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Aims and method The prevalence of delaying psychiatric care until the patient has received ‘medical clearance’, and the definitions and understanding of ‘medical clearance’ terminology by relevant clinicians, are largely unknown. In a service evaluation of adult liaison psychiatry services across England, we explore the prevalence, definitions and understanding of ‘medical clearance’ terminology in three parallel studies: (a) an analysis of trust policies, (b) a survey of liaison psychiatry services and (c) a survey of referring junior doctors. Content and thematic analyses were performed. Results ‘Medical clearance’ terminology was used in the majority of trust policies, reported as a referral criterion by many liaison psychiatry services and had been encountered by most referring doctors. ‘Medical clearance’ was identified as a common barrier to liaison psychiatry referral. Terms were inconsistently used and poorly defined. Clinical implications Many liaison psychiatry services seem not to comply with guidance promoting parallel assessment. This may affect parity of physical and mental healthcare provision.

Hibernomas are rare brown fat tumors that garnered attention in the literature with the increasing use of [18F] Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography ([18F] FDG PET/CT) for the staging workup and follow-up of solid malignancies. Despite being benign tumors, they exhibit high metabolic activity due to their thermogenic nature, leading to significant radiotracer uptake on functional imaging. This can pose a challenge in differentiating them from the malignant lesions, especially the fat-containing malignancies such as liposarcoma. Hibernomas are typically found in the thigh, shoulder, back, and neck. Here, we present a unique case of Hibernoma in a patient undergoing PET/CT for melanoma follow-up in an unusual perihepatic location. To the best of the authors’ knowledge, this represents the first reported case of a perihepatic hibernoma in the literature. The report also offers a literature review on hibernomas, including the influence of ambient temperature on their metabolism, diagnostic challenges, management strategies, and reports of hibernomas detected on functional imaging with a range of radiotracers. These observations could serve as a valuable clue in identifying hibernomas, potentially aiding in avoiding unnecessary biopsies or resections.

Southern Ocean phytoplankton form the base of the Antarctic food web, influencing higher trophic levels through biomass and community structure. We examined phytoplankton distribution and abundance in the Indian Sector of the Southern Ocean during austral summer as part a multidisciplinary ecosystem survey: Trends in Euphausiids off Mawson, Predators and Oceanography (TEMPO, 2021). Sampling covered six meridional transects from 55-80°E, and from 62°S or 63°S to the ice edge. To determine phytoplankton groups, CHEMTAX analysis was undertaken on pigments measured using HPLC. Diatoms were the dominant component of phytoplankton communities, explaining 56% of variation in chlorophyll a (Chl a), with haptophytes also being a major component. Prior to sampling the sea ice had retreated in a south-westerly direction, leading to shorter ice-free periods in the west (< 44 days, ≤65°E) compared to east (> 44 days, ≥70°E), inducing a strong seasonal effect. The east was nutrient limited, indicated by low-iron forms of haptophytes, and higher silicate:nitrate drawdown ratios (5.1 east vs 4.3 west), pheophytin a (phaeo) concentrations (30.0 vs 18.4 mg m-2) and phaeo:Chl a ratios (1.06 vs 0.53). Biological influences were evident at northern stations between 75-80°E, where krill “super-swarms” and feeding whales were observed. Here, diatoms were depleted from surface waters likely due to krill grazing, as indicated by high phaeo:Chl a ratios (> 0.75), and continued presence of haptophytes, associated with inefficient filtering or selective grazing by krill. Oceanographic influences included deeper mixed layers reducing diatom biomass, and a bloom to the north of the southern Antarctic Circumpolar Current Front in the western survey area thought to be sinking as waters flowed from west to east. Haptophytes were influenced by the Antarctic Slope Front with high-iron forms prevalent to the south only, showing limited iron transfer from coastal waters. Cryptophytes were associated with meltwater, and greens (chlorophytes + prasinophytes) were prevalent below the mixed layer. The interplay of seasonal, biological and oceanographic influences on phytoplankton populations during TEMPO had parallels with processes observed in the BROKE and BROKE-West voyages conducted 25 and 15 years earlier, respectively. Our research consolidates understanding of the krill ecosystem to ensure sustainable management in East Antarctic waters.

Circulation and water masses in the greater Prydz Bay region were surveyed in the austral summer 2021 (January-March) during the ‘Trends in Euphausiids off Mawson, Predators and Oceanography’ (TEMPO) experiment, and are described in this paper. The Southern Antarctic Circumpolar Current Front is found in the northern part of the survey area, generally near 63-64°S, whereas the Southern Boundary Front is located between 64 and 65.5°S. The westward flowing Antarctic Slope Front (ASF) is found in the southern part of the survey area near the continental slope on most transects. Highest concentrations of oxygen (> 300 µmol kg−1) are found in shelf waters at stations in Prydz Bay, south of 67°S along 75°E, whereas the lowest oxygen values are found in the Circumpolar Deep Water layer, with an average of roughly 215 µmol kg−1. North of the northern extension of the ASF, surface mixed layers are between 20 and 60 m deep. Mixed layers tend to deepen slightly in the northern part of the survey, generally increasing north of 64°S where the ocean has been ice-free the longest. We find evidence of upwelling of waters into the surface layers, based on temperature anomaly, particularly strong along 80°E. Enhanced variability of biogeochemical properties - nutrients, DIC, DO - in the AASW layer is driven by a combination of sea-ice and biological processes. Antarctic Bottom Water, defined as water with neutral density > 28.3 kg m-3, was sampled at all the offshore full-depth stations, with a colder/fresher variety along western transects and a warmer/saltier variety in the east. Newly formed Antarctic Bottom Water – the coldest, freshest, and most recently ventilated – is mostly found in the deep ocean along 65°E, in the base of the Daly Canyon.

In 2021, a Clinical Research Fellow (CRF) scheme was created to serve the North West Coast (NWC) region in line with the key health priorities set out by the Clinical Research Network. Five doctors in pre-specialist training were placed in NHS trust research departments across the NWC. The scheme aimed to provide early career research experience while also enhancing the provision of research across the region. The CRFs were involved in writing clinical trial grant applications and study protocols, with the scheme providing additional experience in leadership roles and time management. In addition, the CRF scheme has had a positive impact in adopted NHS trusts, which have seen their overall research capacity and capability improve, through increased flexibility and medical oversight. Research departments have benefited from increased financial income and improved national reputations. Overall, this real-world experience provided a vital ‘foot in the door’, which is essential for research-interested medics to advance in a future academic career. In the wider NWC region, the CRF scheme successfully delivered achievable and financially sustainable research. Innovative programmes such as this one should be seen as a viable option for research provision through the NHS, in the UK.

Background: Outbreaks, such as the COVID-19 pandemic in 2020, exacerbate barriers to accessing early childhood developmental care. Tele-assessment may serve as an innovative approach to developmental monitoring to overcome service delivery amidst challenging circumstances. It is vital to collect caregivers’ perspectives of this potential service delivery method to inform clinical decision making. Objectives: This study aimed to determine caregivers’ perspectives of interview-based early developmental tele-assessment in a South African context. Method: Thirty caregivers of children (aged birth – 36 months) completed a caregiver-report developmental assessment via a telecommunications platform, as well as an online questionnaire probing their perspectives on the tele-assessment. Results: Most participants (96.7%, n = 29 out of 30) rated their overall experience of the tele-assessment as positive; however, 53.8% (n = 14 out of 26 that answered the question) indicated that they would additionally still prefer in-person assessment. Conclusion: Tele-assessment appears to be a viable approach for caregivers to access developmental care during circumstances such as COVID-19. Contribution: This study provided valuable insight into a novel approach using interview-based early developmental tele-assessment and the perspectives of caregivers thereof.

Background The CaRi-Heart® device estimates risk of 8-year cardiac death, using a prognostic model, which includes perivascular fat attenuation index, atherosclerotic plaque burden and clinical risk factors. Objectives To provide an Early Value Assessment of the potential of CaRi-Heart Risk to be an effective and cost-effective adjunctive investigation for assessment of cardiac risk, in people with stable chest pain/suspected coronary artery disease, undergoing computed tomography coronary angiography. This assessment includes conceptual modelling which explores the structure and evidence about parameters required for model development, but not development of a full executable cost-effectiveness model. Data sources Twenty-four databases, including MEDLINE, MEDLINE In-Process and EMBASE, were searched from inception to October 2022. Methods Review methods followed published guidelines. Study quality was assessed using Prediction model Risk Of Bias ASsessment Tool. Results were summarised by research question: prognostic performance; prevalence of risk categories; clinical effects; costs of CaRi-Heart. Exploratory searches were conducted to inform conceptual cost-effectiveness modelling. Results The only included study indicated that CaRi-Heart Risk may be predictive of 8 years cardiac death. The hazard ratio, per unit increase in CaRi-Heart Risk, adjusted for smoking, hypercholesterolaemia, hypertension, diabetes mellitus, Duke index, presence of high-risk plaque features and epicardial adipose tissue volume, was 1.04 (95% confidence interval 1.03 to 1.06) in the model validation cohort. Based on Prediction model Risk Of Bias ASsessment Tool, this study was rated as having high risk of bias and high concerns regarding its applicability to the decision problem specified for this Early Value Assessment. We did not identify any studies that reported information about the clinical effects or costs of using CaRi-Heart to assess cardiac risk. Exploratory searches, conducted to inform the conceptual cost-effectiveness modelling, indicated that there is a deficiency with respect to evidence about the effects of changing existing treatments or introducing new treatments, based on assessment of cardiac risk (by any method), or on measures of vascular inflammation (e.g. fat attenuation index). A de novo conceptual decision-analytic model that could be used to inform an early assessment of the cost effectiveness of CaRi-Heart is described. A combination of a short-term diagnostic model component and a long-term model component that evaluates the downstream consequences is anticipated to capture the diagnosis and the progression of coronary artery disease. Limitations The rapid review methods and pragmatic additional searches used to inform this Early Value Assessment mean that, although areas of potential uncertainty have been described, we cannot definitively state where there are evidence gaps. Conclusions The evidence about the clinical utility of CaRi-Heart Risk is underdeveloped and has considerable limitations, both in terms of risk of bias and applicability to United Kingdom clinical practice. There is some evidence that CaRi-Heart Risk may be predictive of 8-year risk of cardiac death, for patients undergoing computed tomography coronary angiography for suspected coronary artery disease. However, whether and to what extent CaRi-Heart represents an improvement relative to current standard of care remains uncertain. The evaluation of the CaRi-Heart device is ongoing and currently available data are insufficient to fully inform the cost-effectiveness modelling. Future work A large (n = 15,000) ongoing study, NCT05169333, the Oxford risk factors and non-invasive imaging study, with an estimated completion date of February 2030, may address some of the uncertainties identified in this Early Value Assessment. Study registration This study is registered as PROSPERO CRD42022366496. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135672) and is published in full in Health Technology Assessment; Vol. 28, No. 31. See the NIHR Funding and Awards website for further award information. Plain language summary Coronary artery disease affects around 2.3 million people in the United Kingdom. It is caused by a build-up of fatty plaques on the walls of the blood vessels that supply the heart muscle. This can reduce the flow of blood to the heart and result in people experiencing chest pain (angina), especially when they exercise. Over time, the fatty plaques can grow and block more or all of the artery and blood clots can also form, causing blockage. A heart attack happens when the supply of blood to the heart muscle is blocked. People who have episodes of chest pain, whose doctors think that they may have coronary artery disease, can have a type of imaging (computed tomography coronary angiography) which shows whether there is any narrowing of their coronary arteries. When offering treatment, specialist heart doctors are likely to consider a person’s symptoms and other risk factors (such as family history of heart disease, diabetes and smoking history), as well as how much narrowing of the arteries has happened. CaRi-Heart® is a computer programme that uses information about inflammation in a person’s coronary arteries, together with recognised risk factors, such as age, sex, smoking, high cholesterol levels, high blood pressure and diabetes, to estimate an individual’s risk of dying from a heart attack in the next 8 years. There is evidence that CaRi-Heart® is better at estimating this risk than using information recognised risk factors alone. However, there is a lack of information about how treatment could change as a result of using CaRi-Heart® and whether any changes would improve outcomes for patients. There is also a lack of information about how much CaRi-Heart® would cost the National Health Service. Scientific summary Background Coronary artery disease (CAD) and acute myocardial infarction (AMI) are a significant health burden in the UK, with ischaemic heart disease being the leading cause of death in males. Guidelines from the National Institute for Health and Care Excellence (NICE) and the European Society of Cardiology (ESC) recommend computed tomography coronary angiography (CTCA) for the investigation of CAD in people with stable chest pain. CTCA provides a visualisation of the coronary arteries, which is used to identify plaques, to quantify the extent of any stenosis of the coronary arteries and the length and location of the affected area, and to quantify the extent of coronary artery calcification. Information provided by CTCA is structural rather than functional. Acute coronary events can arise from unstable, but anatomically non-significant, atherosclerotic plaques. The vascular inflammatory response is a modulator of atherogenesis and can be a factor in plaque rupture, leading to acute coronary events. CaRi-Heart® is a cloud-based CE-marked medical device (Caristo Diagnostics Ltd, Oxford, UK) that analyses images from CTCA scans to provide information about inflammation in the coronary arteries. The CaRi-Heart device uses this information to generate a perivascular fat attenuation index (FAI) score. It then estimates individual patient risk of 8-year cardiac death with a prognostic model, which includes the perivascular FAI score, as well as atherosclerotic plaque burden and clinical risk factors. This Early Value Assessment (EVA) considers whether CaRi-Heart Risk has potential to provide an effective, safe and cost-effective adjunctive investigation for assessment of cardiac risk, in people with stable chest pain/suspected CAD, who are undergoing CTCA. This assessment does not include the development of an executable cost-effectiveness model but does include conceptual modelling which explores the structure and evidence about parameters required for model development. Objectives A series of research questions were defined that could inform both a full assessment of the clinical and cost effectiveness of using CaRi-Heart, as an adjunctive investigation for assessment of cardiac risk, in people with stable chest pain/suspected CAD, who are undergoing CTCA and consideration of the potential of this technology to be cost-effective: What is the prognostic performance of CaRi-Heart, in people with stable chest pain, who are undergoing CTCA, where: the dependent variable is cardiac death? the dependent variable is a major adverse cardiovascular event (MACE)? What is the prevalence of ‘low’, ‘medium’ and ‘high’ CaRi-Heart Risk in people with no evidence of CAD, people with evidence of non-obstructive CAD and people with evidence of obstructive CAD, based on currently available CTCA imaging? What are the clinical effects of using CaRi-Heart to assess cardiac risk? How does CaRi-Heart Risk affect treatment decisions and patient adherence in people with no evidence of CAD, people with evidence of non-obstructive CAD and people with evidence of obstructive CAD, based on currently available CTCA imaging? What are the clinical effects of any changes to treatment, based on CaRi-Heart Risk, in people with no evidence of CAD, people with evidence of non-obstructive CAD and people with evidence of obstructive CAD, based on currently available CTCA imaging? What are the costs, from a UK NHS and Personal Social Services (PSS) perspective, using CaRi-Heart, as an adjunctive investigation for assessment of cardiac risk, in people with stable chest pain, who are undergoing CTCA? How might a conceptual model be specified in terms of structure and evidence required for parameterisation in order to estimate the cost-effectiveness of CaRi-Heart in people with stable chest pain, who are undergoing CTCA? Methods Questions 1–4 were addressed using a rapid review process. Twenty-four databases were searched from inception to October 2022, using a variety of databases including MEDLINE, EMBASE, Cochrane, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Kleijnen Systematic Reviews Ltd (KSR) Evidence and Epistemonikos. One reviewer screened titles and abstracts of all reports identified by the searches, and a minimum of 20% were independently screened by a second reviewer. Full copies of all studies deemed potentially relevant, by either reviewer, were obtained and both reviewers independently assessed these for inclusion; any disagreements were resolved by consensus or discussion with a third reviewer. Data were extracted by one reviewer and checked by a second reviewer; any disagreements were resolved by consensus or discussion with a third reviewer. Study quality was assessed using appropriate risk-of-bias tools. Results were summarised by research question: prognostic performance; prevalence of risk categories; clinical effects; costs of CaRi-Heart. In addition to the rapid review, evidence that might be required to inform parameterisation of a future cost-effectiveness model was explored, as part of the conceptual modelling process, using a pragmatic, iterative searching approach; model parameterisation questions, other than costs, were not included in the rapid review. Results Rapid review The rapid review identified one relevant model development and validation study, which included a total of 3912 patients who were undergoing clinically indicated CTCA for the evaluation of stable coronary disease. The training/development (USA) cohort comprised 2040 patients, with a median (range) follow-up duration of 53.8 (4–105) months; a total of 85 deaths were reported during follow-up, of which 48 were cardiac. The validation (Germany) cohort comprised 1872 patients, with a median (range) follow-up duration of 72 (51–109) months; there were a total of 114 deaths during follow-up, of which 26 were confirmed cardiac deaths and 16 were deaths of unknown cause. Based on Prediction model Risk Of Bias ASsessment Tool (PROBAST), this study was rated as having high risk of bias and high concerns regarding its applicability to the decision problem specified for this EVA. Importantly, there has been no external validation of the CaRi-Heart Risk model, as the reported validation data set was used in a previous study to develop methods and thresholds for the main imaging predictors (FAI scores). With respect to applicability, the CaRi-Heart study evaluated CaRi-Heart Risk for the prediction of 8-year cardiac death; it did not consider prediction of cardiac risk, as specified in the scope for this EVA (i.e. including risk of non-fatal adverse cardiovascular events). In addition, it is unclear whether the clinical comparator model can be considered representative of standard of care in the UK NHS. The included study provided information relevant to research question 1: ‘What is the prognostic performance of CaRi-Heart, in people with stable chest pain, who are undergoing CTCA where: (1) the dependent variable is cardiac death? (2) the dependent variable is MACE?’ The hazard ratio (HR) for 8-year cardiac death, per unit increase in CaRi-Heart Risk, adjusted for ‘traditional risk factors’ (smoking, hypercholesterolaemia, hypertension, diabetes mellitus, Duke index, presence of high-risk plaque features and epicardial adipose tissue volume), was 1.05 [95% confidence interval (CI) 1.03 to 1.06] in the training/development cohort and 1.04 (95% CI 1.03 to 1.06) in the validation cohort. With respect to the subgroups of clinical interest, the predictive value of the CaRi-Heart Risk model was consistent across patients with and without obstructive CAD. In addition, the results of the included study indicated that the CaRi-Heart Risk model showed improved risk discrimination, when compared to a baseline clinical risk model, which included age, sex, hypertension, hypercholesterolaemia, diabetes mellitus and smoking (Δ c-statistic 0.149, p 10%) CaRi-Heart Risk scores, estimated from this study, was 3060/3912 (78.2%), 423/3912 (10.8%) and 429/3912 (11.0%), respectively. No studies were identified which addressed research question 3 (‘What are the clinical effects of using CaRi-Heart to assess cardiac risk?) or research question 4 (‘What are the costs, from a UK NHS and PSS perspective, using CaRi-Heart®, as an adjunctive investigation for assessment of cardiac risk, in people with stable chest pain, who are undergoing CTCA?’). Exploratory searches to inform model parameterisation Additional exploratory searches were conducted to inform the conceptual cost-effectiveness modelling, focusing on changes to treatment that might be made based on CaRi-Heart Risk and potential alternative technologies to CaRi-Heart. The results of these searches indicated that there is a deficiency with respect to evidence about the effects of changing existing treatments or introducing new treatments, based on assessment of cardiac risk (by any method), or on measures of vascular inflammation, such as perivascular FAI. However, the evidence is broadly supportive of a positive relationship between FAI and risk of adverse coronary events and hence of the future inclusion of FAI as an alternative technology (in evaluations of the CaRi-Heart device) should a method of measurement become commercially available in the UK NHS. The evidence also supports the efficacy of colchicine for secondary prevention of adverse cardiac events in unselected patients with CAD but does not provide unequivocal evidence about the mechanism by which this effect is mediated. Importantly, for the aims of this EVA, the evidence identified does not provide any indication of the efficacy of targeting colchicine treatment using CaRi-Heart Risk or separate measures of coronary inflammation, such as FAI. It should also be noted that colchicine is not currently recommended by NICE, or licensed in the UK, for this indication. Finally, the evidence suggests some uncertainty about whether and to what extent the efficacy of statins, for the secondary prevention of MACE in people with CAD, may vary with baseline risk assessed using currently available methods. In addition, there is currently no information about the effects of introducing statin treatment or changing the dose of existing statin treatment, based on CaRi-Heart Risk or on any assessment of coronary artery inflammation. Conceptual modelling A de novo conceptual decision-analytic model that could be used to inform an early assessment of the cost effectiveness of CaRi-Heart has been described. A combination of a short-term diagnostic model component and a long-term model component that evaluated the downstream consequences is anticipated to capture the diagnosis and the progression of CAD, respectively. It is expected that for the CaRi-Heart strategy, the initial diagnostic groups based on CTCA only would be, in turn, further split by the CaRi-Heart information into groups of low, medium or high CaRi-Heart Risk. If other competing alternatives are identified, those could be added to the model, if there is sufficient available evidence. Conclusions The rapid review methods and pragmatic approach to additional exploratory searches used to inform this EVA mean that, although areas of potential uncertainty have been described, our findings cannot be used to definitively state where there are evidence gaps. The evidence about the clinical utility of CaRi-Heart Risk is, as yet, sparse and is subject to considerable limitations, both in terms of risk of bias and applicability to UK clinical practice. There is some evidence to indicate that CaRi-Heart Risk may be predictive of an individual patient’s 8-year risk of cardiac death, for patients undergoing CTCA for suspected CAD. However, whether and to what extent CaRi-Heart represents an improvement relative to current standard of care remains unclear. Currently available data are insufficient to fully inform cost-effectiveness modelling. A large (n = 15,000) ongoing study, NCT05169333, the Oxford risk factors and non-invasive imaging (ORFAN) study, with an estimated completion date of February 2030, may address some of the uncertainties identified in this EVA. Suggested research priorities External validation of the CaRi-Heart Risk model should be considered a high priority. The external validation process could also be used to address some of the applicability concerns, for example, the ability of CaRi-Heart Risk to predict non-fatal adverse cardiovascular events (in addition to cardiac death) could be considered. It remains unclear whether and to what extent CaRi-Heart represents an improvement relative to current standard of care; this is largely because the definition of standard of care and hence the applicability of the comparator used in the CaRi-Heart study are uncertain. If a consensus could be reached, among clinical experts, as to what should constitute standard of care, then the prognostic performance of CaRi-Heart Risk could be compared to this standard. There is currently a lack of information about the costs, from a UK NHS and PSS perspective, using CaRi-Heart, as an adjunctive investigation for assessment of cardiac risk, in people with stable chest pain, who are undergoing CTCA. The company have indicated that the ORFAN study will collect data on costs to the NHS of adding CaRi-Heart to CTCA, including cardiologists’ time in training to interpret CaRi-Heart analyses, and the implementation costs per CTCA (if any) added to the price of a CaRi-Heart analysis to estimate the total cost per CTCA of introducing CaRi-Heart into the NHS. There is also a lack of information about the clinical effects of any changes to treatment/management that may be made as a result of adding assessment using CaRi-Heart Risk to current standard of care, in patients undergoing CTCA for suspected CAD. The optimum study design would be a randomised controlled trial (RCT) or cluster RCT, where patients or study centres are randomised to receive CTCA with or without the addition of CaRi-Heart Risk assessment, and information about changes to treatment/management and long-term clinical effects is collected. Observational study designs, including ‘before and after’ implementation studies or using matching techniques to provide a control, could provide an alternative approach. Acknowledging that the collection of data about the long-term clinical effects of using CaRi-Heart Risk will take a number of years, alternative, pragmatic approaches to populating this component of a full cost-effectiveness model may be considered useful. Such approaches could include estimation of the potential effects of treatment changes based on risk-stratified effects of treatment (e.g. statins), where risk stratification has been based on methods other than CaRi-Heart Risk and/or estimation of the potential effects of introducing new treatments (e.g. colchicine) where the ‘target condition’ (coronary inflammation) has been assessed by methods other than CaRi-Heart Risk (e.g. FAI alone). Study registration This study is registered as PROSPERO CRD42022366496. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135672) and is published in full in Health Technology Assessment; Vol. 28, No. 31. See the NIHR Funding and Awards website for further award information.

Background: Stroma AReactive Invasion Front Areas (SARIFA) is a novel prognostic histopathologic biomarker measured at the invasive front in haematoxylin & eosin (H&E) stained colon and gastric cancer resection specimens. The aim of the current study was to validate the prognostic relevance of SARIFA-status in colorectal cancer (CRC) patients and investigate its association with the luminal proportion of tumour (PoT). Methods: We established the SARIFA-status in 164 CRC resection specimens. The relationship between SARIFA-status, clinicopathological characteristics, recurrence-free survival (RFS), cancer-specific survival (CSS), and PoT was investigated. Results: SARIFA-status was positive in 22.6% of all CRCs. SARIFA-positivity was related to higher pT, pN, pTNM stage and high grade of differentiation. SARIFA-positivity was associated with shorter RFS independent of known prognostic factors analysing all CRCs (RFS: hazard ratio (HR) 2.6, p = 0.032, CSS: HR 2.4, p = 0.05) and shorter RFS and CSS analysing only rectal cancers. SARIFA-positivity, which was measured at the invasive front, was associated with PoT-low (p = 0.009), e.g., higher stroma content, and lower vessel density (p = 0.0059) measured at the luminal tumour surface. Conclusion: Here, we validated the relationship between SARIFA-status and prognosis in CRC patients and provided first evidence for a potential prognostic relevance in the subgroup of rectal cancer patients. Interestingly, CRCs with different SARIFA-status also showed histological differences measurable at the luminal tumour surface. Further studies to better understand the relationship between high luminal intratumoural stroma content and absence of a stroma reaction at the invasive front (SARIFA-positivity) are warranted and may inform future treatment decisions in CRC patients.

Poweshiek skipperling (Oarisma poweshiek Parker, 1870) populations have declined precipitously in the past few decades, and their global range is now restricted to two isolated regions, one of which is the managed Manitoba tall grass prairie in Canada. In this paper, we used a decade of survey data from 2010 to 2019 to understand how habitat features, management practices, and extreme weather impact Poweshiek skipperling abundance in Manitoba. The strongest predictor of abundance was the density of black-eyed Susans (Rudbeckia hirta L.), a primary nectar plant for adults. Poweshiek skipperling abundance also had a negative relationship with both the number of years since a burn occurred and the number of years since grazing occurred. Cumulative precipitation during their active period (May–June) had a negative relationship with skipperling abundance, whereas warm early springs and cool temperatures during the active period had positive relationships. These results suggest that management actions that maintain tall grass prairie habitat in an early successional stage (burning and grazing) and maintain important nectar sources benefit this population. In contrast, extreme weather events had varying effects on Poweshiek skipperling abundance. Results from this study inform ongoing management practices in the Manitoba tall grass prairie to support this endangered population.

Abstract Background Anthropogenic habitat change is occurring rapidly, and organisms can respond through within-generation responses that improve the match between their phenotype and the novel conditions they encounter. But, plastic responses can be adaptive or maladaptive and are most likely to be adaptive only when contemporary conditions reasonably mimic something experienced historically to which a response has already evolved. Noise pollution is a ubiquitous anthropogenic stressor that accompanies expanding urbanization. We tested whether the amplitude of traffic noise influences a suite of fitness-related traits (e.g. survival, life history, reproductive investment, immunity) and whether that depends on the life stage at which the noise is experienced (juvenile or adult). Our treatments mimic the conditions experienced by animals living in urban roadside environments with variable vehicle types, but continuous movement of traffic. We used the Pacific field cricket, an acoustically communicating insect that was previously shown to experience some negative behavioral and life history responses to very loud, variable traffic noise, as a model system. Results After exposing crickets to one of four traffic noise levels (silence, 50dBA, 60dBA, and 70dBA which are commonly experienced in their natural environment) during development, at adulthood, or both, we measured a comprehensive suite of fifteen fitness-related traits. We found that survival to adulthood was lower under some noise treatments than under silence, and that the number of live offspring hatched depended on the interaction between a female’s juvenile and adult exposure to traffic noise. Both of these suggest that our noise treatments were indeed a stressor. However, we found no evidence of negative or positive fitness effects of noise on the other thirteen measured traits. Conclusions Our results suggest that, in contrast to previous work with loud, variable traffic noise, when noise exposure is relatively constant, plasticity may be sufficient to buffer many negative fitness effects and/or animals may be able to habituate to these conditions, regardless of amplitude. Our work highlights the importance of understanding how the particular characteristics of noise experienced by animals influence their biological responses and provides insight into how commensal animals thrive in human-dominated habitats.

Background: While it has been posited that young people with language needs may be viewed more negatively (e.g., as more rude, less cooperative) than those without language needs, the impact of knowing about a person's language needs on others' perceptions has yet to experimentally tested. Aims: To examine whether the presence of a developmental language disorder (DLD) diagnosis in a defendant's information would affect mock juror ratings of guilt, sentence length, credibility and blameworthiness. Methods & Procedures: A total of 143 jury eligible participants read a vignette of a non-violent crime. Half of the participants (N = 73) were told the defendant has a diagnosis of DLD, while half (N = 70) were not told. Outcomes & Results: Preregistered analyses found that DLD information affected ratings of credibility and blameworthiness, though not judgements of guilt or sentence length. Unregistered content analyses were applied to the justifications participants gave for their ratings: these suggested that participants who did not have the DLD information judged the defendant more on his personality and attitude, and drew more links to his (perceived) background, while participants who received the DLD information condition made more reference to him having cognitive problems. Conclusions & Implications: Unlike in previous studies of the impact of autism information, information about a defendant's DLD did not affect mock jurors' likelihood of finding them guilty, or lead participants to give longer sentences. However, our findings suggest knowing a person has DLD does affect others' perceptions of credibility and blameworthiness.

Purpose: This study aims to examine the following across a six-month period in post-graduate research (PGR) students: mental health and well-being; the effect of academic pressures on depression, anxiety and well-being; and the extent to which psychological resilience buffered against academic pressures. Design/methodology/approach: This was a longitudinal questionnaire study with predictor variables of six types of academic pressure, outcome variables of depression, anxiety and well-being, and a moderator of resilience. Findings: Well-being significantly worsened across the six-month timeframe, but levels of depression and anxiety remained relatively stable. Negative perceptions of academic challenges at baseline significantly predicted anxiety, but not depression or well-being, six months later. Negative appraisals of relationships with supervisors, other university staff and work peers were not predictors of anxiety. Social support resilience which was present at baseline buffered the relationship between perceived academic challenges and anxiety. Practical implications: Higher education institutions have a duty of care towards PGR students, many of whom struggle with the escalating interactions between mental health problems and academic pressures. Actively nurturing psychological resilience related to social support is key at the level of individual students and the PGR community but more broadly at an institutional level. Originality/value: To the best of the authors' knowledge, this is the first study to examine the effects of negative perceptions of multiple facets of academic life on depression, anxiety and well-being longitudinally. Additionally, it is the first study to investigate, and demonstrate, the extent to which psychological resilience can lessen the relationship between academic challenges and anxiety over time.

Background The rapid global emergence of the COVID-19 pandemic in early 2020 created urgent demand for leading indicators to track the spread of the virus and assess the consequences of public health measures designed to limit transmission. Public transit mobility, which has been shown to be responsive to previous societal disruptions such as disease outbreaks and terrorist attacks, emerged as an early candidate. Methods We conducted a longitudinal ecological study of the association between public transit mobility reductions and COVID-19 transmission using publicly available data from a public transit app in 40 global cities from March 16 to April 12, 2020. Multilevel linear regression models were used to estimate the association between COVID-19 transmission and the value of the mobility index 2 weeks prior using two different outcome measures: weekly case ratio and effective reproduction number. Results Over the course of March 2020, median public transit mobility, measured by the volume of trips planned in the app, dropped from 100% (first quartile (Q1)–third quartile (Q3) = 94–108%) of typical usage to 10% (Q1–Q3 = 6–15%). Mobility was strongly associated with COVID-19 transmission 2 weeks later: a 10% decline in mobility was associated with a 12.3% decrease in the weekly case ratio (exp(β) = 0.877; 95% confidence interval (CI): [0.859–0.896]) and a decrease in the effective reproduction number (β = −0.058; 95% CI: [−0.068 to −0.048]). The mobility-only models explained nearly 60% of variance in the data for both outcomes. The adjustment for epidemic timing attenuated the associations between mobility and subsequent COVID-19 transmission but only slightly increased the variance explained by the models. Discussion Our analysis demonstrated the value of public transit mobility as a leading indicator of COVID-19 transmission during the first wave of the pandemic in 40 global cities, at a time when few such indicators were available. Factors such as persistently depressed demand for public transit since the onset of the pandemic limit the ongoing utility of a mobility index based on public transit usage. This study illustrates an innovative use of “big data” from industry to inform the response to a global pandemic, providing support for future collaborations aimed at important public health challenges.

A long-term horticultural experiment was conducted at two geographically distinct sites in southern Missouri in 2011–15 to study the response of American elderberry [Sambucus nigra (L.) subsp. canadensis (L.) Bolli] to various soil nitrogen (N) fertilizer levels. Three commercially available elderberry cultivars (‘Adams II’, ‘Bob Gordon’, and ‘Wyldewood’) were used. The three cultivars were each assigned to 16 of 48 four-plant plots in a completely randomized manner at each site. Four replications of four N fertilizer treatments (0, 56, 112, 169 kg⋅ha−1 N) were randomly assigned to each cultivar’s plots and applied for 4 years (2012–15). Fruit yields, plant growth, phenology, and pest incidence were determined each year. Fruit quality was assessed by analyzing basic juice characteristics as well as organic acids, carbohydrates, anthocyanins, and polyphenols from 2012–14 samples. Leaf tissue analysis determined the plants’ mineral contents in 2012–14. Most factors evaluated were significantly affected by site, year, and cultivar, whereas the effects of N fertilizer treatment were less definitive. Fruit yields and plant growth increased with increasing N levels. For example, plants fertilized with 0, 56, 112, and 169 kg⋅ha−1 N produced 123, 137, 155, and 161 fruiting cymes per plot (5.8 m2), respectively. The eriophyid mite incidence was higher on fertilized plants, but other pests were not influenced by the N treatment. Basic fruit juice characteristics (soluble solids, pH, titratable acidity, polyphenols) were not influenced by the N treatment, whereas total anthocyanins were statistically higher in unfertilized plants. Levels of organic acids and carbohydrates in juice varied statistically among N treatments, but patterns were difficult to discern. Leaf N concentrations were correlated with N fertilizer levels—2.75% N with the highest fertilizer level compared with 2.55% N in unfertilized plants. Leaf levels of most other macronutrients varied, but consistent patterns did not emerge, and none of the micronutrients was different among N treatments. Although elderberry plants responded positively to increased N fertilizer levels in terms of plant growth and fruit yield, genetics (cultivar) and environment (site, year) were more influential on most other experimental factors evaluated.

Abstract Despite a gendered approach being increasingly applied across global health challenges, this has been a notable oversight in antimicrobial resistance (AMR) research. Failing to consider the complexity of human behaviours and roles in healthcare, animal production, and environmental settings compromises programmatic effectiveness and sustainability, while risking entrenching or widening existing social disparities. Research demonstrates how gender norms influence health-related behaviours across various sectors, from accessing healthcare to livestock rearing, with strong implications for antimicrobial stewardship and zoonotic disease transmission. The sparse literature connecting and investigating gender, equity and AMR – especially in a One Health context – hampers our ability to comprehensively address this global issue. The responsibility is however shared. This commentary advocates for funders to propel the inclusion of gender and equity-focused perspectives in AMR research and to set expectations in research landscapes, thus fostering a more equitable global health landscape and strengthening strategies against AMR. We outline our rationale and recommendations for other funders to support an ecosystem in AMR that supports gender and equity as a common aspect of AMR research and not an exception. One Health impact statement While AMR is increasingly recognised as a One Health challenge encompassing humans, animals, plants and the environment, sector-specific and cross-sectoral solutions needed to address AMR too often lack the multidisciplinary approach needed for a holistic response to this challenge. To date, AMR research has been largely biomedical, with limited social investigation including on gender and its interplay with factors that drive AMR in different settings such as healthcare, community or farm settings. Intentionally integrating gender analysis that informs AMR research design and implementation across sectors, including with supportive research funding opportunities, will help build the evidence base on how research projects and public programs should integrate and address gender disparities in AMR across the One Health spectrum. This is needed to ensure contextually relevant gender-informed solutions with sustainable impact.

Background The indication for this assessment is the use of the KardiaMobile six-lead electrocardiogram device for the assessment of QT interval-based cardiac risk in service users prior to the initiation of, or for the monitoring of, antipsychotic medications, which are associated with an established risk of QT interval prolongation. Objectives To provide an early value assessment of whether KardiaMobile six-lead has the potential to provide an effective and safe alternative to 12-lead electrocardiogram for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications. Review methods Twenty-seven databases were searched to April/May 2022. Review methods followed published guidelines. Where appropriate, study quality was assessed using appropriate risk of bias tools. Results were summarised by research question; accuracy/technical performance; clinical effects (on cardiac and psychiatric outcomes); service user acceptability/satisfaction; costs of KardiaMobile six-lead. Results We did not identify any studies which provided information about the diagnostic accuracy of KardiaMobile six-lead, for the detection of corrected QT-interval prolongation, in any population. All studies which reported information about agreement between QT interval measurements (corrected and/or uncorrected) with KardiaMobile six-lead versus 12-lead electrocardiogram were conducted in non-psychiatric populations, used cardiologists and/or multiple readers to interpret electrocardiograms. Where reported or calculable, the mean difference in corrected QT interval between devices (12-lead electrocardiogram vs. KardiaMobile six-lead) was generally small (≤ 10 ms) and corrected QT interval measured using KardiaMobile six-lead was consistently lower than that measured using 12-lead electrocardiogram. All information about the use of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication, was taken from retrospective surveys of staff and service users who had chosen to use KardiaMobile six-lead during pilots, described in two unpublished project reports. It is important to note that both these project reports relate to pilot studies which were not intended to be used in wider evaluations of KardiaMobile six-lead for use in the NHS. Both reports included survey results which indicated that the use of KardiaMobile six-lead may be associated with reductions in the time taken to complete an electrocardiogram and costs, relative to 12-lead electrocardiogram, and that KardiaMobile six-lead was preferred over 12-lead electrocardiogram by almost all responding staff and service users. Limitations There was a lack of published evidence about the efficacy of KardiaMobile six-lead for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications. Conclusions There is insufficient evidence to support a full diagnostic assessment evaluating the clinical and cost effectiveness of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication. The evidence to inform the aims of this early value assessment (i.e. to assess whether the device has the potential to be clinically effective and cost-effective) was also limited. This report includes a comprehensive list of research recommendations, both to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. Study registration This study is registered as PROSPERO CRD42022336695. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135520) and is published in full in Health Technology Assessment; Vol. 28, No. 19. See the NIHR Funding and Awards website for further award information. Plain language summary Some medicines used for people with certain mental health problems can increase the risk of developing serious heart conditions. Although these heart conditions are rare, it is generally recommended that people have an electrocardiogram examination before starting to take these medicines. People who need to continue these medications over a period of time may need additional electrocardiograms every so often, to check for any heart problems that have developed recently. KardiaMobile six-lead (or 6-lead) is a portable electrocardiogram that may offer a less intrusive way to take electrocardiogram measurements. This is because less undressing is needed as the electrodes are only applied to fingers of the left and right hand and the left ankle or knee and the cold gel is not needed. Testing using the KardiaMobile six-lead device can be carried out at the patient’s home. These features might mean that the KardiaMobile six-lead device could be more acceptable than the 12-lead electrocardiogram to some patients. This assessment considered whether the KardiaMobile six-lead device has the potential to provide an effective and safe alternative to 12-lead electrocardiogram for initial assessment and monitoring of the risk of heart problems in people taking antipsychotic medications. Based on the available evidence, it remains unclear whether KardiaMobile six-lead has adequately demonstrated sufficient evidence of potential advantage(s) over current practice to justify further research to inform assessment of its clinical effectiveness and cost effectiveness. Our report provides detailed recommendations about the research needed, to provide further information about potential benefits so that a decision can be made about whether it should be used in the NHS in England, after further research has been completed. Scientific summary Background The primary indication for this assessment is the use of the KardiaMobile six-lead (6L) electrocardiogram (ECG) device for the assessment of QT interval-based cardiac risk in service users prior to the initiation of antipsychotic medications, which are associated with an established risk of QT interval prolongation, and for monitoring QT interval-based cardiac risk once medication has been established. Current UK guidance recommends that a person should be offered an ECG before starting antipsychotic medication if: specified in the drug’s summary of product characteristics or a physical examination has identified specific cardiovascular risk or there is a family history of cardiovascular disease, sudden collapse or other cardiovascular risk factors such as arrhythmia or the service user is being admitted as an inpatient. This early value assessment (EVA) considers the potential clinical effectiveness of using KardiaMobile 6L for the initial assessment (triage) of QT interval-based cardiac risk in service users prior to the initiation of antipsychotic medications, which are associated with an established risk of QT interval prolongation, and for monitoring QT interval-based cardiac risk once medication has been established. The assessment of KardiaMobile 6L as a triage step means that patients with QT prolongation, identified by KardiaMobile 6L, would be followed up using 12-lead ECG; this would be the case both for assessment prior to the initiation of antipsychotic medications and for monitoring QT interval-based cardiac risk once medication has been established. There may be additional circumstances where follow-up 12-lead ECG is required, for example where the KardiaMobile 6L readout is considered to be of insufficient quality for clinical decision-making. Objectives The overall aim of this project was to provide a comprehensive summary of all available evidence that may be relevant to the potential implementation of KardiaMobile 6L, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication. We defined a series of research questions that would need to be addressed, to support a full assessment of the clinical effectiveness and cost effectiveness of using KardiaMobile 6L for the initial assessment (triage) of QT interval-based cardiac risk in service users prior to the initiation of antipsychotic medications which are associated with an established risk of QT interval prolongation, and for monitoring QT interval-based cardiac risk once medication has been established: What is the accuracy/technical performance of KardiaMobile 6L, where prolonged corrected QT interval (QTc), determined by 12-lead ECG (the reference standard method) is the target condition? What are the clinical effects (on cardiac and psychiatric outcomes) of using KardiaMobile 6L for the initial assessment (triage) of QT interval-based cardiac risk in service users taking antipsychotic medications that are associated with QT prolongation, both for baseline assessment before initiating medication and for ongoing monitoring, compared to 12-lead ECG in all patients (no triage step) or no ECG? What are the effects of using KardiaMobile 6L on service user acceptability/satisfaction and on training and workflow issues? What are the costs, from a UK NHS and Personal Social Services perspective, of using KardiaMobile 6L for the initial assessment (triage) of QT interval-based cardiac risk in service users taking antipsychotic medications that are associated with QT prolongation? What existing, published cost-effectiveness studies are available about QT interval assessment for service users who require antipsychotic medication? Given the anticipated limitations of the evidence base, this assessment used a broader scope to consider whether the KardiaMobile 6L device has the potential to provide an effective and safe alternative to 12-lead ECG for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications. For example, the inclusion criteria for questions 1 and 3 allowed the inclusion of data for any population not just those starting or maintained on antipsychotic medications that are associated with QT prolongation, observational studies were included for all questions other than question 5, and concordance studies (a study type which cannot provide estimates of the clinical accuracy of a test) were included for question 1. The available evidence has been summarised, with consideration of its relevance to the above research questions, and a detailed description of evidence gaps where further research is needed is provided. This assessment does not include cost-effectiveness modelling, because the evidence currently available is not sufficient to support this. Methods Twenty-seven databases, including MEDLINE and EMBASE, research registers, conference proceedings and a pre-print resource were searched for relevant studies from inception to April/May 2022. Search results were screened for relevance independently by two reviewers. Full-text inclusion assessment, data extraction and quality assessment were conducted by one reviewer and checked by a second. The methodological quality of included technical validation studies was assessed using relevant components of QUADAS-2. No formal quality assessment was applied to the other study types (case series) included in this report. We did not consider formal assessment of methodological quality or risk of bias to be appropriate for non-research study pilot project reports; however, our report includes a qualitative summary of the key issues, with respect to the reliability of the information provided by these reports to address the aims of this EVA. Meta-analysis was considered inappropriate, due to the small number of included studies and wide variation in study design, study populations and outcomes reported; we therefore employed a narrative synthesis. The results section of this report is structured by research question. Results The evidence to inform this EVA of KardiaMobile 6L, for use in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication, was extremely limited. We did not identify any studies, which addressed any of the five research questions defined for this EVA, in the target population (service users who require antipsychotic medication). All eight included studies were technical validation studies or case series, which reported some limited information about agreement between QT interval measurements derived from KardiaMobile 6L and 12-lead ECG. All of these studies were conducted in non-psychiatric populations [e.g. cardiac patients, coronavirus disease 2019 (COVID-19) patients], and all used cardiologists to interpret all ECGs and, in some instances, also applied optimised methods of interpreting ECGs (multiple reader assessment). Where reported or calculable, the mean difference in QTc between devices (12-lead ECG vs. KardiaMobile 6L) was generally small (≤ 10 ms) and QTc measured using KardiaMobile 6L was consistently lower than that measured by 12-lead ECG. However, it should be noted that none of the included studies provided any information to indicate in how many (if any) patients observed differences in measured QTc would have resulted in a change of clinical category. All the information about the use of KardiaMobile 6L in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication, included in this EVA report, was taken from two unpublished pilot project reports. It is important to note that both these project reports relate to work undertaken as part of a wider Academic Health Science Network (AHSN) pilot, which was not intended to be used in wider evaluations of KardiaMobile 6L for use in the NHS. Both reports included information from surveys of staff and service users, which indicated that the use of KardiaMobile 6L may be associated with reductions in the time taken to complete an ECG and costs, relative to 12-lead ECG, and that KardiaMobile 6L was preferred over 12-lead ECG by almost all of the staff and service users who responded. It should be noted that estimates of the time taken to complete an ECG were based on opinion, retrospectively obtained from staff who had chosen to use KardiaMobile 6L during the pilot period, rather than real-world measurement of actual time taken. It should also be noted that estimates of overall potential cost savings associated with KardiaMobile 6L did not include the costs of any follow-up 12-lead ECGs required. Conclusions As anticipated during the scoping phase of this assessment and reflected in the decision to undertake an EVA, there is insufficient evidence to support a full diagnostic assessment evaluating the clinical and cost effectiveness of KardiaMobile 6L, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication. The evidence to inform the aims of this EVA (i.e. to assess whether the device has the potential to be clinically effective and cost-effective) was also limited. This report includes a comprehensive list of research recommendations, both to reduce the uncertainty around this EVA and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. Study registration This study is registered as PROSPERO CRD42022336695. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135520) and is published in full in Health Technology Assessment; Vol. 28, No. 19. See the NIHR Funding and Awards website for further award information.

Cancer affects tens of millions of the world’s population each year with a stark mortality rate. It is well established that in order to be effective in treating solid tumor cancers, the current treatment methods used often sacrifice surrounding healthy tissue and cause damage at the site of treatment, inducing changes to the surrounding microenvironment. These changes to the microenvironment can lead to adverse side effects as well as long-term damage which continues to have a detrimental impact on the patient’s quality of life, even after remission. It is believed that by modulating the tumor microenvironment (TME) post-treatment, not only may the efficacy of current treatments be improved, but such associated negative side effects, as well as further complications arising from treatment, including metastasis, have the potential to be reduced. Mediating the microenvironment is also considered to aid in repairing the damaged site post-treatment, subsequently making the conditions more favourable for promoting regenerative processes. This review provides a brief overview of the alterations in the TME resulting from the three main cancer treatments–chemotherapy, radiation therapy and surgery–and the most common tissue engineering methods currently used in an attempt to mediate the TME post-cancer therapy. Furthermore, it investigates new emerging technologies within this field and the progress of such methods in terms of reaching the clinical setting.

Background Artificial intelligence-derived software technologies have been developed that are intended to facilitate the review of computed tomography brain scans in patients with suspected stroke. Objectives To evaluate the clinical and cost-effectiveness of using artificial intelligence-derived software to support review of computed tomography brain scans in acute stroke in the National Health Service setting. Methods Twenty-five databases were searched to July 2021. The review process included measures to minimise error and bias. Results were summarised by research question, artificial intelligence-derived software technology and study type. The health economic analysis focused on the addition of artificial intelligence-derived software-assisted review of computed tomography angiography brain scans for guiding mechanical thrombectomy treatment decisions for people with an ischaemic stroke. The de novo model (developed in R Shiny, R Foundation for Statistical Computing, Vienna, Austria) consisted of a decision tree (short-term) and a state transition model (long-term) to calculate the mean expected costs and quality-adjusted life-years for people with ischaemic stroke and suspected large-vessel occlusion comparing artificial intelligence-derived software-assisted review to usual care. Results A total of 22 studies (30 publications) were included in the review; 18/22 studies concerned artificial intelligence-derived software for the interpretation of computed tomography angiography to detect large-vessel occlusion. No study evaluated an artificial intelligence-derived software technology used as specified in the inclusion criteria for this assessment. For artificial intelligence-derived software technology alone, sensitivity and specificity estimates for proximal anterior circulation large-vessel occlusion were 95.4% (95% confidence interval 92.7% to 97.1%) and 79.4% (95% confidence interval 75.8% to 82.6%) for Rapid (iSchemaView, Menlo Park, CA, USA) computed tomography angiography, 91.2% (95% confidence interval 77.0% to 97.0%) and 85.0 (95% confidence interval 64.0% to 94.8%) for Viz LVO (Viz.ai, Inc., San Fransisco, VA, USA) large-vessel occlusion, 83.8% (95% confidence interval 77.3% to 88.7%) and 95.7% (95% confidence interval 91.0% to 98.0%) for Brainomix (Brainomix Ltd, Oxford, UK) e-computed tomography angiography and 98.1% (95% confidence interval 94.5% to 99.3%) and 98.2% (95% confidence interval 95.5% to 99.3%) for Avicenna CINA (Avicenna AI, La Ciotat, France) large-vessel occlusion, based on one study each. These studies were not considered appropriate to inform cost-effectiveness modelling but formed the basis by which the accuracy of artificial intelligence plus human reader could be elicited by expert opinion. Probabilistic analyses based on the expert elicitation to inform the sensitivity of the diagnostic pathway indicated that the addition of artificial intelligence to detect large-vessel occlusion is potentially more effective (quality-adjusted life-year gain of 0.003), more costly (increased costs of £8.61) and cost-effective for willingness-to-pay thresholds of £3380 per quality-adjusted life-year and higher. Limitations and conclusions The available evidence is not suitable to determine the clinical effectiveness of using artificial intelligence-derived software to support the review of computed tomography brain scans in acute stroke. The economic analyses did not provide evidence to prefer the artificial intelligence-derived software strategy over current clinical practice. However, results indicated that if the addition of artificial intelligence-derived software-assisted review for guiding mechanical thrombectomy treatment decisions increased the sensitivity of the diagnostic pathway (i.e. reduced the proportion of undetected large-vessel occlusions), this may be considered cost-effective. Future work Large, preferably multicentre, studies are needed (for all artificial intelligence-derived software technologies) that evaluate these technologies as they would be implemented in clinical practice. Study registration This study is registered as PROSPERO CRD42021269609. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133836) and is published in full in Health Technology Assessment; Vol. 28, No. 11. See the NIHR Funding and Awards website for further award information. Plain language summary Stroke is a serious life-threatening medical condition caused by a blood clot or haemorrhage in the brain. Quick and effective management, including a brain scan, of the patients with suspected stroke can make a big difference in their outcome. Artificial intelligence-derived computer programmes exist that are intended to help with the interpretation of computed tomography scans of the brain in stroke. We undertook a thorough review of the existing research into the effectiveness and value for money of using these programmes to help doctors and other specialists to interpret computed tomography brain scans. We found very little evidence to tell us how well artificial intelligence-derived computer programmes work in practice. Some studies have looked at artificial intelligence-derived computer programmes on their own (i.e. not taken together with a doctor’s judgement, as they were designed to be used). Other studies have looked at what happens to patients who are treated for stroke when artificial intelligence-derived computer programmes are used; these studies provide no information about whether using artificial intelligence-derived computer programmes may have led to patients who could have benefitted from treatment being missed. It is unclear how well artificial intelligence-derived software-assisted review works when added to current clinical practice. Scientific summary Background The primary population for this assessment was people presenting or attending secondary care with a suspected acute stroke who were last known to be well within the previous 24 hours. Stroke is a serious life-threatening medical condition defined by the World Health Organization (WHO) as a clinical syndrome consisting of ‘rapidly developing clinical signs of focal (at times global) disturbance of cerebral function, lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin’. Timely and effective management of the patients with suspected stroke substantially impacts patients’ outcomes. A number of software products with artificial intelligence (AI)-derived software technologies have been developed, which are intended to facilitate the review of computed tomography (CT) images of the brain in patients with suspected stroke. These products are not intended to provide a diagnosis but to support review and reporting healthcare professionals. Objectives This assessment aimed to evaluate the clinical and cost-effectiveness of using AI-derived software to support the review of CT brain scans in acute stroke, in the NHSs setting. Three research questions were considered. (1) Does AI-derived software-assisted review of non-enhanced CT brain scans for guiding thrombolysis treatment decisions for people with suspected acute stroke represent a clinically and cost-effective use of NHS resources? (2a) Does AI-derived software-assisted review of CT angiography (CTA) brain scans for guiding mechanical thrombectomy treatment decisions for people with an ischaemic stroke represent a clinically and cost-effective use of NHS resources? (2b) Does AI-derived software-assisted review of CT perfusion brain scans for guiding mechanical thrombectomy treatment decisions for people with an ischaemic stroke after a CTA brain scan represent a clinically and cost-effective use of NHS resources? Methods Assessment of clinical effectiveness Twenty-five databases, including MEDLINE and Embase, research registers, conference proceedings and a preprint resource, were searched for relevant studies from inception to July 2021; update searches were conducted in October 2021. Search results were screened for relevance independently by two reviewers. Full-text inclusion assessment, data extraction and quality assessment were conducted by one reviewer and checked by a second. The methodological quality of included diagnostic test accuracy studies was assessed using QUADAS-2 (Bristol Medical School, University of Bristol, Bristol, UK). The methodological quality of observational ‘before and after’ studies was assessed using a checklist, devised by the authors, for this review. The hierarchical summary receiver operating characteristic (HSROC) model was used to estimate summary sensitivity and specificity with 95% confidence intervals (CIs) and prediction regions around the summary points, and to derive HSROC curves for meta-analyses of diagnostic test accuracy, where four or more studies evaluated the same intervention for a given research question. All other results, including those of ‘before and after’ studies, were summarised in a narrative synthesis, grouped by research question addressed, AI-derived software evaluated and study type. Assessment of cost-effectiveness The health economic analysis focused on research question 2a: (2a) Does AI-derived software-assisted review of CT angiography brain scans for guiding mechanical thrombectomy treatment decisions for people with an ischaemic stroke represent a clinically and cost-effective use of NHS resources? All diagnostic accuracy studies identified by the systematic review conducted for this assessment assessed the accuracy of AI-derived software technologies as stand-alone interventions. As a result, information about how AI-derived software technologies would perform when used as an adjunct/aid to human readers (i.e. as recommended by the manufacturers, as specified for this assessment and as they would be used in clinical practice) is lacking. This is because the accuracy of the device by itself tells us nothing about how, or indeed whether, it might improve the accuracy of a human reader. It would not make sense to infer that any of the variation in sensitivity observed between stand-alone AIs can tell us something about precisely the variation in a hypothetical, small improvement in sensitivity of the human reader. To perform cost-effectiveness analysis (CEA), we elicited expert opinion to estimate the diagnostic accuracy of AI as adjunct to human reader. Experts were provided with the evidence on AI alone and human reader alone. Because it was considered too difficult for experts to differentiate between different AI-derived software-assisted review technologies, AI-derived software-assisted review in general (not specified by manufacturer or specific technology) is considered. The de novo model (developed in R Shiny, R Foundation for Statistical Computing, Vienna, Austria) consisted of a decision tree (short-term) and a state transition model (long-term) to calculate the mean expected costs and quality-adjusted life-years (QALYs) for people with ischaemic stroke and suspected large-vessel occlusion (LVO). The decision tree was used to estimate short-term costs and consequences (first 90 days). Subsequently, patients with LVO were classified as either eligible for thrombectomy or not eligible. Those with both LVO and eligibility for thrombectomy were further classified, based on the sensitivity of the diagnostic strategy, into whether a LVO was detected (and thus thrombectomy received) or not. Based on the classification in the decision tree, patients were subdivided into health states according to the modified Rankin Scale (mRS). Notably, patients without LVO were subdivided based on the specificity of the diagnostic strategy into whether a LVO was incorrectly detected or not. If a LVO was incorrectly detected (i.e. false positive), this had cost consequences only (e.g. due to potential unnecessary transfer to experienced stroke centre qualified to perform thrombectomy). The long-term consequences in terms of costs and QALYs were estimated using a state transition cohort model with a lifetime time horizon (annual cycle length) and health states defined as per mRS states. Probabilistic sensitivity analyses, deterministic sensitivity analyses and scenario analyses were performed. Results Assessment of clinical effectiveness A total of 22 studies (30 publications) were included in the review; for 9 of the 13 manufacturers of AI-derived software included in the scope, no studies were identified. All included studies concerned AI-derived software produced by Avicenna, Brainomix, iSchemaView or Viz. The majority (18/22 studies) reported data concerning research question 2a (i.e. evaluated AI-derived software for the interpretation of CTA). All included studies either assessed the diagnostic accuracy of AI-derived software alone (i.e. not as it would be used in clinical practice, as recommended by the manufacturers and as specified in the inclusion criteria for this assessment) or were ‘before and after’ observational studies reporting information about the effects of implementing AI-derived software in treated patients. Eleven studies provided information about the accuracy of various AI-derived software technologies for the detection of LVO on CTA scans in patients with acute ischaemic stroke. Where the target condition included occlusions of internal carotid artery, carotid terminus or the M1 or M2 segments of the middle cerebral artery (MCA), the sensitivity and specificity estimates were 95.4% (95% CI 92.7% to 97.1%) and 79.4% (95% CI 75.8% to 82.6%) for Rapid CTA (iSchemaView, Menlo Park, CA, USA), 91.2% (95% CI 77.0% to 97.0%) and 85.0 (95% CI 64.0% to 94.8%) for Viz LVO, 83.8% (95% CI 77.3% to 88.7%) and 95.7% (95% CI 91.0% to 98.0%) for Brainomix e-CTA, and 98.1% (95% CI 94.5% to 99.3%) and 98.2% (95% CI 95.5% to 99.3%) for Avicenna CINA LVO, based on one study each. There was some evidence to indicate that, where studies included more distal (e.g. M3 segment of the MCA) elements of the anterior circulation or included posterior circulation in their definition of the target condition, sensitivity was reduced. All four studies that provided information about the effects of implementing Viz LVO and one study that provided information about the effects of implementing Rapid CTA reported that implementation was associated with reductions in time to treatment for thrombectomy patients and, where reported, with no significant change in clinical outcomes (mRS). However, it should be noted that two of the studies of Viz LVO and the study of Rapid CTA evaluated implementation in the context of providing an automated alert system (i.e. not as specified in the scope for this assessment); it is plausible that reductions in time to intervention, observed in these studies, may be driven by this ‘early alert’ step. The information provided by studies of this type is also limited in that it concerns only treated (i.e. test positive) patients; no information is provided about test negative patients and hence there is no information about the extent to which AI-derived software, as implemented, may miss patients with LVO. There is no evidence about the accuracy of AI-derived software when used as an aid to human interpretation; all evidence concerns only stand-alone AI. This might imply that a CEA is not feasible for any of the three research questions. However, we conducted a CEA in relation to the research question 2a, where there is most evidence about the performance of AI-derived software technologies alone and one study comparing an AI-derived software technology alone with human reader alone. These studies were not considered appropriate to inform cost-effectiveness modelling but formed the basis by which the accuracy of AI plus human reader could be elicited by expert opinion. Assessment of cost-effectiveness Base-case analysis The probabilistic results indicated that the addition of AI to detect LVO is potentially more effective (QALY gain of 0.003), more costly (increased costs of £8.61) and cost-effective for willingness-to-pay thresholds of £3380 per QALY and higher. The cost-effectiveness plane illustrated the negative correlation between incremental costs and incremental QALYs; that is if a technology is more effective it also tends to be less costly. The cost-effectiveness acceptability curve indicated that at willingness-to-pay values of £20,000 and £30,000 per QALY gained the probabilities of current practice with AI being cost-effective are 54% and 56%, respectively. The expected risks per patient associated with adding AI at willingness-to-pay values of £20,000 and £30,000 per QALY gained are £80 and £95, respectively (these were £122 and £163 respectively without adding AI; see expected loss curves). At a population level (assuming 87,635 patients imaged, per year, in the UK), the estimated annual risks associated with adding AI are £7.0 million and £8.4 million, at willingness-to-pay values of £20,000 and £30,000 per QALY gained, respectively. Secondary analysis sensitivity and scenario analyses Sensitivity analyses indicated that the sensitivity of both technologies (i.e. with and without the addition of AI-derived software-assisted review) was the most important input parameter. In addition, the proportion of patients with LVO that are eligible for mechanical thrombectomy is important to determine the most optimal strategy in terms of costs and QALYs. For the estimated costs (specificity), the additional costs of the AI technology, costs related to mRS 4 and mRS 5 were input parameters (in addition to those mentioned above), which can change the strategy that is most expensive. Consistently, the most influential scenario analyses were related to the sensitivity (for both strategies), the proportion of patients with LVO eligible for mechanical thrombectomy with AI, removing the general population mortality cap and the additional costs of the AI technology. Conclusions The available evidence is not suitable to determine the clinical effectiveness of using AI-derived software to support the review of CT brain scans in acute stroke. The economic analyses did not provide evidence to prefer the AI-derived software strategy over current clinical practice. However, results indicated that if the addition of AI-derived software-assisted review for guiding mechanical thrombectomy treatment decisions increased the sensitivity of the diagnostic pathway (i.e. reduced the proportion of undetected LVOs) this may be considered cost-effective. Nevertheless, the sensitivity of AI-derived software-assisted review when added to current clinical practice is largely uncertain and probably depends on the implementation of AI-derived software-assisted review. Study registration This study is registered as PROSPERO CRD42021269609. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133836) and is published in full in Health Technology Assessment; Vol. 28, No. 11. See the NIHR Funding and Awards website for further award information.

Many aphid-vectored viruses are transmitted nonpersistently via transient attachment of virus particles to aphid mouthparts and are most effectively acquired or transmitted during brief stylet punctures of epidermal cells. In Arabidopsis thaliana, the aphid-transmitted virus cucumber mosaic virus (CMV) induces feeding deterrence against the polyphagous aphid Myzus persicae. This form of resistance inhibits prolonged phloem feeding but promotes virus acquisition by aphids because it encourages probing of plant epidermal cells. When aphids are confined on CMV-infected plants, feeding deterrence reduces their growth and reproduction. We found that CMV-induced inhibition of growth as well as CMV-induced inhibition of reproduction of M. persicae are dependent upon jasmonate-mediated signalling. BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1) is a co-receptor enabling detection of microbe-associated molecular patterns and induction of pattern-triggered immunity (PTI). In plants carrying the mutant bak1-5 allele, CMV induced inhibition of M. persicae reproduction but not inhibition of aphid growth. We conclude that in wildtype plants CMV induces two mechanisms that diminish performance of M. persicae: a jasmonate-dependent and PTI-dependent mechanism that inhibits aphid growth, and a jasmonate-dependent, PTI-independent mechanism that inhibits reproduction. The growth of two crucifer specialist aphids, Lipaphis erysimi and Brevicoryne brassicae, was not affected when confined on CMV-infected A. thaliana. However, B. brassicae reproduction was inhibited on CMV-infected plants. This suggests that in A. thaliana CMV-induced resistance to aphids, which is thought to incentivize virus vectoring, has greater effects on polyphagous than on crucifer specialist aphids.

Societal Impact Statement Understanding the current state of trees within the United States is imperative for protecting those species, their habitats, and the countless communities they support, as well as the ecosystem services they provide. We present an updated checklist of all tree species native to the contiguous United States, their state distribution, extinction risk, and most common threats. Knowledge of national threat “hotspots” and conservation priorities facilitates efficient conservation efforts and the allocation of resources to safeguard the 11–16% of US tree species that are threatened. These results lay the groundwork for tree and ecosystem conservation efforts in the United States that contribute to achieving critical international conservation goals, including the United Nations Decade for Ecosystem Restoration and the Global Tree Assessment. Summary The Global Tree Assessment aims to complete threat assessments for all the world's ~60,000 tree species, but most species native to the continental United States had either never been assessed or were outdated on the two most widely used threat assessment platforms in the United States, International Union for the Conservation of Nature (IUCN) Red List and NatureServe. There was also no coordinated mechanism for sharing data between these platforms, resulting in missing, duplicated, or outdated information. We (1) created an updated checklist of all tree species native to the contiguous United States based on the standardized Global Tree Assessment tree definition, (2) created over 700 new or updated IUCN Red List assessments and NatureServe Global Ranks, and (3) developed a replicable assessment data sharing process. We present an updated checklist of native US trees that includes 881 species from 269 genera, with Quercus and Crataegus as the most species‐rich tree genera. We present the first country‐wide analysis of tree extinction risk, patterns of geographic and taxonomic diversity, and leading threats. An estimated 11–16% of US tree species are threatened with extinction, with the most common threat being invasive and problematic pests and diseases. We introduce a “crosswalk” process for efficient, large‐scale data sharing between the IUCN Red List and NatureServe, using IUCN Red List Species Information Service (SIS) Connect, which can be applied to other taxonomic groups in North America. The checklist, threat assessments, and crosswalk methodology represent a significant advancement in prioritizing conservation action for at‐risk tree species and restoration of forests in the United States, supporting the global goals of the United Nations Decade for Ecosystem Restoration and the Global Tree Assessment effort.

This position statement guides cardiovascular magnetic resonance (CMR) imaging program directors and learners on the key competencies required for Level II and III CMR practitioners, whether trainees come from a radiology or cardiology background. This document is built upon existing curricula and was created and vetted by an international panel of cardiologists and radiologists on behalf of the Society for Cardiovascular Magnetic Resonance (SCMR).

Larval dispersal is critical to the survival of coral reefs. As the only motile stage of the reproductive cycle, coral larvae choose a suitable location to settle and mature into adult corals. Here, we present a detailed study of ciliary propulsion in the common stony reef coral Acropora millepora. Using high-speed, high-resolution imaging, particle image velocimetry, and electron microscopy, we reveal the arrangement of the densely packed cilia over the larval body surface, and their organization into diaplectic (transversely propagating) metachronal waves. We resolve the individual cilium's beat dynamics and compare the resulting flows with a computational model of a dense ciliary array, and evaluate the efficiency of flow pumping associated with diaplectic metachronism in different regimes.

ABSTRACTAims Repetitive peripheral magnetic stimulation (rPMS) is a novel nonpharmacological treatment modality. This noninvasive approach can stimulate peripheral nerves to provide analgesia through neuromodulation. We report the first case of ultrasound-guided rPMS to treat a case of severe refractory glossopharyngeal neuralgia.Methods A 70-year-old female with an 8-year history of glossopharyngeal neuralgia reported refractory pain unresponsive to pharmacological and interventional treatments. After consenting to treatment, the patient received high-frequency rPMS in three different sessions using intermittent theta burst stimulation below motor thresholds. rPMS was applied over the skin directed at the glossopharyngeal nerve identified using ultrasound guidance. Session 1 included 20 min of continuous treatment, session 2 included 40 min of treatment (two 20-min treatments separated by a 10-min break), session 3 included 40 min of treatment (similar to Session 2) repeated daily for 5 days. Pre- and postintervention pain levels were collected with a daily 1-week pain diary and pain questionnaires.Results Session 1 led to an immediate 30% decrease in pain after treatment. Session 2 led to a 75% decrease in pain immediately after treatment that remained reduced for approximately 2 days. Session 3 produced complete pain relief immediately after treatment and remained lower for 5 days after treatment and returned to baseline levels at 1 week.Conclusion rPMS provided immense but temporary relief in a severe case of refractory glossopharyngeal neuralgia. Further work is needed to determine the most effective regimen to treat complex pain disorders in the head and neck.

This article describes the evolution of inclusive education in Hong Kong, moving from segregation via integration to inclusion. The outside influence of education policies and trends from Britain, Australia, and the United States are identified, and the current situation is described. In particular, obstacles that are encountered on the route to inclusion are compared with those found in other countries. These obstacles include large class size, teachers' often negative attitudes, parents' expectations, teachers' lack of expertise for adapting the curriculum and for providing differentiated teaching, and ongoing conflicts between the notion of 'inclusive schooling for all' and the 'academic standards agenda'.

BackgroundClimate change is an era-defining health concern, with healthcare related emissions paradoxically compounding negative impacts. The NHS produces 5% of the UK's carbon footprint, with operating theatres a recognised carbon hotspot. NHS England aims to become Net Zero by 2045. Consequently, UK Royal Colleges of Surgery have published guidance to foster an evidence-based sustainable transformation in surgical practice.MethodsA single-centre quality improvement project was undertaken, aiming to provide an overview of sustainable practice locally. The Intercollegiate “Green Theatre Checklist” was taken as an audit standard, focusing on “preparing for surgery” and “intraoperative equipment” subsections. Any general surgical procedure was eligible for inclusion. Usage of reusable textiles, non-sterile gloves, catheters, antibiotics, alcohol vs. water-based scrub techniques, skin sterilisation choices, and skin closure materials were recorded. Baseline data collection occurred over a 3 week period, followed by dissemination of results locally via clinical governance meetings and poster displays. A re-audit of practice was conducted using the same methodology and duration.ResultsDatasets 1 (n = 23) and 2 (n = 23) included open (n = 22), laparoscopic (n = 24), elective (n = 22) and non-elective (n = 24) cases. Good practice was demonstrated in reusable textiles (trolley covers 96%, 78%, drapes 100%, 92%) however procurement issues reduced otherwise good reusable gown use in Dataset 2 in (90%, 46%). No unnecessary catheter use was identified, and loose skin preparations were used unanimously. Uptake of alcohol-based scrubbing techniques was low (15%, 17%) and unnecessary non-sterile glove use was observed in >30% of procedures. All laparoscopic ports and scissors were single use. Carbon footprints were 128.27 kgCO2e and 117.71 kgCO2e in datasets 1 and 2 respectively.ConclusionThis project evidences good practice alongside future local focus areas for improved sustainability. Adoption of hybrid laparoscopic instruments, avoiding unnecessary equipment opening, and standardising reusable materials could reduce carbon and environmental impact considerably. Successful implementation requires considered procurement practices, improved awareness and education, clear leadership, and a sustained cultural shift within the healthcare community. Collaboration among professional institutions and access to supporting evidence is crucial in driving engagement and empowering clinicians to make locally relevant changes a reality.