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Introduction: Artificial intelligence (AI) encompasses a wide range of algorithms with risks when used to support decisions about diagnosis or treatment, so professional and regulatory bodies are recommending how they should be managed. Areas covered: AI systems may qualify as standalone medical device software (MDSW) or be embedded within a medical device. Within the European Union (EU) AI software must undergo a conformity assessment procedure to be approved as a medical device. The draft EU Regulation on AI proposes rules that will apply across industry sectors, while for devices the Medical Device Regulation also applies. In the CORE-MD project (Coordinating Research and Evidence for Medical Devices), we have surveyed definitions and summarize initiatives made by professional consensus groups, regulators, and standardization bodies. Expert opinion: The level of clinical evidence required should be determined according to each application and to legal and methodological factors that contribute to risk, including accountability, transparency, and interpretability. EU guidance for MDSW based on international recommendations does not yet describe the clinical evidence needed for medical AI software. Regulators, notified bodies, manufacturers, clinicians and patients would all benefit from common standards for the clinical evaluation of high-risk AI applications and transparency of their evidence and performance.

This article explores how digital agri-food system transformations are framed and by whom. To answer these questions, we searched for webpages linked to Twitter and by Google that describe the role of emerging digital technologies in agri-food systems. From these, we characterize three framings of transformation. The first framing proposes that digital tools make farms optimally productive. A second framing emphasizes inequities in access to digital tools and increased farmer participation in tech development. A third framing highlights how technology creates more traceable agri-food systems. We then conducted a social network analysis of webpage authors, finding three network clusters. The largest centres on intergovernmental and international development organizations that typically promote the first and third framings. The second framing is mostly promoted by academic and civil society actors and was least common across webpages, suggesting that digital agriculture trajectories may overlook farmer autonomy and agency. Framings vary in the degree of transformation they promote and their consideration of smaller-scale farms’ needs. We suggest that digital agri-food system transformation efforts are more diverse than typically described in the literature. We recommend public and private actors work with academics and civil society organizations to enhance farmer inclusion in designing novel transformative approaches.

Background Colorectal cancer (CRC) screening using faecal tests reduces disease-specific mortality. To investigate mortality and its association with sex, rates in women and men, and in different age ranges, were examined, before and after screening began in Scotland. Methods From 1990–99, no structured screening existed. Three pilots ran from 2000 to 2007 and subsequent full roll-out completed in 2009. Crude mortality rates for 1990–2020 were calculated relative to Scottish population estimates, and age–sex standardized rates calculated for all, pre-screening (74 years) age ranges. Results CRC mortality declined from 1990 to 2020, but not linearly, and differed between sexes. In women, 1990–99 showed a steady decline [average annual percentage change (AAPC): −2.1%, 95% confidence interval (CI): −2.8% to −1.4%], but a less marked decline after 2000 (AAPC: −0.7%, 95% CI: −0.9% to −0.4%). In men, no clear decline was seen from 1990 to 1999 (AAPC: −0.4%, 95% CI: −1.1% to 0.4%), but mortality declined from 2000 to 2020 (AAPC: −1.7%, 95% CI: −1.9% to −1.5%). This pattern was exaggerated in the screening age ranges. For 2000–20, the overall reduction in mortality was less in women and in the screening age range. In the post-screening age range, reductions were smaller, but an increase was seen in the pre-screening age range, greater in women. Conclusions CRC mortality fell during 1990–2020, but the decline differed markedly between sexes, indicating a larger beneficial effect of screening on CRC mortality in men compared to women: use of different thresholds for the sexes might lead to equality.

Introduction The EU Medical Device Regulation 2017/745 defines new rules for the certification and post-market surveillance of medical devices (MD), including an additional review by Expert Panels of clinical evaluation data for high-risk MD if reports and alerts suggest possibly associated increased risks. Within the EU-funded CORE-MD project, our aim was to develop a tool to support such process in which web-accessible safety notices (SN) are automatically retrieved and aggregated based on their specific MD categories and the European Medical Device Nomenclature (EMDN) classification by applying an Entity Resolution (ER) approach to enrich data integrating different sources. The performance of such approach was tested through a pilot study on the Italian data. Methods Information relevant to 7622 SN from 2009 to 2021 was retrieved from the Italian Ministry of Health website by Web scraping. For incomplete EMDN data (68%), the MD best match was searched within a list of about 1.5 M MD on the Italian market, using Natural Language Processing techniques and pairwise ER. The performance of this approach was tested on the 2440 SN (32%) already provided with the EMDN code as reference standard. Results The implemented ER method was able to correctly assign the correct manufacturer to the MD in each SN in 99% of the cases. Moreover, the correct EMDN code at level 1 was assigned in 2382 SN (97.62%), at level 2 in 2366 SN (96.97%) and at level 3 in 2329 SN (95.45%). Conclusion The proposed approach was able to cope with the incompleteness of the publicly available data in the SN. In this way, grouping of SN relevant to a specific MD category/group/type could be used as possible sentinel for increased rates in reported serious incidents in high-risk MD.

Stress cardiomyopathy (SCM), also known as Takatsubo cardiomyopathy or broken heart syndrome has been well documented in literature since its first description. With more awareness of the condition and increasing evidence base, the reported incidence of SCM has steadily increased over years and currently estimated at 1-2 % of the patients presenting with acute coronary syndrome. There are different criteria proposed for diagnosis of stress cardiomyopathy and this address more or less the same clinical questions while diagnosing this not so uncommon condition. Despite extensive research , there has been a lack of understanding on the exact mechanism and causative factors leading to SCM. We report a variety of cases where a different trigger appears to have been responsible for causation of SCM. It would seem that irrespective of the original trigger, the final clinical picture and course remains identical. These further strengths the idea that the condition is mediated by a common neurocardiovacular pathway in susceptible individuals. Further exploration of these mechanisms would be crucial to improve our strategies to try to prevent and effectively manage this potentially disabling condition.

Echocardiography is less than 70 years old, and many major advances have occurred within living memory, but already some pioneering contributions may be overlooked. In order to consider what circumstances have been common to the most successful innovations, we have studied and here provide a timeline and summary of the most important developments in transthoracic and transoesophageal ultrasound imaging and Doppler techniques, as well as in intravascular ultrasound and imaging in paediatric cardiology. The entries are linked to a comprehensive list of first publications and to a collection of first-hand historical accounts published by early investigators. Review of the original manuscripts highlights that it is difficult to establish unequivocal precedence for many new imaging methods, since engineers were often working independently but simultaneously on similar problems. Many individuals who are prominently linked with particular developments were not the first in their field. Developments in echocardiography have been highly dependent on technological advances, and most likely to be successful when engineers and clinicians were able to collaborate with open exchange between centres and disciplines. As with many other new medical technologies, initial responses were sceptical and introduction into clinical practice required persistence and substantial energy from the first adopters. Current developments involve advances in software as much as in equipment, and progress will depend on continuing collaborations between engineers and clinical scientists, for example to identify unmet needs and to investigate the clinical impact of particular imaging approaches.

Objective How faecal haemoglobin concentrations (f-Hb) vary from one round to the next in a colorectal cancer (CRC) screening programme, and relate to colonoscopy findings, are unknown. Our aim was to use data from the first two rounds of the faecal immunochemical test (FIT) based Scottish Bowel Screening Programme (SBoSP) to explore these issues. Methods Faecal haemoglobin concentration (f-Hb) percentiles in the second round were compared with those in the first when the first round yielded a negative FIT result (Results The profiles of f-Hb in the first and second rounds differed in (a) those who had had a negative FIT result in the first round and (b) those in whom neoplastic pathology had been found. In contrast, the pattern of difference between profiles in those who had had a negative colonoscopy was very similar to that in those in whom an adenoma had been found. In addition, the risk of CRC being diagnosed in the second round after a negative colonoscopy in the first was 3.0%, not very different to that after a negative test result (4.9%). Conclusions Adenomas may be rarely the cause of a positive FIT result. An alternative explanation as to why these are detected using FIT is required. In addition, a negative colonoscopy for a positive FIT result does not rule out the finding of significant neoplastic pathology in the next round.

To achieve the Sustainable Development Goal of zero hunger, multi-sectoral strategies to improve nutrition are necessary. Building towards this goal, the food and agriculture sector must be considered when designing nutritional interventions. Nevertheless, most frameworks designed to guide nutritional interventions do not adequately capture opportunities for integrating nutrition interventions within the food and agriculture sector. This paper aims to highlight how deeply connected the food and agriculture sector is to underlying causes of malnutrition and identify opportunities to better integrate the food and agriculture sector and nutrition in low and middle income countries. In particular, this paper: (1) expands on the UNICEF conceptual framework for undernutrition to integrate the food and agriculture sector and nutrition outcomes, (2) identifies how nutritional outcomes and agriculture are linked in six important ways by defining evidence-based food and agriculture system components within these pathways: as a source of food, as a source of income, through food prices, women’s empowerment, women’s utilization of time, and women’s health and nutritional status, and (3) shows that the food and agriculture sector facilitates interventions through production, processing and consumption, as well as through farmer practices and behavior. Current frameworks used to guide nutrition interventions are designed from a health sector paradigm, leaving agricultural aspects not sufficiently leveraged. This paper concludes by proposing intervention opportunities to rectify the missed opportunities generated by this approach. Program design should consider the ways that the food and agriculture sector is linked to other critical sectors to comprehensively address malnutrition. This framework is designed to help the user to begin to identify intervention sites that may be considered when planning and implementing multi-sectoral nutrition programs. Supplementary Information The online version contains supplementary material available at 10.1007/s12571-022-01262-3.

Objective Guidelines on colorectal cancer (CRC) screening with guaiac faecal occult blood tests (gFOBTs) and faecal immunochemical tests (FITs) include the need for a pilot before a programme is introduced. Interval cancers (ICs), cancers arising after a negative screening test result but before the next scheduled invite, are important indicators of programme quality. Our aim was to compare IC in the gFOBT-based Scottish Bowel Screening Programme (SBoSP), a FIT-based pilot, and the FIT-based SBoSP, to assess if the pilot provided data that was reflected in the subsequent programme. Design The IC proportions (ICPs) data ([IC/(IC + screen detected CRC)] x 100) from the penultimate year of the gFOBT-based SBoSP, the 6-month pilot and the first year of the FIT-based SBoSP were compared. To ensure appropriate comparison, these data were only from the two pilot NHS Boards. Results For all participants, and females and males, the ICPs were very similar in the gFOBT-based SBoSP and the pilot. The faecal haemoglobin concentration (f-Hb) threshold for the pilot was set at ≥80 μg Hb/g faeces. However, in marked contrast, in the FIT-based SBoSP, at the same threshold, the ICPs were lower. In all three groups, the ICPs were higher in females than in males. Conclusions Data on variables in pilots, including ICP, can be informative, but only if variables such as FIT system are held consistent between pilot and programme. Lowering the f-Hb threshold for females to give the same ICP as males might be a strategy to minimise sex inequality.

Objective There is evidence that colorectal cancer screening using faecal haemoglobin is less effective in women than men. The faecal haemoglobin concentrations were therefore examined in women and men with screen-detected colorectal cancer. Setting Scottish Bowel Screening Programme, following the introduction of a faecal immunochemical test from November 2017, to March 2020. Methods Data were collated on faecal haemoglobin concentrations, pathological stage and anatomical site of the main lesion in participants who had colorectal cancer detected. The data in women and men were compared. Results For the faecal haemoglobin concentrations studied (>80 µg Hb/g faeces), the distributions indicated lower concentrations in women. Marked differences were found between women and men diagnosed with colorectal cancer. The median faecal haemoglobin concentration for women ( n = 720) was 408 µg Hb/g faeces compared to 473 µg Hb/g faeces for men ( n = 959) ( p = 0.004) and 50.6% of the results were >400 µg Hb/g faeces in women; in men, this was 57.8%. The difference in faecal haemoglobin concentrations in women and men became less statistically significant as stage advanced from stages I–IV. For right-sided, left-sided and rectal colorectal cancer, a similar gender difference persisted in all sites. Differences in faecal haemoglobin between the genders were significant for left-sided cancers and stage I and approached significance for rectal cancers and stage II, but all sites and stages showed lower median faecal haemoglobin concentrations for women. Conclusions To minimise gender inequalities, faecal immunochemical test-based colorectal cancer screening programmes should evaluate a strategy of using different faecal haemoglobin concentration thresholds in women and men.

Objectives\udThe aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM).\ud\udBackground\udLeft ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD).\ud\udMethods\udA 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death.\ud\udResults\udMWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years’ experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range –59% to 117% [SD ±20%] and –61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk).\ud\udConclusions\udUsing the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM.

Objectives The exploration of the metabolites in the degradation pathways of vitamin D (VTD) has gained importance in recent years and simultaneous quantitation of twenty-five-hydroxy vitamin D (25(OH)D) mass concentration together with 24,25-dihydroxyvitamin D (24,25(OH)2D) has been proposed as a newer approach to define VTD deficiency. Yet, no data are available on 24,25(OH)2D biological variation (BV). In this study, we evaluated 24,25(OH)2D’s BV on the European Biological Variation Study (EuBIVAS) cohort samples to determine if analytical performance specifications (APS) for 24,25(OH)2D could be generated. Methods Six European laboratories recruited 91 healthy participants. 25(OH)D and 24,25(OH)2D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate with a validated LC-MS/MS method. The Vitamin D Metabolite Ratio (24,25(OH)2D divided by 25(OH)D × 100) was also calculated at each time point. Results Linear regression of the mean 24,25(OH)2D concentrations at each blood collection showed participants were not in steady state. Variations of 24,25(OH)2D over time were significantly positively associated with the slopes of 25(OH)D concentrations over time and the concentration of 25(OH)D of the participant at inclusion, and negatively associated with body mass index (BMI), but not with age, gender, or location of the participant. The variation of the 24,25(OH)2D concentration in participants over a 10 weeks period was 34.6%. Methods that would detect a significant change linked to the natural production of 24,25(OH)2D over this period at pu%) Conclusions We have defined for the first time APS for 24,25(OH)2D examinations. According to the growing interest in this metabolite, several laboratories and manufacturers might aim to develop specific methods for its determination. The results presented in this paper are thus necessary prerequisites for the validation of such methods.

In 1955, when John McCarthy and his colleagues proposed their first study of artificial intelligence, they suggested that ‘every aspect of learning or any other feature of intelligence can in principle be so precisely described that a machine can be made to simulate it’. Whether that might ever be possible would depend on how we define intelligence, but what is indisputable is that new methods are needed to analyse and interpret the copious information provided by digital medical images, genomic databases, and biobanks. Technological advances have enabled applications of artificial intelligence (AI) including machine learning (ML) to be implemented into clinical practice, and their related scientific literature is exploding. Advocates argue enthusiastically that AI will transform many aspects of clinical cardiovascular medicine, while sceptics stress the importance of caution and the need for more evidence. This report summarizes the main opposing arguments that were presented in a debate at the 2021 Congress of the European Society of Cardiology. Artificial intelligence is an advanced analytical technique that should be considered when conventional statistical methods are insufficient, but testing a hypothesis or solving a clinical problem—not finding another application for AI—remains the most important objective. Artificial intelligence and ML methods should be transparent and interpretable, if they are to be approved by regulators and trusted to provide support for clinical decisions. Physicians need to understand AI methods and collaborate with engineers. Few applications have yet been shown to have a positive impact on clinical outcomes, so investment in research is essential.

Aims\ud In healthy subjects, adrenergic stimulation augments left ventricular (LV) long-axis shortening and lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise in HFpEF would further impair passive LV filling in early-mid diastole, during conduit flow from pulmonary veins.\ud \ud Methods and results\ud Twenty HFpEF patients (67.8 ± 9.8 years; 11 women), diagnosed using 2007 ESC recommendations, underwent ramped semi-supine bicycle exercise to submaximal target heart rate (∼100 bpm) or symptoms. Seventeen asymptomatic subjects (64.3 ± 8.9 years; 7 women) were controls. Simultaneous LA and LV volumes were measured from pyramidal 3D-echocardiographic full-volume datasets acquired from an apical window at baseline and during stress, together with brachial arterial pressure. LA conduit flow was computed from the increase in LV volume from its minimum at end-systole to the last frame before atrial contraction (onset of the P wave), minus the reduction in LA volume during the same time interval; the difference was integrated and expressed as average flow rate, according to a published formula. The slope of single-beat preload recruitable stroke work (PRSW) quantified LV inotropic state. 3D LV torsion (rotation of the apex minus rotation of the base divided by LV length) was also measurable, both at rest and during stress, in 10 HFpEF patients and 4 controls. There were divergent responses in conduit flow rate, which increased by 40% during exercise in controls (+17.8 ± 37.3 mL/s) but decreased by 18% in patients with HFpEF (−9.6 ± 42.3 mL/s) (P = 0.046), along with congruent changes (+1.77 ± 1.13°/cm vs. −1.94 ± 2.73°/cm) in apical torsion (P = 0.032). Increments of conduit flow rate and apical torsion during stress correlated with changes in PRSW slope (P = 0.003 and P = 0.006, respectively).\ud \ud Conclusions\ud In HFpEF, conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with changes in LV inotropic state and torsion, contributing to impaired stroke volume reserve. Conduit flow is measurable using 3D-echocardiographic full-volume atrio-ventricular datasets, and as a marker of LV relaxation can contribute to the diagnosis of HFpEF.

This article refers to 'Diagnostic scores predict morbidity and mortality in patients hospitalised for heart failure with preserved ejection fraction' by F.H. Verbrugge et al., published in this issue on pages xxx.

Objectives This study aimed to develop a risk-scoring model in the Scottish Bowel Screening Programme incorporating faecal haemoglobin concentration with other risk factors for colorectal cancer. Methods Data were collected for all individuals invited to participate in the Scottish Bowel Screening Programme between November 2017 and March 2018 including faecal haemoglobin concentration, age, sex, National Health Service Board, socioeconomic status, and screening history. Linkage with The Scottish Cancer Registry identified all screening participants diagnosed with colorectal cancer. Logistic regression was performed to identify which factors demonstrated significant association with colorectal cancer and could be used in the development of a risk-scoring model. Results Of 232,076 screening participants, 427 had colorectal cancer: 286 diagnosed following a screening colonoscopy and 141 arising after a negative screening test result giving an interval cancer proportion of 33.0%. Only faecal haemoglobin concentration and age showed a statistically significant association with colorectal cancer. Interval cancer proportion increased with age and was higher in women (38.1%) than men (27.5%). If positivity in women were mirrored in men at each age quintile interval cancer proportion would still have remained higher in women (33.2%). Moreover, an additional 1201 colonoscopies would be required to detect 11 colorectal cancers. Conclusions Development of a risk scoring model using early data from the Scottish Bowel Screening Programme was not feasible due to most variables showing insignificant association with colorectal cancer. Tailoring the faecal haemoglobin concentration threshold according to age could help to diminish some of the disparity in interval cancer proportion between women and men. Strategies to achieve sex equality using faecal haemoglobin concentration thresholds depend considerably on which variable is selected for equivalency and this requires further exploration.

Nil.

With the implementation of Regulation (European Union [EU]) 2017/746 on in vitro diagnostic medical devices (IVDR), from May 26, 2022, onwards, the development and use of diagnostic tests will be governed by a vastly expanded and upgraded EU regulatory framework. We provide here an overview of the amended transition timelines, the role of notified bodies, EU reference laboratories, expert panels, and the Medical Device Coordination Group (MDCG). We also describe the implications of the IVDR for innovative laboratory medicine by explaining the exemption for in-house devices (IH-IVDs). Two key challenges faced by the academic diagnostic sector are: (1) the stipulation on equivalence of tests (article 5.5d), which poses a new condition for the use of IH-IVDs and (2) the gray area between CE marked in vitro diagnostics (CE-IVDs), modified CE-IVDs, Research Use Only (RUO) tests, and IH-IVDs. Furthermore, the results of a questionnaire on current diagnostic practice conducted by European medical societies collaborating in the BioMed Alliance indicate widespread use of IH-IVDs in diagnostic laboratories across Europe and emphasize the need for support and guidance to comply with the IVDR. Diagnostic equivalents of the European Reference Networks (ERNs) for rare diseases could help ensure affordable and equal access to specialized diagnostics across the EU. Concerted action by clinical and laboratory disciplines, regulators, industry, and patient organizations is needed to support the efficient and effective implementation of the IVDR in a way that preserves innovation and safeguards the quality, safety, and accessibility of innovative diagnostics.

Objective Roll-out of population-based colorectal cancer (CRC) screening with faecal immunochemical test (FIT) is limited by availability of further investigations, particularly colonoscopy and examination of excised lesions. Our objective was to assess whether variation in number of faecal samples and threshold adjustment can optimise resource utilisation and CRC detection rate. Methods Three different screening strategies were compared for the same FIT threshold using a quantitative FIT system: one FIT, positive when >20 µg Hb/g faeces; two FIT, positive when either was >20 µg Hb/g faeces; and two FIT, positive when the mean was >20 µg Hb/g faeces. We calculated changes in the size of population the provider could invite to screening for an equal number of screening positive results, and CRC and adenoma detected. Results In our setting, Region of Murcia, south of Spain (not fully rolled out screening programme), changing the usual strategy of two FIT, positive when either to positive when the mean was >20 µg Hb/g faeces, would increase population invited by 37.81% with the same number of positive results (which would generate a CRC detection rate of 19.2%). In a fully rolled out programme, changing the strategy from one to two FIT (positive when the mean is >20 µg Hb/g faeces), would increase CRC detection rate by 4.64% with an increase of only 13.34% in positive FIT. Conclusions In a population-based CRC screening programme, smart use of number of FITs and positivity threshold can increase population invited and CRC detection without increasing the number of colonoscopies and pathological examinations needed.

In the European Union (EU), the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, while authorising the placing on the market of medical devices is decentralised to independent ‘conformity assessment’ organisations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the Medical Device Directive, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details – which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE–MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024. Here, we describe how it may contribute to the development of regulatory science in Europe. Cite this article: EFORT Open Rev 2021;6:839-849. DOI: 10.1302/2058-5241.6.210081

Background Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote "non-microbial" inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age. Methods Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS). Results Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190. Conclusions Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components.

The application of technologies such as artificial intelligence, robotics, blockchain, cellular agriculture, and big data analytics to food systems has been described as a digital agricultural revolution with the potential to increase food security and reduce agriculture’s environmental footprint. Yet, the scientific evidence informing how these technologies may impact or enhance ecosystem services has not been comprehensively reviewed. In this scoping review, we examine how digital agricultural technologies may enhance agriculture’s support of ecosystem services. Keyword searches in academic databases resulted in 2337 records, of which 74 records met review criteria and were coded. We identify three clusters of digital agricultural technologies including those that make farm management more precise, increase connectivity, and create novel foods. We then examine modelling and empirical evidence gaps in research linking these technologies to ecosystem services. Finally, we overview barriers to implementing digital agricultural technologies for better ecosystem services management in the Canadian context including economic and political systems; lack of policies on data management, governance, and cybersecurity; and limited training and human resources that prevents producers from fully utilizing these technologies.

Climate change will create warmer temperatures, greater precipitation, and longer growing seasons in northern latitudes making agriculture increasingly possible in boreal regions. To assess the potential of any such expansion, this paper provides a first-order approximation of how much land could become suitable for four staple crops (corn, potato, soy, and wheat) in Canada by 2080. In addition, we estimate how the environmental trade-offs of northern agricultural expansion will impact critical ecosystem services. Primarily, we evaluate how the regulatory ecosystem services of carbon storage and sequestration and the habitat services supporting biodiversity would be traded for the provisioning services of food production. Here we show that under climate change projected by Canadian Earth System Model (CanESM2) Representative Concentration Pathway 4.5, ∼1.85 million km2of land may become suitable for farming in Canada’s North, which, if utilized, would lead to the release of ∼15 gigatonnes of carbon if all forests and wetlands are cleared and plowed. These land-use changes would also have profound implications for Indigenous sovereignty and the governance of protected and conserved areas in Canada. These results highlight that research is urgently needed so that stakeholders can become aware of the scope of potential economic opportunities, cultural issues, and environmental trade-offs required for agricultural sustainability in Canada.

Place-based social-ecological research is often designed to improve local environmental governance, but it can also inform decisions at larger scales or in other places. However, the focus on local perspectives in such research creates challenges for transferring insights to other locations, and for aggregating understanding to larger scales. In this paper, we discuss how ResNet, a new pan-Canadian network of researchers working on place-based social-ecological case studies via ecosystem services, will face (and hopefully overcome) these challenges while taking advantage of the unique benefits of a place-based approach. Drawing on insights from the literature and from the first 10 years of the Programme for Ecosystem Change and Society (PECS), we outline solutions to six key challenges to multi-scale knowledge integration across place-based cases, and explore how ResNet is employing some of these solutions.

Background: Fecal immunochemical test (FIT) performance can be affected by post-collection variables. Collection technique might also affect fecal hemoglobin concentration (f-Hb). Variation in quantity of feces collected in samples returned in a colorectal cancer detection program, and the effects of under-sampling, were assessed. Methods: Collection devices obtained from patients undergoing FIT were assessed for the color (in five classes) of the feces in buffer, mass, and f-Hb. Associations between these were examined in an in vitro study on Hb-spiked feces. Variables possibly associated with under-sampling were investigated using multivariable logistic regression. The effect of low sample mass on clinical performance (false-negative results) was determined. Results: Of 6,898 samples collected by 3,449 individuals (46.9% male, median age: 65.3 years), the buffer was lightest in color in 362 (5.2%), and darkest in 420 (6.1%). Samples with the lightest color had a significantly lower f-Hb compared with all darker classes (P < 0.001). Mass was recorded for 650 devices: The lightest colored samples had significantly lower mass (P < 0.05). The correlation between mass and f-Hb was confirmed in vitro (r = 0.897, P < 0.001). Low mass was not associated with age, sex, or technical factors (P > 0.05). Under-sampling related to the lightest color was not associated with false-negative results for colorectal cancer and advanced adenoma, but was for all neoplasia and inflammatory bowel disease. Conclusions: Wide variation existed in the amount of feces collected. Under-sampling results in lower measured f-Hb and may increase false-negative results. Impact: Color of sample buffer could be used to identify inadequate sampling.

Background Faecal haemoglobin concentration (f-Hb), estimated using a faecal immunochemical test, can be safely implemented in primary care to assess risk of colorectal cancer (CRC). Clinical outcomes of patients presenting with symptoms of lower gastrointestinal disease were examined using an extensive range of f-Hb thresholds to decide on reassurance or referral for further investigation. Methods All patients who attended primary care and submitted a single faecal specimen faecal immunochemical test in the first year of the routine service had f-Hb estimated using HM-JACKarc: f-Hb thresholds from Results Low f-Hb thresholds of 400 µg/g, ≥200 µg/g and ≥100 µg/g. However, patients with a f-Hb concentration of Conclusions In primary care, f-Hb, in conjunction with clinical assessment, can safely and objectively determine individual risk of CRC and decide on simple reassurance or urgent, or routine referral.

AimsThe presence of detectable faecal haemoglobin (f-Hb) has been shown to be associated with all-cause mortality and with death from a number of chronic diseases not known to cause gastrointestinal blood loss. This effect is independent of taking medicines that increase the risk of bleeding. To further investigate the association of f-Hb with chronic disease, the relationship between f-Hb and prescription of medicines for a variety of conditions was studied.MethodsAll subjects (134 192) who participated in guaiac faecal occult blood test (gFOBT) screening in Tayside, Scotland, between March 2000 and March 2016, were studied in a cross-sectional manner by linking their gFOBT result (abnormal or normal) with prescribing data at the time of the test.ResultsThe screening participants with an abnormal gFOBT result were more likely to have been being prescribed medicines for heart disease, hypertension, diabetes and depression than those with a normal test result. This association persisted after adjustment for sex, age and deprivation (OR 1.35 (95%CI 1.23 to 1.48), 1.39 (1.27 to 1.52), 1.35 (1.15 to 1.58), 1.36 (1.16 to 1.59), all pConclusionsThe results of this study confer further substantial weight to the concept that detectable f-Hb is associated with a range of common chronic conditions that have a systemic inflammatory component; we speculate that f-Hb might have potential in identifying individuals who are high risk of developing chronic conditions or are at an early stage of disease.

Background Performing high-quality surveillance for influenza-associated hospitalization (IAH) is challenging, time-consuming, and essential. Objectives Our objectives were to develop a fully automated surveillance system for laboratory-confirmed IAH at our multihospital health system, to evaluate the performance of the automated system during the 2018 to 2019 influenza season at eight hospitals by comparing its sensitivity and positive predictive value to that of manual surveillance, and to estimate the time and cost savings associated with reliance on the automated surveillance system. Methods Infection preventionists (IPs) perform manual surveillance for IAH by reviewing laboratory records and making a determination about each result. For automated surveillance, we programmed a query against our Enterprise Data Vault (EDV) for cases of IAH. The EDV query was established as a dynamic data source to feed our data visualization software, automatically updating every 24 hours.To establish a gold standard of cases of IAH against which to evaluate the performance of manual and automated surveillance systems, we generated a master list of possible IAH by querying four independent information systems. We reviewed medical records and adjudicated whether each possible case represented a true case of IAH. Results We found 844 true cases of IAH, 577 (68.4%) of which were detected by the manual system and 774 (91.7%) of which were detected by the automated system. The positive predictive values of the manual and automated systems were 89.3 and 88.3%, respectively.Relying on the automated surveillance system for IAH resulted in an average recoup of 82 minutes per day for each IP and an estimated system-wide payroll redirection of $32,880 over the four heaviest weeks of influenza activity. Conclusion Surveillance for IAH can be entirely automated at multihospital health systems, saving time, and money while improving case detection.

Background Quantitative faecal immunochemical tests measure faecal haemoglobin concentration (f-Hb), which increases in the presence of colorectal neoplasia. Objective We examined the diagnostic accuracy of faecal immunochemical test (FIT)in patients at increased risk of colorectal cancer (CRC) attending for surveillance colonoscopy as per national guidelines. Methods A total of 1103 consecutive patients were prospectively invited to complete a FIT before their scheduled colonoscopy in two university hospitals in 2014– 2016. F-Hb was analysed on an OC-Sensor io automated analyser (Eiken Chemical Co., Ltd, Tokyo, Japan) with a limit of detection of 2 µg Hb/g faeces. The diagnostic accuracy of f-Hb for CRC and higher-risk adenoma was examined. Results A total of 643 patients returned a faecal test. After excluding 4 patients with known inflammatory bowel disease, 639 (57.9%) remained in the study: age range: 25–90 years (median: 64 years, interquartile range (IQR): 55–71): 54.6% male. Of 593 patients who also completed colonoscopy, 41 (6.9%) had advanced neoplasia (4 CRC, 37 higher-risk adenoma). Of the 238 patients (40.1%) who had detectable f-Hb, 31 (13.0%) had advanced neoplasia (2 CRC, 29 higher-risk adenoma) compared with 10 (2.8%) in those with undetectable f-Hb (2 CRC, 8 higher-risk adenoma). Detectable f-Hb gave negative predictive values of 99.4% for CRC and 97.2% for CRC plus higher-risk adenoma. Conclusion In patients at increased risk of CRC under colonoscopy surveillance, a test measuring faecal haemoglobin can provide an objective estimate of the risk of advanced neoplasia, and could enable tailored scheduling of colonoscopy.

Objectives Faecal immunochemical tests for haemoglobin (FIT) are becoming widely used in colorectal cancer (CRC) screening and assessment of symptomatic patients. Faecal haemoglobin concentration (f-Hb) thresholds are used to guide subsequent investigation. We established the distributions of f-Hb in a large screening population by sex, age, deprivation and geography. Methods Single estimates of f-Hb were documented for all individuals participating in the first 18 months of the Scottish Bowel Screening Programme (SBoSP). The distributions of f-Hb were generated for all participants, all men and women, and men and women by age quintile and deprivation quintile. Distributions were also generated by geographical region for all participants, men and women, and by deprivation. Comparisons of f-Hb distributions with those found in a pilot evaluation of FIT and three other countries were performed. Results f-Hb was documented for 887,248 screening participants, 422,385 men and 464,863 women. f-Hb varied by sex, age, deprivation quintile and geographical region. The f-Hb distributions by sex and age differed between the SBoSP and the pilot evaluation and the three other countries. Conclusions f-Hb is higher in men than in women and increases with age and deprivation in both sexes. f-Hb also varies by geographical region, independently of deprivation, and by country. The f-Hb distribution estimated by pilot evaluation may not represent the population distribution. Decision limits have advantages over reference intervals. Use of partitioned f-Hb thresholds for further investigation, based on the data generated, has advantages and disadvantages, as do risk scores based on a spectrum of influencing variables.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes. Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression. Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12–3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism. Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significance More insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolism Biomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials. Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.

Background Polypectomy may be performed at colonoscopy and then subsequent surveillance undertaken. It is thought that faecal haemoglobin concentration (f-Hb), estimated by quantitative faecal immunochemical tests (FIT), might be a useful tumour marker. Methods Consecutive patients enrolled in colonoscopy surveillance were approached at two hospitals. A specimen for FIT was provided before colonoscopy and, ideally after 3 weeks, a second FIT sample from those who had polypectomy. A single FIT system (OC-Sensor io, Eiken Chemical Co., Ltd) was used to generate f-Hb. Results 1103 Patients were invited; 643 returned a FIT device (uptake: 58.3%). Four patients had known inflammatory bowel disease (IBD) and were excluded, leaving 639 (57.9%) with an age range of 25–90 years (median 64 years), 54.6% male. Of 593 patients who had a f-Hb result and completed colonoscopy, advanced neoplasia was found in 41 (6.9%); four colorectal cancer (CRC): 0.7% and 37 advanced adenoma (AA): 6.3%, and a further 127 (21.4%) had non-advanced adenoma (NAA). The median f-Hb was significantly greater in AA as compared to NAA; 6.0 versus 1.0 μg Hb/g faeces, p < 0.0001.134/164 (81.7%) of invited patients returned a second FIT device: 28 were patients with AA in whom median pre-polypectomy f-Hb was 19.2, falling to 3.5 μg Hb/g faeces post-polypectomy, p = 0.01, and 106 with NAA had median pre-polypectomy f-Hb 0.8 compared to 1.0 μg Hb/g faeces post-polypectomy, p = 0.96. Conclusions Quantitative FIT could provide a good tumour marker in post-polypectomy surveillance, reduce colonoscopy requirements and minimise potential risk to patients.

Microsporidia are ubiquitous obligate intracellular pathogens of animals. These parasites often infect hosts through an oral route, but little is known about the function of host intestinal proteins that facilitate microsporidia invasion. To identify such factors necessary for infection by Nematocida parisii, a natural microsporidian pathogen of Caenorhabditis elegans, we performed a forward genetic screen to identify mutant animals that have a Fitness Advantage with Nematocida (Fawn). We isolated four fawn mutants that are resistant to Nematocida infection and contain mutations in T14E8.4, which we renamed aaim-1 (Antibacterial and Aids invasion by Microsporidia). Expression of AAIM-1 in the intestine of aaim-1 animals restores N. parisii infectivity and this rescue of infectivity is dependent upon AAIM-1 secretion. N. parisii spores in aaim-1 animals are improperly oriented in the intestinal lumen, leading to reduced levels of parasite invasion. Conversely, aaim-1 mutants display both increased colonization and susceptibility to the bacterial pathogen Pseudomonas aeruginosa and overexpression ofaaim-1 reduces P. aeruginosa colonization. Competitive fitness assays show that aaim-1 mutants are favored in the presence of N. parisii but disadvantaged on P. aeruginosa compared to wild-type animals. Together, this work demonstrates how microsporidia exploits a secreted protein to promote host invasion. Our results also suggest evolutionary trade-offs may exist to optimizing host defense against multiple classes of pathogens.

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&qid=1628781352814) to IVDR 2017/746 https://eur-lex.europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infrastructural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its “droit d’exister”.

The development of modern, industrial agriculture and its high input-high output carbon energy model is rendering agricultural landscapes less resilient. The expected continued increase in the frequency and intensity of extreme weather events, in conjunction with declining soil health and biodiversity losses, could make food more expensive to produce. The United Nations has called for global action by establishing 17 sustainable development goals (SDGs), four of which are linked to food production and security: declining biodiversity (SDG 15), loss of ecosystem services and agroecosystem stability caused by increasing stress from food production intensification and climate change (SDG 13), declining soil health caused by agricultural practices (SDGs 2 and 6), and dependence on synthetic fertilizers and pesticides to maintain high productivity (SDG 2). To achieve these SDGs, the agriculture sector must take a leading role in reversing the many negative environmental trends apparent in today's agricultural landscapes to ensure that they will adapt and be resilient to climate change in 2030 and beyond. This will demand fundamental changes in how we practice agriculture from an environmental standpoint. Here, we present a perspective focused on the implementation of an agrosystem approach, which we define to promote regenerative agriculture, an integrative approach that provides greater resilience to a changing climate, reverses biodiversity loss, and improves soil health; honors Indigenous ways of knowing and a holistic approach to living off and learning from the land; and supports the establishment of emerging circular economies and community well-being. Integr Environ Assess Manag 2022;18:1199-1205. © 2021 SETAC.

International audience

Theoretically, climate change will create warmer temperatures and greater precipitation in mountainous regions, making agriculture possible in areas that were once unsuitable for cropping. But the extent and the nature of these ‘agricultural frontiers’ is as yet unknown. Building upon recent research on Climate Change Driven Agricultural Frontiers [CCDAFs], this paper assesses the potential of agricultural expansion in the Hindukush Himalaya [HKH]. Using FAO crop suitability data, we estimated the extent of CCDAFs under three Representative Concentration Pathways for 13 crops as well as the potential impacts of developing these frontiers on ecosystem services. We show that under climate change projected by the IPSL- CM5A-LR climate model, 34,507 km2 of agricultural frontiers may emerge in the HKH by 2100 under RCP 6.0. Additionally, results suggest that there will be new opportunities for crop diversification as individual crops will gain frontier area. However, developing these CCDAFs will impact supportive and regulating ecosystem services including carbon storage and sequestration, soil quality, biodiversity, and hydrological processes—with implications for regional water security. These impacts must be considered alongside the benefits of additional food production when evaluating the net benefits of developing CCDAFS.