stage 2 Disinfectants and Disinfection Byproducts (DBP) Rule is often achieved by treating water at a treatment plant to reduce DBP formation. However, it could be more cost‐effective to use localized treatment in the distribution system to target specific problem areas. [ABSTRACT FROM AUTHOR]

The aims of this systematic review and meta-analysis were to: (1) describe the prevalence of commonly reported comorbidities in psoriatic arthritis (PsA), (2) compare the incidence and/or prevalence of comorbidities between PsA and control populations; and (3) examine the impact of comorbidities on PsA outcomes. We systematically searched Medline, PubMed, Scopus, and Web of Science using a predefined protocol in accordance with PRISMA guidelines. Studies reporting only one comorbidity, or a few closely related diseases within one organ system, were excluded. Where possible, meta-analysis was performed using random-effects models. We included 39 studies amounting to over 152 thousand PsA patients. We performed meta-analysis for the prevalence of 21 commonly reported comorbidities. The most prevalent comorbidities were hypertension (pooled prevalence 34%), metabolic syndrome (29%), obesity (27%), hyperlipidaemia (24%) and any cardiovascular diseases (19%). Eleven studies consistently showed higher prevalence of comorbidities in PsA than controls. Five studies showed that comorbid patients had more severe disease, poorer quality of life, and increased discontinuation of treatment. Comorbidities, particularly cardiometabolic disorders, were highly prevalent in PsA and more common than in healthy controls. Comorbidities were associated with adverse disease features, but more research is needed on their impact on longitudinal outcomes such as treatment response, work productivity and mortality. [ABSTRACT FROM AUTHOR]

Background: From January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK. Following this, the Delta variant (B.1.617.2) then became the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Prior to the Delta variant, most vaccine effectiveness studies focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing symptomatic and asymptomatic infection with respect to the Delta variant in a UK setting.Methods: We used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK. Vaccines were assumed to be effective after 21 days for 1 dose and 14 days for 2 doses.Results: We determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34, 43]) and 64% (95% credible interval [61, 67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10, 28]) and 84% (95% credible interval [82, 86]) for a single-dose and a double dose respectively.Conclusion: Vaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This reinforces the need to complete the full course programme to maximise individual protection and reduce transmission. [ABSTRACT FROM AUTHOR]

The aims of this systematic review and meta-analysis were to describe prevalence of cardiovascular disease in gout, compare these results with non-gout controls and consider whether there were differences according to geography. PubMed, Scopus and Web of Science were systematically searched for studies reporting prevalence of any cardiovascular disease in a gout population. Studies with non-representative sampling, where a cohort had been used in another study, small sample size (< 100) and where gout could not be distinguished from other rheumatic conditions were excluded, as were reviews, editorials and comments. Where possible meta-analysis was performed using random-effect models. Twenty-six studies comprising 949,773 gout patients were included in the review. Pooled prevalence estimates were calculated for five cardiovascular diseases: myocardial infarction (2.8%; 95% confidence interval (CI)s 1.6, 5.0), heart failure (8.7%; 95% CI 2.9, 23.8), venous thromboembolism (2.1%; 95% CI 1.2, 3.4), cerebrovascular accident (4.3%; 95% CI 1.8, 9.7) and hypertension (63.9%; 95% CI 24.5, 90.6). Sixteen studies reported comparisons with non-gout controls, illustrating an increased risk in the gout group across all cardiovascular diseases. There were no identifiable reliable patterns when analysing the results by country. Cardiovascular diseases are more prevalent in patients with gout and should prompt vigilance from clinicians to the need to assess and stratify cardiovascular risk. Future research is needed to investigate the link between gout, hyperuricaemia and increased cardiovascular risk and also to establish a more thorough picture of prevalence for less common cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Objective: To describe the prevalence of depression among patients with primary systemic vasculitides (PSV); compare prevalence according to vasculitis type and against controls; and examine the impact of depression on PSV outcomes. Methods: We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with PRISMA guidelines. We included all studies that reported the prevalence or impact of depression in PSV. We also included polymyalgia rheumatica (PMR) given its association with giant cell arteritis (GCA). Meta-analyses of prevalence estimates were performed using random-effects models and reported as percentages (95% confidence interval). Results: We reviewed a total of 15 studies that described the prevalence of depression, categorised into small (n = 10) and large vessel vasculitis (n = 7). Pooled prevalence estimate for depression in a small vessel (predominantly ANCA-associated) vasculitis was 28% (95% CI 20–38%) with significant heterogeneity (I2 = 93%). Depression prevalence in large-vessel vasculitis (Takayasu and GCA/PMR) was 24% (95% CI 17–34%), again with significant heterogeneity (I2 = 96%). One study reported 56% prevalence of depression in medium vessel disease. The prevalence of depression in small vessel vasculitis was higher than healthy controls. In these patients, depression and depressive symptoms were associated with poorer quality of life, adherence, and work disability, but not disease activity or damage. Conclusion: Depression is highly prevalent among patients with primary systemic vasculitis and associated with poorer outcomes across a range of measures in studies of small vessel disease. Further studies are needed for depression in medium and large vessel vasculitides. [ABSTRACT FROM AUTHOR]

• The Reward Positivity encodes a reward-prediction error. • Extraversion is positively associated with the Reward Positivity. • This association generalises across multiple measures of Extraversion. • This association is specific to Extraversion, versus other personality traits. Trait extraversion has been theorized to emerge from functioning of the dopaminergic reward system. Recent evidence for this view shows that extraversion modulates the scalp-recorded Reward Positivity, a putative marker of dopaminergic signaling of reward-prediction-error. We attempt to replicate this association amid several improvements on previous studies in this area, including an adequately-powered sample (N = 100) and thorough examination of convergent-divergent validity. Participants completed a passive associative learning task presenting rewards and non-rewards that were either predictable or unexpected. Frequentist and Bayesian analyses confirmed that the scalp recorded Reward Positivity (i.e., the Feedback-Related-Negativity contrasting unpredicted rewards and unpredicted non-rewards) was significantly associated with three measures of extraversion and unrelated to other basic traits from the Big Five personality model. Narrower sub-traits of extraversion showed similar, though weaker associations with the Reward Positivity. These findings consolidate previous evidence linking extraversion with a putative marker of dopaminergic reward-processing. [ABSTRACT FROM AUTHOR]

Introduction: Risk prediction is important for preventing and managing cardiovascular disease (CVD). CVD risk prediction tools designed for the general population may be inaccurate in people with inflammatory diseases., Objectives: To investigate the performance of four cardiovascular risk prediction tools (QRISK3, Framingham Risk Score, Reynolds Risk Score and SCORE) in psoriatic arthritis (PsA) and psoriasis. We also compare performance in participants with no inflammatory conditions and in people with rheumatoid arthritis (RA)., Methods: This research utilised the UK Biobank Resource. We identified participants with PsA, psoriasis and RA and calculated their cardiovascular risk using each risk tool. We assessed model calibration by comparing observed and predicted outcomes. Discrimination of 10-year risk prediction was assessed using time-dependent area under ROC curve (AUC), sensitivity, specificity, positive and negative predictive values., Results: We included 769 individuals with PsA, 8062 with psoriasis and 4772 with RA when assessing the QRISK3 tool. Predictions for individuals with psoriasis were roughly as accurate as those with no inflammatory conditions with time-dependent AUC of 0.74 (95%CI, 0.72, 0.76) and of 0.74 (95%CI, 0.72, 0.77) respectively. In contrast, individuals with PsA obtained the least accurate predictions with an AUC of 0.70 (95%CI, 0.64, 0.76). Individuals with RA also obtained less accurate predictions with AUC of 0.72 (0.69,0.74). For the Framingham risk score, AUCs varied between 0.61 (95%CI, 0.55, 0.68) for participants with PsA and 0.71 (95%CI, 0.68, 0.74) for individuals with no inflammatory condition., Conclusions: In general, CVD risk prediction accuracy was similar for individuals with psoriasis or no inflammatory condition, but lower for individuals with PsA or RA., Competing Interests: Compliance with ethical standards. Ethics approval: The study protocol and access to the Biobank data were approved by the UK Biobank study team (Application number 67547). Disclosures: None., (© 2025. The Author(s).)

Background: Transanal endoscopic microsurgery (TEMS) is an organ-preserving approach for treatment of early rectal cancer (ERC). However, adverse histopathological features identified post-TEMS often necessitate adjuvant therapy. This study aims to compare the long-term oncological outcomes of patients who underwent TEMS and were offered adjuvant treatments with total mesorectal excision (TME), chemoradiotherapy (CRT), radiotherapy (RT), active surveillance, or dose escalation with contact X-ray brachytherapy (CXB). Methods: This study included patients treated with TEMS for ERC between September 2012 and December 2022, with follow-up until December 2023. Patients with adverse histopathological features (extra-mural venous invasion, lympho-vascular invasion, R1 margins, tumour budding) were assigned to adjuvant treatments. Inverse probability of treatment weighting (IPTW) was applied to mitigate selection bias. Results: Of the 117 patients, 24 underwent TME, 17 received CRT, 25 received RT, 14 underwent active surveillance, and 37 patients received CXB boost along with CRT. The median follow-up was 60 months (IQR 52-73). During this time, 29 patients developed recurrence, and 15 died. The 5-year overall survival (OS) was 78.6%, and disease-free survival (DFS) was 70.9%. Compared to CXB, the mortality risk for CRT (HR = 0.81; 95% CI: 0.20-3.28; p = 0.77) and TME (HR = 3.68; 95% CI: 0.46-29.79; p = 0.22) was not significantly different. However, TME was associated with a significantly higher recurrence risk compared to CXB (HR = 7.57; 95% CI: 1.23-46.84; p = 0.029). Conclusions: An organ-preserving strategy with CRT or CRT combined with a CXB boost may offer comparable long-term outcomes and reduced recurrence risks for patients undergoing TEMS for ERC with poor prognostic features. Further research with larger cohorts is needed to validate these results.

Introduction: Type 2 diabetes is associated with excess hospital admissions and increased mortality. Structured diabetes self-management education (DSME) is recommended internationally and is associated with improved self-management skills, well-being and minor improvements in glycated haemoglobin (HBA1c), but does it reduce hospital admissions or prevent premature mortality? Our aim is to examine the relationship between DSME attendance, hospitalisations, mortality and 3-point major adverse cardiovascular events (MACE) in people with type 2 diabetes to inform future healthcare policy and diabetes care., Methods and Analysis: This protocol details a 10-year retrospective open cohort study of patients aged over 18 years old who have a clinical diagnosis of type 2 diabetes and were registered to an English GP practice from 29 March 2011 to 29 March 2021 and have attended DSME. Patients in the 'ever' cohort will be matched at baseline for age, sex, age at diagnosis and diabetes duration, to those who have 'never' attended DSME. Data will be identified via the UK Clinical Practice Research Datalink and linked to Hospital Episode Statistics Admitted Patient Care data, Office for National Statistics death registrations and patient Index of Multiple Deprivation deciles. Patients will be followed-up through serial cross-sections. Multiple imputation will be considered to manage covariates where data are >12-months from baseline or are not expected to be missing at random. Cox proportional hazard regression and time to event modelling adjusted a priori for cofounding during multivariate analysis will be used., Ethics and Dissemination: This study was approved by CPRD (24&#95;003744). Study findings will be disseminated through peer-reviewed publications and international conferences., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Standard bodyweights are an essential component of calculations that summarise many population-level measures in companion animals, including the defined daily doses for veterinary species (DDDVet) reporting antimicrobial usage. Standard species bodyweights may originate from data derived from clinical records, but current methods to obtain these values risk inaccuracy because they exclude measurements obtained from juvenile animals and consider only individuals that have achieved stable adult bodyweight. This study aimed to improve the accuracy of standard population level species bodyweights through the development of a prediction modelling approach to estimate point mean population bodyweight in dogs, cats, rabbits, and guinea pigs. Data were obtained from the VetCompass database and included bodyweight measurements from approximately three million dogs, two million cats, 220,000 rabbits and 62,000 guinea pigs across 1,800 veterinary practices in the United Kingdom. Initially, Loess models were used to identify the age at which juvenile animals transitioned from growth to stable adult bodyweight. Linear mixed effects models were developed to predict juvenile growth, calibrated such that predicted cessation of growth matched that observed in the Loess models. The prediction models were then used to adjust bodyweight measurements obtained from clinical records of juvenile patients, allowing historical measurements to be included for estimation of a point mean population bodyweight on a subsequent specified target date. Juvenile growth transitioned to stable adult bodyweight at approximately 14 months in dogs, and 13 months in cats, rabbits, and guinea pigs. Point mean whole-population bodyweights estimated on 31st December for each year 2014 - 2023 found that the mean bodyweight of cats, rabbits, and guinea pigs was approximately 4.2 kg, 2.3 kg, and 1.0 kg respectively and changed little over this time period. However, dogs showed a trend to lower mean bodyweight over time, with a mean value of 17.6 kg in 2014, reducing to 16.1 kg by 2023., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Becker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Radical surgery following neoadjuvant therapy is the standard of care for locally advanced rectal cancer. A contact x-ray brachytherapy (CXB) boost can alternatively be used to treat residual disease postneoadjuvant (chemo)radiation, especially in patients who are not suitable for or do not wish to have surgery. Its role has mostly been studied to date in low- to intermediate-risk patients. We have now evaluated the utility of CXB boost in high-risk rectal cancers after their tumors have been significantly downstaged by neoadjuvant (chemo)radiation., Materials and Methods: Oncological outcomes and treatment tolerability were evaluated in 328 patients based on rectal cancer treatment risk stratification: low-/intermediate-risk (cT1-3ab, N0-1, M0, no extramural venous invasion, mesorectal fascia involvement >1 mm) and high-risk (cT3cd-4/N2, M0, mesorectal fascia ≤1 mm, and/or extramural venous invasion positive)., Results: With a median follow-up of 33 (IQR, 15-54) months and a median age of 73 (IQR, 62-80) years, no significant differences were found between low/intermediate and high-risk groups in clinical complete response (78% vs. 73%, P = .32), local regrowth (16.6% vs. 22.4%, P = .41), nodal (1.8% vs. 5.8%, P = .051) or regional (1.3% vs. 2.9%, P = .33) relapse, or postradiation toxicities (P = .16). However, the high-risk group had a higher distant relapse rate (21.2% vs. 10.7%, P = .01), with no significant differences in 3-year organ preservation (80% vs. 87%, P = .25), 5-year disease-free survival (62% vs. 64%, P = .46), or overall survival (67% vs. 64%, P = .88). Longer treatment time, treatment gap >24 weeks between therapies, and administration of a higher than standard CXB dose were newly identified factors that negatively impacted outcomes., Conclusions: High-risk patients with rectal cancer treated with CXB boost had more distant relapses, but comparable locoregional tumor control, organ preservation, disease-free survival, and overall survival to lower risk patients, with acceptable toxicities. CXB boost is, therefore, a viable option for selected high-risk patients with rectal cancer. Timely reassessment, prompt referral, and CXB dose optimization are crucial for improving outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Cardiovascular risk prediction tools developed for the general population often underperform for individuals with RA, and their predictive accuracy are unclear for other inflammatory conditions that also have increased cardiovascular risk. We investigated the performance of QRISK-3, the Framingham Risk Score (FRS) and the Reynolds Risk Score (RRS) in RA, psoriatic disease (PsA and psoriasis) and AS. We considered OA as a non-inflammatory comparator., Methods: We utilized primary care records from the Clinical Practice Research Datalink (CPRD) Aurum database to identify individuals with each condition and calculated 10-year cardiovascular risk using each prediction tool. The discrimination and calibration of each tool was assessed for each disease., Results: The time-dependent area under the curve (AUC) for QRISK3 was 0.752 for RA (95% CI 0.734-0.777), 0.794 for AS (95% CI 0.764-0.812), 0.764 for PsA (95% CI 0.741-0.791), 0.815 for psoriasis (95% CI 0.789-0.835) and 0.698 for OA (95% CI 0.670-0.717), indicating reasonably good predictive performance. The AUCs for the FRS were similar, and slightly lower for the RRS. The FRS was reasonably well calibrated for each condition but underpredicted risk for patients with RA. The RRS tended to underpredict CVD risk, while QRISK3 overpredicted CVD risk, especially for the most high-risk individuals., Conclusion: CVD risk for individuals with RA, AS and psoriatic disease was generally less accurately predicted using each of the three CVD risk prediction tools than the reported accuracies in the original publications. Individuals with OA also had less accurate predictions, suggesting inflammation is not the sole reason for underperformance. Disease-specific risk prediction tools may be required., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Antimicrobial susceptibility testing is a key weapon against antimicrobial resistance. Diagnostic microbiology laboratories use one-size-fits-all testing approaches that are often imprecise, inefficient, and inequitable. Here, we report a personalised approach that adapts laboratory testing for urinary tract infection to maximise the number of appropriate treatment options for each patient. We develop and assess susceptibility prediction models for 12 antibiotics on real-world healthcare data using an individual-level simulation study. When combined with decision thresholds that prioritise selection of World Health Organisation Access category antibiotics (those least likely to induce antimicrobial resistance), the personalised approach delivers more susceptible results (results that encourage prescription of that antibiotic) per specimen for Access category antibiotics than a standard testing approach, without compromising provision of susceptible results overall. Here, we show that personalised antimicrobial susceptibility testing could help tackle antimicrobial resistance by safely providing more Access category antibiotic treatment options to clinicians managing urinary tract infection., Competing Interests: Competing interests: Alex Howard declares personal consulting work for Pfizer outside the submitted work, and a donation from Pfizer to the University of Liverpool for a public and professional engagement project outside the submitted work. Iain Buchan declares consulting fees via University of Liverpool from AstraZeneca outside the submitted work. William Hope holds or has recently held research grants with UKRI, EU (FP7, IMI-1, IMI-2), Wellcome, F2G, Spero Therapeutics, Antabio, Pfizer, Allecra, Bugworks, Phico Therapeutics, BioVersys, Global Antimicrobial Research and Development Partnership (GARDP). He is (or has recently been) a consultant for Appili Therapeutics, F2G, Spero Therapeutics, Pfizer, GSK, Phico Therapeutics, Pulmocide, and Mundipharma Research Ltd. He was a member of the Specialist Advisory Committee for GARDP (2020-2023), a member of the British Society for Antimicrobial Chemotherapy (BSAC) Breakpoint Committee (2020-2023), a member of Health Technology Appraisal (HTA) Prioritisation Committee for hospital care and was the Specialty National Co-lead for Infection for the National Institute of Health Research (NIHR) (2020-2024). The other authors declare no competing interests., (© 2024. The Author(s).)

Background and Purpose: Radical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery., Materials and Methods: This retrospective multi-centre study (2009-2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer., Results: With a median follow-up of 26(IQR:12-49) months, initial clinical Complete Response (cCR) was 82(70-93)% with rates of local regrowth 18(8-29)%, 3-year actuarial local control (LC) 84(75-95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48-78)% and 58(44-75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients., Conclusion: CXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery., 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., (© 2024 The Author(s).)

Prior research has suggested that GATA6 + pericardial macrophages may traffic to the myocardium to prevent interstitial fibrosis after myocardial infarction (MI), while subsequent literature claims that they do not. We demonstrate that GATA6 + pericardial macrophages are critical for preventing IL-33 induced pericarditis and attenuate trafficking of inflammatory monocytes and granulocytes to the pericardial cavity after MI. However, absence of GATA6 + macrophages did not affect myocardial inflammation due to MI or coxsackievirus-B3 induced myocarditis, or late-stage cardiac fibrosis and cardiac function post MI. GATA6 + macrophages are significantly less transcriptionally active following stimulation in vitro compared to bone marrow-derived macrophages and do not induce upregulation of inflammatory markers in fibroblasts. This suggests that GATA6 + pericardial macrophages attenuate inflammation through their interactions with surrounding cells. We therefore conclude that GATA6 + pericardial macrophages are critical in modulating pericardial inflammation, but do not play a significant role in controlling myocardial inflammation or fibrosis., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Purpose: A watch-and-wait approach is an alternative to surgery for rectal cancer patients who have achieved a clinical complete response (cCR) following neoadjuvant (chemo)radiotherapy. However, approximately 25-38% of patients experience subsequent local tumor re-growth that requires salvage surgery. We evaluated the effectiveness of contact X-ray brachytherapy (CXB) as an alternative method of salvage therapy for those patients who were either unfit for or refused surgery. Oncological outcomes, tolerability, and feasibility of subsequent surgery for local treatment failure following CXB were reported., Material and Methods: From 2009-2021, all patients treated with CXB as salvage therapy for local rectal cancer re-growth after watch-and-wait approach at our center were analyzed., Results: Contact X-ray brachytherapy as a salvage treatment (range, 90-110 Gy) was offered to 56 patients who experienced tumor re-growth following (chemo)radiation and watch-and-wait protocol. Median age was 76 (IQR = 66-83) years. Most patients (82%) had early-stage re-growth (ycT1/ycT2, ycN0), and 18% had more advanced stages (ycT3/ycT4, ycN0). After a median of 37-month follow-up (IQR = 19-53), 48% of patients who had early-stage re-growth achieved a sustained complete remission after CXB compared with 20% of those who had more advanced tumor stages. Disease-free and overall survivals for the whole cohort were 69% and 100% at 1-year, 51% and 82% at 3-year, and 51% and 65% at 5-years. CXB effectively controlled local re-growth-related symptoms. Mild post-CXB side effects occurred in 18% of cases. All (100%) eight patients who developed further local relapse, and 29% of those who had residual disease post-CXB salvage were successfully managed with subsequent surgery., Conclusions: Contact X-ray brachytherapy offers a new treatment option for patients in this situation whose other therapy options are not suitable for or refused initial surgery. Early local tumor re-growth responded best with minimal treatment-related toxicity and excellent symptom control. Disease-free and overall survival rates were acceptable, and delaying surgical salvage for local re-growth did not compromise patients' eventual long-term outcomes., Competing Interests: Approval of the Bioethics Committee was not required. The authors report no conflict of interest. Supplementary material is available on journal’s website., (Copyright © 2024 Termedia.)

Introduction: Various factors including body weight-associated treatment cost may influence the probability of dispensing antibiotics to dogs in first-opinion practice, but their effect on specific drug choice remains unclear., Methods: Multiple membership regression modeling was used to investigate the probability of dispensing 12 different antibiotics to dogs of different weights in the context of various disease presentations, using anonymized data obtained from electronic health records of 18 clinics between 2020 and 2022. Data from 14,259 dogs were analyzed., Results: Treatment choice varied significantly with animal weight. Higher body weight was associated with an increased likelihood of dispensing lower cost antimicrobials such as amoxicillin and trimethoprim sulfonamide, while use of higher cost antimicrobials such as cefovecin was strongly biased to smaller animals. However, these effects were limited when restricted treatment options were available for the target condition., Conclusion: This work demonstrates that anticipated financial costs may result in different treatment choices for canine patients depending on their body weight. Further work is needed to understand the impact of financial pressures on veterinarians' treatment choices, and the implications for the optimization of antimicrobial stewardship in first opinion practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Becker and Hughes.)

Objectives: To understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission risks, perceived risks and the feasibility of risk mitigations from experimental mass cultural events before coronavirus disease 2019 (COVID-19) restrictions were lifted., Design: Prospective, population-wide observational study., Setting: Four events (two nightclubs, an outdoor music festival and a business conference) open to Liverpool City Region UK residents, requiring a negative lateral flow test (LFT) within the 36 h before the event, but not requiring social distancing or face-coverings., Participants: A total of 12,256 individuals attending one or more events between 28 April and 2 May 2021., Main Outcome Measures: SARS-CoV-2 infections detected using audience self-swabbed (5-7 days post-event) polymerase chain reaction (PCR) tests, with viral genomic analysis of cases, plus linked National Health Service COVID-19 testing data. Audience experiences were gathered via questionnaires, focus groups and social media. Indoor CO 2 concentrations were monitored., Results: A total of 12 PCR-positive cases (likely 4 index, 8 primary or secondary), 10 from the nightclubs. Two further cases had positive LFTs but no PCR. A total of 11,896 (97.1%) participants with scanned tickets were matched to a negative pre-event LFT: 4972 (40.6%) returned a PCR within a week. CO 2 concentrations showed areas for improving ventilation at the nightclubs. Population infection rates were low, yet with a concurrent outbreak of >50 linked cases around a local swimming pool without equivalent risk mitigations. Audience anxiety was low and enjoyment high., Conclusions: We observed minor SARS-CoV-2 transmission and low perceived risks around events when prevalence was low and risk mitigations prominent. Partnership between audiences, event organisers and public health services, supported by information systems with real-time linked data, can improve health security for mass cultural events., Competing Interests: DeclarationsCompeting Interests: The City of Liverpool received a donation from Innova Medical Group Inc. towards the foundation of the Liverpool Pandemic Institute after the conduct of this study. None of that donation has supported the research reported here or any of the authors’ work to date. WJE was a member of the UK Events Research Programme Science Board. This paper was commisioned by Commissioned by the UK Department for Culture, Media and Sport.

Introduction: Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations., Methods: A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models., Results: A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17)., Conclusions: Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Gastro-esophageal reflux disease (GORD) has been associated with a greater risk of idiopathic pulmonary fibrosis (IPF) in observational studies, but results are limited by confounding. We used multivariable Mendelian randomization to examine their causal relationship, adjusting for BMI., Methods: We selected genetic instruments for GORD from genome-wide association studies of 80,265 cases and 305,011 controls. Genetic association data for IPF were obtained from 2668 cases and 8591 controls, and BMI from 694,649 individuals. We used the inverse-variance weighted method and a series of sensitivity analyses including weak instrument robust methods., Results: Although genetic liability to GORD increased IPF risk (OR 1.58; 95% CI 1.10-2.25), this result was attenuated to include the null after adjusting for BMI (OR 1.14; 95% CI 0.85-1.52)., Conclusion: Intervention for GORD alone is unlikely to reduce the risk of IPF, whereas reducing obesity may be a better approach., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 [The Author/The Authors]. Published by Elsevier B.V. All rights reserved.)

Background: Our study examines if SARS-CoV-2 infections varied by vaccination status, if an individual had previously tested positive and by neighbourhood socioeconomic deprivation across the Delta and Omicron epidemic waves of SARS-CoV-2., Methods: Population cohort study using electronic health records for 2.7 M residents in Cheshire and Merseyside, England (3rd June 2021 to 1st March 2022). Our outcome variable was registered positive test for SARS-CoV-2. Explanatory variables were vaccination status, previous registered positive test and neighbourhood socioeconomic deprivation. Cox regression models were used to analyse associations., Results: Originally higher SARS-CoV-2 rates in the most socioeconomically deprived neighbourhoods changed to being higher in the least deprived neighbourhoods from the 1st September 2021, and were inconsistent during the Omicron wave. Individuals who were fully vaccinated (two doses) were associated with fewer registered positive tests (e.g., individuals engaged in testing between 1st September and 27th November 2021-Hazards Ratio (HR) = 0.48, 95% Confidence Intervals (CIs) = 0.47-0.50. Individuals with a previous registered positive test were also less likely to have a registered positive test (e.g., individuals engaged in testing between 1st September and 27th November 2021-HR = 0.16, 95% CIs = 0.15-0.18. However, the Omicron period saw smaller effect sizes for both vaccination status and previous registered positive test., Conclusions: Changing patterns of SARS-CoV-2 infections during the Delta and Omicron waves reveals a dynamic pandemic that continues to affect diverse communities in sometimes unexpected ways., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Rectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol., Methods: Included studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted., Trial Registration: CRD42022277704., (© 2022. The Author(s).)

Background and Aims: The aMAP score is a model that predicts risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. Its performance in a 'real world' surveillance setting has not yet been ascertained., Patients and Methods: We had access to a cohort of 3473 individuals enrolled in a rigorously implemented and prospectively accrued surveillance programme (patients undergoing regular ultrasound and biomarker examination between 1998 and 2021). During this period 445 had HCC detected. Of these, 77.8% had early stage disease (within Milan criteria), permitting potentially curative therapy to be implemented in nearly 70% of cases. We applied the recently developed aMAP score to classify patients according to their initial aMAP score in to low, medium and high-risk groups as proposed in the original publication. The performance of the aMAP score was assessed according to the concordance-index and calibration (i.e. agreement between observed and predicted risk). Allowance was made for competing causes of death., Results: The aMAP score achieved an overall C-index of 0.81 (95% CI: 0.79-0.82) consistent with the initial report and was unaffected by allowance for competing causes of death. Sub-group analysis showed that the results did not change significantly according to gender, or aetiology. However, aMAP discrimination was greater for younger individuals (versus older individuals), and also for individuals without cirrhosis. The HCC incidence rate was 0.98, 7.05 and 29.1 events per 1000 person-years in the low-, moderate- and high-risk aMAP groups, respectively., Conclusions: The results from this 'real-world' cohort demonstrate that risk stratification is a realistic prospect and that identification of a subgroup of chronic liver disease patients who have a very low risk of HCC is feasible., (© 2022. The Author(s).)

Objective: Osteoarthritis (OA) is a progressive disease for which there is no disease modifying therapy. Vitamin K levels and vitamin K antagonism have been associated with risk and progression of OA which may have direct implications for clinical management, but these observational findings are susceptible to confounding. We aimed to estimate the causal association between vitamin K and OA risk using Mendelian randomisation (MR)., Methods: We used data from the largest genome-wide association study (GWAS) of OA to date (up to 826,690 individuals) to estimate the effect of genetically predicted vitamin K level (instrumented using four variants derived from a GWAS of 2,138 individuals) on risk of all OA types, knee, hip, spine, hand OA, and total joint replacement. We employed the inverse-variance weighted method for the primary analysis and, in a series of sensitivity analyses, adjusted for sub-genome wide significant instruments and tested for potential bias from pleiotropy., Results: We showed that genetically predicted vitamin K levels were not causally associated with risk of OA overall (OR 0.98 per unit increase in log-transformed vitamin K1; 95%CI 0.96-1.01), knee (OR 0.98; 0.92-1.03), hip (OR 0.97; 0.88-1.07), spine (OR 0.97; 0.90-1.04), hand OA (OR 0.97; 0.91-1.04) or joint replacement (OR 0.96; 0.89-1.04). Results were similar across all sensitivity analyses., Conclusion: We found little evidence of a causal association between genetically predicted vitamin K and OA risk. Larger genetic and interventional studies of vitamin K are required to confirm our findings., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Covid-19 test-to-release from quarantine policies affect many lives. The SMART Release pilot was the foundation of these policies and an element of the world's largest population cohort study of community-wide, SARS-CoV-2 rapid antigen testing. The objective of the study was to evaluate daily lateral flow testing (LFT) as an alternative to 10-14 days quarantine for key worker contacts of known Covid-19 (or SARS-CoV-2 infection) cases., Methods: Prospective cohort study incorporating quantitative and qualitative research methods to consider how serial LFT compares with PCR testing to detect SARS-CoV-2 infections and to understand experiences/compliance with testing and the viability of this quarantine harm-reduction strategy. Participants were residents of the Liverpool area who were key workers at participating fire, police, NHS and local government organisations in Liverpool, and who were identified as close contacts of cases between December 2020 and August 2021. Thematic qualitative analysis was used to evaluate stakeholder meetings., Findings: Compliance with the daily testing regime was good across the three main organisations in this study with 96·9%, 93·7% and 92·8% compliance for Merseyside Police, Merseyside Fire & Rescue Service and Alder Hey Children's Hospital respectively. Out of 1657 participants, 34 positive Covid-19 cases were identified and 3 undetected by the daily LFT regime. A total of 8291 workdays would have been lost to self-isolation but were prevented due to negative daily tests. Organisations reported that daily contact testing proved useful, flexible and well-tolerated initiative to sustain key worker services., Interpretation: Compliance with daily testing among key workers was high, helping sustain service continuity during periods of very high risk of staffing shortage. Services reported that the pilot was a "lifeline" and its successful delivery in Liverpool has been replicated elsewhere., Funding: This report is independent research commissioned by DHSC and part funded by DHSC and NIHR. Further funding was received from Liverpool City Council, the EPSRC and MRC., Competing Interests: IB reports consultancy fees from Astra Zeneca for work not related to this manuscript, and is a member of the UK Testing Initiatives Evaluation Board. IB received grants from the Department of Health and Social Care and from the National Institute for Health Research. DMH reports a small grant from the Psoriasis and Psoriatic Arthritis Alliance for work unrelated to this manuscript. DMH received grants from the Department for Health and Social Care, MRC and Halton Borough Council. MGF reports participation on advisory boards for UK DPFS, UK NC3Rs, and HRCI-HRC-JFS-2022 - Review Panel. This was unrelated to this work. MGF received grants from the Department for Health and Social Care and Halton Borough Council. All the other authors report no conflicts., (© 2022 The Authors.)

Background: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19., Methods: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy., Findings: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury., Interpretation: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2., Funding: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health., Competing Interests: Declaration of interests None exist., (Copyright © 2022. Published by Elsevier B.V.)

Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor used for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Clinical and operational barriers may exist that warrant bridging or switching from thrombopoietin receptor agonists (TPO-RAs), such as volatility or unpredictability of platelets, adverse events, and quality of life or patient preference. While fostamatinib demonstrated durable platelet responses, the safety and efficacy in combination, bridging, and/or switching with TPO-RAs is not well documented. The objective of this article is to provide guidance from real-world case studies for a safe and effective strategy for the transitioning of patients from TPO-RAs to fostamatinib, with some degree of overlap between the two agents. Currently, the evidence does not exist to guide the safe and effective use of combination therapy or transition between therapies in ITP. This case series highlights the importance to further understand the complexities of managing this disease, as well as successfully combining, bridging, and/or switching patients over to fostamatinib without the need for rescue therapy or increase in adverse events. The need for real-world evidence that guides providers on the safety and efficacy of short- and long-term combination therapy of fostamatinib and TPO-RAs is crucial. The rationale for combination therapy is to target different pathways, platelet destruction, and production without added toxicities. Additionally, gradual tapering off of TPO-RAs may provide a more favorable clinical outcome when switching to fostamatinib. The need for additional data is necessary to provide clinicians with guidance when managing patients with ITP., Competing Interests: Dr. Hughes, Dr. Toste, Mr. Nelson, and Ms. Escalon have participated on an advisory board for Rigel Pharmaceuticals. Mr. Shah has served on the speakers bureau for Rigel Pharmaceuticals., (© 2021 Harborside™.)

Proton pump inhibitors are widely used, but up to 70% of patients take them without an appropriate indication and face risk of adverse effects associated with long-term use., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.