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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.

The article is intended to stimulate the discussions on sustainable development and separate Sustainable Development Goals. It was initially prepared for the 21st session of the UN Committee of Experts on Public Administration “Transforming institutions and governance to build forward better towards 2030”. The article covers the progress, lessons learned and challenges of the COVID-19 pandemic and its impacts on the implementation of Goals 4, 5, 14 and 15 and on leaving no one behind, as well as reflections on the challenges of state-building. The authors suggest that building strong and effective public institutions is crucial for achieving the Goals and building forward better after the pandemic. This should be accompanied by investments in the public sector workforce to align competences and values with the challenges ahead. Supporting developing countries in making their public institutions, societal and physical infrastructure and economies more resilient and agile not only against COVID-19 but against all potential future shocks is crucial and in the interest of all nations. Global cooperation and solidarity are therefore critical, and all countries should work together to address the virus and ensure equitable vaccine distribution while also ensuring that no one – and no country – is left behind.

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.

Background Faecal Immunochemical tests (FITs) in the assessment of patients presenting with symptoms have generally used a single sample. Little evidence pertains to the use of replicate, where a number of tests are done prior to decision-making or repeat FIT, where additional FIT are performed following clinical decision-making. Overwhelmingly, research has focussed on FIT to help identify colorectal cancer (CRC). The aim of this review is to assess the available literature concerning replicate and repeat FIT in symptomatic patients to help generate consensus and guide future research. Methods The terms ‘faecal immunochemical test’ or ‘FIT’ were combined with ‘multiple’ or ‘repeat’. EMBASE, Medline and PubMed database and other searches were conducted. All papers published in English were included with no exclusion date limits until November 2021. Results Of the 161 initial papers screened, seven were included for review. Qualitative and quantitative FIT outcomes were assessed in the studies. The primary aims of most related to whether replicate FIT increased diagnostic yield of CRC, with colonoscopy used as the reference standard. One publication assessed the impact of a new COVID-adapted pathway on CRC detection. No consensus on replicate FIT was apparent. Some concluded that FITs may help minimise missed CRC diagnoses: others showed no increase in diagnostic yield of CRC. Conclusions Current evidence on replicate and repeat FIT is both minimal and conflicting. FIT is a superb clinical tool, but significant gaps surrounding application remain. Further studies relating to replicate and repeat FIT are required.

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.

C. elegansis a free-living nematode that must adapt to a wide range of environments including both aerobic and anaerobic conditions. To survive in low oxygen,C. eleganscan use an unusual form of anaerobic respiration that relies on rhodoquinone (RQ) as an alternative electron carrier. Parasitic nematodes like hookworm and whipworm also require rhodoquinone-dependent metabolism (RQDM) to survive in the highly anaerobic conditions in the human gut. Understanding how RQDM is regulated inC. elegansmay thus identify new ways to combat these closely-related major human pathogens. We previously established a simple movement-based assay for RQDM inC. elegans. In this study, we tested a panel of wild-type isolates ofC. elegansin our RQDM assay and find substantial variation in their ability to use RQDM. We carried out a genome-wide association study (GWAS) to identify loci that affect RQDM — this identified a single major QTL on the right arm of Chromosome III. We used RNAi to test almost all genes within the QTL region for involvement in RQDM and found one gene,wah-1, that strongly modulates RQDM-dependent recovery inC. elegans. WAH-1 is a mitochondrial flavoprotein that affects the electron transport chain, consistent with a role in RQDM. We show thatwah-1expression varies between isolates due to major changes inwah-1transcript structures and this correlates tightly with variation in RQDM. Finally, we show that there is similar complexity towah-1transcription in parasitic nematodes and thatwah-1transcript structures change as parasites shift from aerobic to anaerobic, RQ- requiring metabolism. We thus conclude that reducedwah-1expression correlates with increased ability to survive in conditions where RQDM is essential.

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.

Background There is recognition that a reduction of consumer demand for foods that have large environmental footprints is necessary. Recent innovations in food production technologies (“food frontiers”) claim to offer gains in ecological sustainability and global food security, thereby transitioning our food system toward a more sustainable future. Yet, scientific evidence to support these claims has not been critically reviewed for several high-profile innovations. Scope and approach In this paper, we undertake a critical review of the literature on five food frontiers: cellular agriculture, climate-driven northern agricultural expansion (NAE), controlled environment agriculture (CEA), entomophagy, and seaweed aquaculture. We estimate the feasibility of each frontier’s widespread implementation by 2050 and their potential positive impacts on food system sustainability. We highlight uncertainty regarding ecological tradeoffs and future production potential in the literature, research gaps, and policy pathways that may maximize the benefits of these food frontiers. Key findings and conclusions Entomophagy, cellular agriculture, CEA, and seaweed aquaculture have similar positive impact values. Yet, CEA appears to be the most feasible technology to implement at scale. The mixed potential impacts of NAE suggest that such expansion poses multiple risks to the global food system. Standardized approaches to modeling environmental parameters in life cycle analyses are required, so that predicted impacts can be reasonably compared within and among these bodies of literature. Further critical social scientific engagement is needed to better understand the political and institutional frameworks in which these food frontiers will be implemented.

Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene

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.

This report is the unmodified work-in-progress monograph written by Sandy Fraser from 2003 onwards to capture his vision for a global network architecture that would scale to levels of quality and resilience beyond that of anything existing at the time. There are multiple areas of the document that are marked as “to do” or are otherwise incomplete. We believe it to be a valuable historical record of the original research that occurred first at AT&T Labs Research and subsequently at Fraser Research, and have preserved it in its entirety in this technical report.

Australian sediment-hosted mineral systems are important sources of base metals and critical minerals that are vital to delivering Australia’s low-carbon economy. In Australia, sediment-hosted resources account for ~82% and ~86% of the total zinc (Zn) and lead (Pb) resources respectively. Given their significance to the Australian economy, four national-scale mineral potential models for sediment-hosted Zn-Pb mineral systems have been developed: clastic-dominated siliciclastic carbonate, clastic-dominated siliciclastic mafic, Mississippi Valley-type and Irish-type. In addition to the potential for Zn-Pb mineralisation, the uncertainty related to data availability has been examined. The mineral potential models were created using a mineral systems-based approach where mappable criteria have been used to assess the prospectivity of each system. Each model has been derived from a large volume of precompetitive geoscience data. The clastic-dominated siliciclastic carbonate mineral potential model predicts 92% of known deposits and occurrences within 15.5% of the area, the clastic-dominated siliciclastic mafic mineral potential model predicts 85% of deposits and occurrences within 27% of the area, and the Mississippi Valley-type mineral potential model predicts 66% of known deposits and occurrences within 31% of the area. Each model successfully predict the location of major sediment-hosted Zn-Pb deposits while highlighting new areas of elevated prospectivity in under-explored regions of Australia, reducing the exploration search space by up to 85% for sediment-hosted Zn-Pb mineral systems.

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.

Trisomy 21 or Down syndrome is associated with multiple orthopaedic manifestations. Although cervical instability is the most common spinal condition associated with Down syndrome, the prevalence of scoliosis has been estimated at 4.8% to 8.7%. Very few prior studies have documented the role of spinal fusion in this population, and all have included ≤10 patients.An institutional review board-approved multicenter retrospective analysis of patients with Down syndrome treated with spinal fusion between January 2009 and December 2019 was performed by cross-referencing Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10) codes. Patients were followed for ≥2 years, with a mean follow-up of 3.77 years. Clinical and radiographic outcomes were collected, and complications were documented using the Clavien-Dindo-Sink (CDS) classification.A total of 23 patients were included: 96% had ≥1 medical comorbidities, including 16 (70%) with congenital heart disease, of whom 88% had previous cardiac surgery, and 10 (44%) with thyroid disorders. All 23 patients underwent posterior spinal fusion. The mean estimated blood loss was 617 ± 459 mL, the mean length of the surgical procedure was 290 ± 92.7 minutes, and the mean length of hospital stay was 6.03 ± 2.91 days. The major Cobb angle measured 61.7° ± 17.6°, which corrected to 19.4° ± 14.8° (68.6% correction; p0.001), with well-maintained correction at 2 years of 22.0° ± 10.3° (64.3% correction; p = 0.158). Thirteen (57%) of 23 patients had a change in curve of5°. There were no intraoperative complications; however, 12 patients (52%) sustained postoperative complications (e.g., need for reoperation, implant failure, and pulmonary complications), including 6 patients with CDS type 3 or 4 (e.g., wound dehiscence, late superficial abscess, pleural effusion, pseudarthrosis, and readmission for hypoxia). Four patients (17%) required a revision surgical procedure. One patient (4%) required an unplanned intensive care unit admission.Although instrumented spinal fusion can effectively correct spinal deformity in these patients, complications are more frequent than in children with adolescent idiopathic scoliosis, with over half of patients sustaining a complication.Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Soil-transmitted helminths (STHs) including Ascaris, hookworm, and whipworm are major human pathogens infecting over a billion people worldwide1,2. There are few existing classes of anthelmintics and resistance is increasing3–5 — there is thus an urgent need for new classes of these drugs. Here we focus on identifying compounds that interfere with the unusual anaerobic metabolism that STHs use to survive the highly hypoxic conditions of the host gut6–9. This requires rhodoquinone (RQ), a quinone electron carrier that is not made or used by the STH hosts10. We previously showed that C. elegans also uses this rhodoquinone-dependent metabolism (RQDM)11 and established a high throughput assay for RQDM11. We screened a collection of 480 natural products for compounds that kill worms specifically when they rely on RQDM — these 480 are representatives of a full library of ~25,000 natural products and derivatives12,13. We identify several classes of compound including a novel family of species selective inhibitors of Complex I. These Complex I inhibitors are based on a benzimidazole core but unlike commercial benzimidazole anthelmintics they do not target microtubules14–17. We screened over 1,200 benzimidazoles and identify the key structural requirements for species selective Complex I inhibition. We suggest that these novel benzimidazole species-selective Complex I inhibitors may be potential anthelmintics.

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.

Background: In September 2018, pharmacy antimicrobial stewardship (AMS) services were expanded to include weekends at this academic medical center. Activities performed by AMS pharmacists on the weekends include blood culture rapid diagnostic (RDT) review, antiretroviral therapy (ART) review, prospective audit and feedback (PAF) utilizing clinical decision support, vancomycin dosing, and operational support. The purpose of this study was to assess the operational and clinical impact of these expanded AMS services. Methods: This single-center, quasi-experimental study included data from weekends before (9/2017–11/2017) and after (9/2018–11/2018) implementation. The descriptive primary outcome was the number of activities completed for each AMS activity type in the post-implementation group only. Secondary outcomes were time to AMS opportunity resolution, time to escalation or de-escalation following PAF or RDT alert, time to resolution of miscellaneous AMS related opportunities, length of stay (LOS), and antimicrobial use outcomes. Results: During the post-implementation period 1258 activities were completed, averaging 97/weekend. Inclusion criteria for time to resolution outcomes were met by 72 patients pre-implementation and 59 patients post. The median (IQR) time to AMS opportunity resolution decreased from 18.5 hours pre-intervention (7.7-35.7) to 8.5 hours post-intervention (IQR 1.8-14.0), p < 0.01. Time to escalation was 11.6 hours compared to 1.7 hours (p = 0.1), de-escalation 16.7 hours compared to 10.8 hours (p = 0.03), and miscellaneous opportunity 40.8 hours compared to 13.2 hours (p = 0.01). No differences were observed in LOS or antimicrobial use outcomes. Conclusion: Presence of pharmacist-driven weekend AMS services significantly reduced time to resolution of AMS opportunities. These data support the value of weekend AMS services.

Objective:Clostridioides difficile infection (CDI) causes significant morbidity and mortality; however, the diagnosis of CDI remains controversial. The primary aim of our study was to evaluate the association of polymerase chain reaction (PCR) cycle threshold (Ct) values with CDI disease severity, recurrence, and mortality among adult patients with CDI.Design:Retrospective cohort study.Setting:Single tertiary-care hospital.Patients:Adult patients diagnosed with hospital-onset, healthcare facility–associated CDI from June 2014 to September 2015.Methods:We performed a retrospective chart review of included patients. Univariate and multivariable logistic regression methods were used to evaluate the association between Ct values and CDI severity, 8-week recurrence, and 30-day mortality.Results:Among 318 included patients, 51% were male and the mean age was 62 years; ~32% of the patients developed severe CDI and 11% developed severe–complicated CDI. The 30-day all-cause mortality rate was 11% and the 8-week recurrence rate was 9.5%. The overall mean Ct value was 32.9 (range, 23–40). Multivariable analyses showed that lower values of PCR Ct were associated with increased odds of 30-day morality (odds ratio [OR] 0.83; 95% confidence interval [CI], 0.72–0.96) but were not independently associated with CDI severity (OR, 0.99; 95% CI, 0.90–1.09) or recurrence (OR, 0.88; 95% CI, 0.77–1.00).Conclusions:Our findings suggest that PCR Ct values at the time of diagnosis may have a limited predictive value and utility in clinical decision making for inpatients with CDI. Larger, prospective studies across different patient populations are needed to confirm our findings.

Nil.

Currently, women are disadvantaged compared to men in colorectal cancer (CRC) screening, particularly in programmes that use faecal immunochemical tests for haemoglobin (FIT) followed by colonoscopy. Although there is no single cause for all the known disadvantages, many can be attributed to the ubiquitous finding that women have lower faecal haemoglobin concentrations (f-Hb) than men; there are many plausible reasons for this. Generally, a single f-Hb threshold is used in CRC screening programmes, leading to lower positivity for women than men, which causes poorer outcomes for women, including lower CRC detection rate, higher interval cancer (IC) proportion, and higher CRC mortality. Many of the now widely advocated risk scoring strategies do include factors taking account of sex, but these have not been extensively piloted or introduced. Using different f-Hb thresholds for the sexes seems advantageous, but there are difficulties, including deciding which characteristic should be selected to achieve equivalency, for example, positivity, IC proportions, or specificity. Moreover, additional colonoscopy resources, often constrained, would be required. Governments and their agencies should be encouraged to prioritise the allocation of resources to put simple strategies into practice, such as different f-Hb thresholds to create equal positivity in both sexes.

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