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Many new methods for single atom skeletal editing of heterocycles have been developed in the past few years with obvious applications to discovery chemistry. In this perspective, we assess the recent advances in this field and the potential application to lead exploration campaigns.

Objective: To investigate the ventilatory and circulatory differences between eccentric (ECC) and concentric (CON) cycling exercise at submaximal, low-dose intensity from onset to end-exercise in healthy middle-aged participants. Design: Randomized controlled crossover trial. Setting: The participants underwent 1 ECC and 1 CON test according to stepwise incremental exercise protocols at identical, submaximal intensities. Breath-by-breath analyses of ventilatory gas exchange and echocardiography were used to assess cardiopulmonary function during exercise. Participants: 24 healthy middle-aged, untrained participants (14 women, 10 men, 50±14 years) were included. Interventions: 1 ECC and 1 CON test at submaximal intensities. Main Outcome Measure: The main outcome was oxygen uptake (V'O2). Results: The V'O2 increase was reduced by -422 mL/min (-52%, 95% confidence interval: -513 to -292, P

Dynamic PET allows quantification of physiological parameters through tracer kinetic modeling. For dynamic imaging of brain or head and neck cancer on conventional PET scanners with a short axial field of view, the image-derived input function (ID-IF) from intracranial blood vessels such as the carotid artery (CA) suffers from severe partial volume effects. Alternatively, optimization-derived input function (OD-IF) by the simultaneous estimation (SIME) method does not rely on an ID-IF but derives the input function directly from the data. However, the optimization problem is often highly ill-posed. We proposed a new method that combines the ideas of OD-IF and ID-IF together through a kernel framework. While evaluation of such a method is challenging in human subjects, we used the uEXPLORER total-body PET system that covers major blood pools to provide a reference for validation. Methods: The conventional SIME approach estimates an input function using a joint estimation together with kinetic parameters by fitting time activity curves from multiple regions of interests (ROIs). The input function is commonly parameterized with a highly nonlinear model which is difficult to estimate. The proposed kernel SIME method exploits the CA ID-IF as a priori information via a kernel representation to stabilize the SIME approach. The unknown parameters are linear and thus easier to estimate. The proposed method was evaluated using 18F-fluorodeoxyglucose studies with both computer simulations and 20 human-subject scans acquired on the uEXPLORER scanner. The effect of the number of ROIs on kernel SIME was also explored. Results: The estimated OD-IF by kernel SIME showed a good match with the reference input function and provided more accurate estimation of kinetic parameters for both simulation and human-subject data. The kernel SIME led to the highest correlation coefficient (R = 0.97) and the lowest mean absolute error (MAE = 10.5 %) compared to using the CA ID-IF (R = 0.86, MAE = 108.2 %) and conventional SIME (R = 0.57, MAE = 78.7 %) in the human-subject evaluation. Adding more ROIs improved the overall performance of the kernel SIME method. Conclusion: The proposed kernel SIME method shows promise to provide an accurate estimation of the blood input function and kinetic parameters for brain PET parametric imaging.

Background Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design A prospective multicentre observational cohort study (the ‘SONAR’ study). Setting Seventeen haemodialysis centres in the UK. Participants Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas’ non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial Registration This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information. Plain language summary What was the problem? For people with advanced kidney disease, haemodialysis is best provided by an ‘arteriovenous fistula’, which is created surgically by joining a vein onto an artery at the wrist or elbow. However, these take about 2 months to develop fully (‘mature’), and as many as 3 out of 10 fail to do so. What was the question? We asked whether we could use early ultrasound scanning of the fistula to identify those that are unlikely to mature. This would allow us to decide whether it would be practical to run a large, randomised trial to find out if using early ultrasound allows us to ‘rescue’ fistulas that would otherwise fail. What did we do? We invited adults to undergo serial ultrasound scanning of their fistula in the first few weeks after it was created. We then analysed whether we could use the data from the early scans to identify those fistulas that were not going to mature by week 10. What did we find? Of the 333 fistulas that were created, about two-thirds reached maturity by week 10. We found that an ultrasound scan 4 weeks after fistula creation could reliably identify those fistulas that were going to mature. However, of those fistulas predicted to fail, about one-third did eventually mature without further intervention, and even without knowing what the early scans showed, another third were successfully rescued by surgery or X-ray-guided treatment at a later stage. What does this mean? Performing an early ultrasound scan on a fistula can provide reassurance that it will mature and deliver trouble-free dialysis. However, because scans are poor at identifying fistulas that are unlikely to mature, we would not recommend their use to justify early surgery or X-ray-guided treatment in the expectation that this will improve outcomes. Scientific summary Background Because of their favourable durability and low infection rates, arteriovenous fistulas (AVFs) are considered the best option for provision of haemodialysis, and they offer survival advantages compared to dialysis through a central venous catheter (CVC). Upon surgical creation, AVFs undergo a period of ‘maturation’, wherein the transit of high-pressure arterial flow through the anastomosis triggers compensatory dilatation and thickening of the draining fistula vein, with marked increases in blood flow through the AVF. This maturation, which generally takes about 2 months, is required to achieve functionality and enables the AVF to be used for dialysis. The main drawback with AVFs is that a large proportion (in excess of 30% in some series) do not develop fully, and either thrombose or remain patent in an immature state. This necessitates further surgical or radiological interventions to aid maturation, or formation of an entirely new fistula, thus potentially prolonging the requirement for dialysis through a CVC. Strategies to increase maturation rates and early patency of AVFs may therefore make a substantial difference to patient outcomes. In this respect, widespread patient and clinician consultation, supported by the James Lind Alliance, has identified the question, ‘What can be done to make fistulas or grafts last as long as possible?’ as one of the top 10 research priorities in vascular access provision. One possible approach to counter early fistula loss from non-maturation/thrombosis is to use Doppler ultrasound (US) surveillance in the first few weeks after creation to identify at-risk fistulas and to inform early radiological or surgical intervention, in anticipation that this improves longer-term fistula patency. This has, however, not yet been tested. The SONAR consortium, representing 17 UK centres that provide vascular access surgery, was established to test the hypothesis: Doppler US surveillance of AVFs immediately after creation improves longer-term AVF patency, by directing early and effective surgical or radiological salvage of those AVFs at risk of failing or not maturing. Objectives In considering the above hypothesis, several conditions must be met if US-guided early salvage intervention is to improve outcomes following AVF creation: that US can effectively distinguish those newly formed fistulas that are unlikely to mature that maturity failure occurs commonly enough that clinically meaningful improvements in fistula outcomes by early identification of at-risk fistulas are plausible that salvage interventions performed on those ‘at-risk’ fistulas are effective and improve fistula patency. The SONAR study thus aimed to address the following objectives sequentially, over a 5-year window: Run an observational cohort study in which consenting participants undergo serial US assessment of their AVF in the first 3 months after its formation (phase 1). Model whether features on early US can reliably identify those fistulas that will not mature or will fail early. Assess from the observational cohort study whether a randomised controlled trial (RCT) evaluating early US-guided salvage intervention is feasible. Run a multicentre RCT in which 1-year fistula patency in a treatment group receiving early US surveillance of their developing fistula is compared against standard care: monitoring of fistula maturation by clinical assessment only (phase 2). Progression to the phase 2 study depended upon accomplishing the first three objectives and, in particular, demonstrating that US surveillance could accurately predict fistula non-maturation. This manuscript will thus focus on the phase 1 study set-up and outcomes. Methods A prospective multicentre observational cohort study of adult patients undergoing formation of AVF for haemodialysis was performed to test the hypothesis: Doppler US surveillance early after AVF creation can reliably identify those AVFs that will not mature or will fail early. Criteria for participation were as follows: Adult, aged 16 years or older. The participant had end-stage renal disease and was either already established on haemodialysis or likely to start imminently. The participant was due creation of an arm AVF (either wrist or elbow) including the following types of fistula: radiocephalic, ulnobasilic, brachiocephalic and brachiobasilic (one- or two-stage) fistula, with a minimal acceptable threshold of 2 mm venous diameter at whatever site was chosen. Full informed consent to participate was provided. Consenting participants underwent serial US scanning at weeks 2, 4, 6 and 10 after fistula formation in addition to standard care (such as regular clinical assessment) as per local centre policy. Fistula flow rates, fistula venous diameter and resistance index were recorded, according to a standard study protocol, with clinical teams blinded to the US findings, unless a scan was simultaneously requested on clinical grounds or the scan confirmed thrombosis of the fistula. The primary outcome measure was fistula maturation at 10 weeks. To encompass participants who remained pre-dialysis, along with clinical examination, maturation was assessed at 10 weeks according to accepted surrogate US parameters: wrist fistula: representative venous diameter ≥ 4 mm, with flow > 400 ml/minute elbow fistula: representative venous fistula diameter ≥ 5 mm, with flow > 500 ml/minute. Three distinct outcomes defined fistula non-maturation: a fistula occlusion/thrombosis within the study period (76 days post AVF creation) fistula abandonment within the study period due to failure to mature or due to thrombosis/occlusion failure to achieve (either reported at the week 10 scan or imputed) maturation, according to the preset US parameters. The following secondary outcome measures were also recorded: for those patients established on dialysis, successful use of the fistula for dialysis on three successive occasions clinical suitability for dialysis 10 weeks after fistula creation based on examination alone according to local practice formation of a new fistula (including fashioning of proximal neoanastomosis) or radiological salvage procedure fistula thrombosis secondary fistula patency patient acceptability, based on the proportion of patients that complete their scans. Assuming that early US surveillance predicts fistula non-maturation/failure in 25% of AVFs, a total of 347 fistulas were required to achieve precision of ± 10% for an estimated 72% positive predictive value (PPV) for detecting non-maturation/failure. The total sample size allows for 10% dropout. Mixed multivariable logistic regression (binary-data population-average model with exchangeable correlation structure) of the early US scan data was then used to build separate models for wrist and elbow AVF that contained the minimum number of measurements required to predict AVF non-maturation by 10 weeks. Receiver operating characteristic curves of the developed risk scores were analysed to determine when surgical or radiological intervention on the developing AVF could be considered. The PPV and negative predictive value (NPV; the probability of AVF maturation given that the model predicts maturation) were calculated alongside a 95% confidence interval (CI) for the chosen risk-score cut-off. Additional modelling was then performed on a subset (n = 192) of the original SONAR cohort available for follow-up, to assess whether fistula failure at 6 and 12 months could be identified by analysis of early US characteristics. The primary outcome measure for the longer-term follow-up was primary fistula patency at 6 months, defined as ‘the interval between access creation to the earliest time of fistula thrombosis, abandonment (except abandonment because of steal), intervention on the fistula (to re-establish or maintain patency) or the time of measurement of patency’. Secondary outcome measures included assisted primary patency (the interval from access creation until access thrombosis or the time of measurement of patency, including any interventions to maintain patency) and secondary patency (the interval from access creation to time of measurement of patency or to abandonment of the fistula). Similar binary-data population-average modelling was performed as for predicting 10-week non-maturation, aiming to build parsimonious models that contained the minimum number of variables from one scan time point (at either week 4 or week 6) to effectively predict primary fistula non-patency at 6 months. Results Of 347 consents to participation (median age 65 years; interquartile range 52–74 years; 64.8% male; 43.2% diabetic; 55.0% pre-dialysis), 333 underwent AVF creation during the study window (47.7% wrist, 52.3% elbow fistula). Early failure before the first US scan occurred in 37 (11.1%) AVFs, but by 10 weeks, 219 of 333 (65.8%) created AVFs had reached maturity (67.2% elbow, 60.4% wrist). Of the remainder, by week 10 a further 20 had failed (57 failures in total; 17.1%), 29 (8.7%) remained patent but not mature and the status of 28 (8.4%) was unknown. Excluding those failures occurring within the first 2 weeks (because it would be impractical to organise salvage so quickly) results in a fistula maturation rate of 74.0% at 10 weeks. Serial US scanning revealed that maturation occurred rapidly (the vast majority of AVFs that were mature by 10 weeks had reached maturation by 2 weeks). Comparison of the early scan data in those AVFs that had matured by week 10 against those AVFs that remained immature (see Figure 4) revealed consistently lower fistula flow rates and fistula vein diameter in the latter. For example, the median blood flow at 2 weeks was 1135.5 and 691.0 ml/minute in those elbow and wrist fistulas, respectively, that reached maturation by week 10, whereas week 2 flows of 349.0 and 395.5 ml/minute were recorded in those elbow and wrist fistulas that did not reach maturation at week 10. Modelling to predict AVF non-maturation at week 10 was optimally built on the week 4 scan data but required separate algorithms for wrist and elbow fistulas, with fistula venous diameter and flow rate at week 4 identified as the most significant variables in explaining wrist fistula maturity failure (PPV 60.6%, 95% CI 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow fistula maturity failure (PPV 66.7%, 95% CI 48.9% to 84.4%). Diagnostic tests for model fit and influential observations were run on the optimum models for wrist and elbow AVFs, with both performing well, with area under the curve values of at least 0.90. Conversely, both models could predict fistula maturation much more reliably [NPVs of 95.4% (91.0–99.8) and 95.6% (91.8–99.4) for wrist and elbow, respectively]. Additional modelling was then performed on a subset (n = 192) of the original SONAR cohort available for follow-up, to assess whether fistula failure at 6 and 12 months could be identified by analysis of early US characteristics. Primary, assisted primary and secondary patency AVF rates at 6 months were 76.5%, 80.7% and 83.3%, respectively, and at 12 months were 68.3%, 74.1% and 79.5%, respectively. Broadly similar US characteristics (fistula vein size, flow rate and resistance index) were identified as the most significant variables predicting primary patency failure at 6 months, with similar predictive power as for 10-week AVF maturity failure, but with wide CIs (wrist AVF: PPV 72.7%, 95% CI 46.4% to 99.0%; elbow AVF: 57.1%, 95% CI 20.5% to 93.8%). Moreover, the models performed very poorly at identifying assisted primary and secondary patency failure, likely because a subset of those identified as liable to fail were instead successfully salvaged by radiological or surgical intervention. Conclusions Although early US can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those unlikely to mature or to fail within 6 months. Allied to the better than expected fistula patency rate achieved by the SONAR consortium (that is further improved by successful radiological or survival salvage without recourse to the early US data), we estimate that a prospective randomised trial comparing early US-guided intervention against standard care (observation only) would require at least 1300 fistulas and would only achieve a minimally clinically important difference in the intervention arm if virtually every intervention were successful in maintaining/restoring fistula patency. Limitations The US scan findings were generally not made available to the clinical teams, so as to avoid their influencing participant management. However, scan results were revealed to the responsible clinical team on 98 occasions (10.7% of all scans), either because an early US scan was standard care for that unit (76 occasions) or because unblinding was requested because of clinical concern relating to the fistula’s maturation. It is therefore possible that in a small number of cases, the study US scans triggered salvage procedures that would not otherwise have been performed on clinical grounds alone. This is particularly problematic for the 12-month follow-up study, because the intervention would mark the end of primary patency – the primary outcome measure for the 6-month analysis – and it would therefore provide false support for the statistical modelling. However, in the majority of cases, unblinding did not prompt further intervention (simply instead confirming fistula maturation), and thus is unlikely to have compromised the statistical modelling. Similarly, to include pre-dialysis patients in the study, it was necessary to adopt surrogate US markers to define fistula maturation, and it is perhaps not ideal to be using the same modality to delineate the maturation process as one uses to define maturation, particularly because fistula maturation is principally a functional concern relating to whether the fistula can be used to provide adequate dialysis. Repeat US was not performed at 6 months for the follow-up study, and the analysis of fistula patency, rather than maturation status, provides a better reflection of fistula functionality. This may partly explain the differences in the modelling findings between the 10-week and 6-month studies. Trial registration The SONAR study was approved by the Cambridgeshire and Hertfordshire Research Ethics Committee and by the Health Research Authority (REC 18/EE/0234) and assigned ISRCTN36033877. The SONAR-12M study was approved by the West Midlands – Edgbaston Research Ethics Committee (REC 20/WM/0331) and assigned ISRCTN17399438. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

Introduction Extrapleural pneumonectomy (EPP) and extended pleurectomy/decortication (ePD) are surgical cytoreductive techniques aimed at achieving macroscopic resection in malignant pleural tumours such as pleural mesothelioma, non-mesothelioma pleural malignancies such as thymoma and sarcoma, and rarely for pleural tuberculosis, in a more limited fashion. Despite extensive studies on both surgical techniques and consequences, a significant knowledge gap remains regarding how best to approach the perioperative anaesthesia challenges for EPP and ePD.It is unknown if the risk stratification processes for such surgeries are standardised or what types of functional and dynamic cardiac and pulmonary tests are employed preoperatively to assist in the perioperative risk stratification. Further, it is unknown whether the types of anaesthesia and analgesia techniques employed, and the types of haemodynamic monitoring tools used, impact on outcomes. It is also unknown whether individualised haemodynamic protocols are used to guide the rational use of fluids, vasoactive drugs and inotropes.Finally, there is a dearth of evidence regarding how best to monitor these patients postoperatively or what the most effective enhanced recovery protocols are to best mitigate postoperative complications and accelerate hospital discharge. To increase our knowledge of the perioperative and anaesthetic treatment for patients undergoing EPP/ePD, this scoping review attempts to synthesise the literature and identify these knowledge gaps.Methods and analysis This scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Review Protocols methodology. Electronic databases, OVID Medline, EMBASE and the Cochrane Library, will be systematically searched for relevant literature corresponding to EPP or ePD and perioperative or anaesthetic management. Data will be analysed and summarised descriptively and organised according to the three perioperative stages: preoperative, intraoperative and postoperative factors in clinical care.Ethics and dissemination Ethics approval was not required. The findings will be disseminated through professional networks, conference presentations and publications in scientific journals.

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000–2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose

Introduction There are no published data on the long-term impact of invasive group B Streptococcus disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and middle-income countries. We assessed the impact of iGBS on healthcare utilisation, costs and HRQoL in Argentina, India, Kenya, Mozambique and South Africa.Methods Inpatient and outpatient visits, out-of-pocket (OOP) healthcare payments in the 12 months before study enrolment, and health-state utility of children and caregivers (using the EuroQol 5-Dimensions-3-Level) were collected from iGBS survivors and an unexposed cohort matched on site, age at recruitment and sex. We used logistic or Poisson regression for analysing healthcare utilisation and zero-inflated gamma regression models for family and health system costs. For HRQoL, we used a zero-inflated beta model of disutility pooled data.Results 161 iGBS-exposed and 439 unexposed children and young adults (age 1–20) were included in the analysis. Compared with unexposed participants, iGBS was associated with increased odds of any healthcare utilisation in India (adjusted OR 11.2, 95% CI 2.9 to 43.1) and Mozambique (6.8, 95% CI 2.2 to 21.1) and more frequent healthcare visits (adjusted incidence rate ratio (IRR) for India 1.7 (95% CI 1.4 to 2.2) and for Mozambique 6.0 (95% CI 3.2 to 11.2)). iGBS was also associated with more frequent days in inpatient care in India (adjusted IRR 4.0 (95% CI 2.3 to 6.8) and Kenya 6.4 (95% CI 2.9 to 14.3)). OOP payments were higher in the iGBS cohort in India (adjusted mean: Int$682.22 (95% CI Int$364.28 to Int$1000.16) vs Int$133.95 (95% CI Int$72.83 to Int$195.06)) and Argentina (Int$244.86 (95% CI Int$47.38 to Int$442.33) vs Int$52.38 (95% CI Int$−1.39 to Int$106.1)). For all remaining sites, differences were in the same direction but not statistically significant for almost all outcomes. Health-state disutility was higher in iGBS survivors (0.08, 0.04–0.13 vs 0.06, 0.02–0.10).Conclusion The iGBS health and economic burden may persist for years after acute disease. Larger studies are needed for more robust estimates to inform the cost-effectiveness of iGBS prevention.

A novel multi-technique approach has been applied for the identification and mapping of wild orchids using a combination of remote sensing and spectral image analysis. The five orchid species identified were the common spotted-orchid (Dactylorhiza fuchsia), heath spotted-orchid (Dactylorhiza maculata), pyramidal orchid (Anacamptis pyramidalis), heath fragrant-orchid (Gymnadenia borealis), and the dark-red helleborine (Epipactis atrorubens). Field studies have been done using a hand-held spectrometer operating in the 400–700 nm visible spectrum, photogrammetry using a digital camera as well as a multispectral image camera operating at the specific spectral bands of 450 nm (blue), 560 nm (green), 650 nm (red), 730 nm (red edge) and 840 nm (near-infrared) attached to an unmanned aerial vehicle Data analysis, using the hand-held spectrometer, followed by pattern recognition using principal component analysis and partial least squares-discriminant analysis, have identified the key distinguishing wavelengths for identification of the 5 orchid types as 400, 410, 420 and 560 nm. The use of remote sensing, using the UAV-MSI, and application of a dedicated spectral index has enabled field identification of the orchids. Finally, object-based image analysis of field gathered photogrammetry imagery, has enabled use of shape, size, and color to identify and distinguish orchid species. The developed data analytic tool, using random forest classification, can be used to identify and characterize wild orchids across multiple sites within their short lifespan with an accuracy of 86%. Any longer-term study would provide invaluable information on the diversity and complexity of orchid habitat, population variation both intra- and inter-site location, as well as the impact of climate change.

Objective.This work assessed the relationship between image signal-to-noise ratio (SNR) and total-body noise-equivalent count rate (NECR)-for both non-time-of-flight (TOF) NECR and TOF-NECR-in a long uniform water cylinder and 14 healthy human subjects using the uEXPLORER total-body PET/CT scanner.Approach.A TOF-NEC expression was modified for list-mode PET data, and both the non-TOF NECR and TOF-NECR were compared using datasets from a long uniform water cylinder and 14 human subjects scanned up to 12 h after radiotracer injection.Main results.The TOF-NECR for the uniform water cylinder was found to be linearly proportional to the TOF-reconstructed image SNR2in the range of radioactivity concentrations studied, but not for non-TOF NECR as indicated by the reducedR2value. The results suggest that the use of TOF-NECR to estimate the count rate performance of TOF-enabled PET systems may be more appropriate for predicting the SNR of TOF-reconstructed images.Significance.Image quality in PET is commonly characterized by image SNR and, correspondingly, the NECR. While the use of NECR for predicting image quality in conventional PET systems is well-studied, the relationship between SNR and NECR has not been examined in detail in long axial field-of-view total-body PET systems, especially for human subjects. Furthermore, the current NEMA NU 2-2018 standard does not account for count rate performance gains due to TOF in the NECR evaluation. The relationship between image SNR and total-body NECR in long axial FOV PET was assessed for the first time using the uEXPLORER total-body PET/CT scanner.

BackgroundMulti-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).ResultsAcross the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.ConclusionsThe discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Atomically dispersed metals on metal oxide supports are a rapidly growing class of catalysts. Developing an understanding of where and how the metals are bonded to the supports is challenging because support surfaces are heterogeneous, and most reports lack a detailed consideration of these points. Herein, we report two atomically dispersed CO oxidation catalysts having markedly different metal-support interactions: platinum in the first layer of crystalline MgO powder and platinum in the second layer of this support. Structural models have been determined on the basis of data and computations, including those determined by extended X-ray absorption fine structure and X-ray absorption near edge structure spectroscopies, infrared spectroscopy of adsorbed CO, and scanning transmission electron microscopy. The data demonstrate the transformation of surface to subsurface platinum as the temperature of sample calcination increased. Catalyst performance data demonstrate the lower activity but greater stability of the subsurface platinum than of the surface platinum.

Total-body PET has come a long way from its first conception to today, with both total-body and long axial field of view (> 1m) scanners now being commercially available world-wide. The conspicuous signal collection efficiency gain, coupled with high spatial resolution, allows for higher sensitivity and improved lesion detection, enhancing several clinical applications not readily available on current conventional PET/CT scanners. This technology can provide (a) reduction in acquisition times with preservation of diagnostic quality images, benefitting specific clinical situations (i.e. pediatric patients) and the use of several existing radiotracers that present transient uptake over time and where small differences in acquisition time can greatly impact interpretation of images; (b) reduction in administered activity with minimal impact on image noise, thus reducing effective dose to the patient, improving staff safety, and helping with logistical concerns for short-lived radionuclides or long-lived radionuclides with poor dosimetry profiles that have had limited use on conventional PET scanners until now; (c) delayed scanning, that has shown to increase the detection of even small and previously occult malignant lesions by improved clearance in regions of significant background activity and by reduced visibility of coexisting inflammatory processes; (d) improvement in image quality, as a consequence of higher spatial resolution and sensitivity of total-body scanners, implying better appreciation of small structures and clinical implications with downstream prognostic consequences for patients; (e) simultaneous total-body dynamic imaging, that allows the measurement of full spatiotemporal distribution of radiotracers, kinetic modeling, and creation of multiparametric images, providing physiologic and biologically relevant data of the entire body at the same time. On the other hand, the higher physical and clinical sensitivity of total-body scanners bring along some limitations and challenges. The strong impact on clinical sensitivity potentially increases the number of false positive findings if the radiologist does not recalibrate interpretation considering the new technique. Delayed scanning causes logistical issues and introduces new interpretation questions for radiologists. Data storage capacity, longer processing and reconstruction time issues are other limitations, but they may be overcome in the near future by advancements in reconstruction algorithms and computing hardware.

BackgroundWhite matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites.MethodsWe studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)

To ensure equitable representation of women and BIPOC (Black, Indigenous, person of colour) individuals in surgical specialties, it is first necessary to understand the presence and extent of the disparities that exist. We explored the websites of the 17 Canadian faculties of medicine to examine sex and racial diversity in surgical specialties and in surgical leadership positions in Canada. We categorized faculty members of each department of surgery as either male or female and White or BIPOC. The relative percentage of female academic surgeons was very low compared with Canadian demographic data, and the relative percentage of BIPOC academic surgeons was similar to Canadian demographic data. Our observations suggest that actions must be taken to improve diversity and inclusion in surgery., Sex and racial diversity is becoming an increasingly important topic in today's society. American studies have reported a deficit of women and racial minorities among physicians, including those in leadership [...]

Abstract Background Epigenetic scores (EpiScores) can provide biomarkers of lifestyle and disease risk. Projecting new datasets onto a reference panel is challenging due to separation of technical and biological variation with array data. Normalisation can standardise data distributions but may also remove population-level biological variation. Results We compare two birth cohorts (Lothian Birth Cohorts of 1921 and 1936 — nLBC1921 = 387 and nLBC1936 = 498) with blood-based DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examine the effect of 16 normalisation methods on a novel BMI EpiScore (trained in an external cohort, n = 18,413), and Horvath’s pan-tissue DNA methylation age, when the cohorts are normalised separately and together. The BMI EpiScore explains a maximum variance of R 2=24.5% in BMI in LBC1936 (SWAN normalisation). Although there are cross-cohort R 2 differences, the normalisation method makes a minimal difference to within-cohort estimates. Conversely, a range of absolute differences are seen for individual-level EpiScore estimates for BMI and age when cohorts are normalised separately versus together. While within-array methods result in identical EpiScores whether a cohort is normalised on its own or together with the second dataset, a range of differences is observed for between-array methods. Conclusions Normalisation methods returning similar EpiScores, whether cohorts are analysed separately or together, will minimise technical variation when projecting new data onto a reference panel. These methods are important for cases where raw data is unavailable and joint normalisation of cohorts is computationally expensive.

Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Abstract Igneous rocks associated with the Cretaceous to Paleogene volcanic arc in SW Japan show ages that young from west to east in a direction parallel to the Median Tectonic Line suggesting corresponding translation of a heat source traditionally interpreted in terms of oblique subduction of a spreading ridge. However, recent oceanic plate reconstructions suggest ridge subduction may be younger than the main arc activity. Age compilations of 1227 points of felsic to intermediate Cretaceous and Cenozoic igneous rocks from the Japan arc show arc magmatism that can be separated into an early active period 130–60 Ma (stage 1), a subsequent period of quiescence 60–46 Ma (stage 2), which is followed by a resumption of igneous activity from 46 Ma onward (stage 3). In southwest Japan, the orientations of the magmatic arcs of stages 1 and 3 show and angular discordance of about 20°. The lack of active arc magmatism and the occurrence patterns of adakitic and high-Mg andesitic magmas indicate that ridge subduction occurred during stage 2. The arc age distribution pattern of stage 1 is explained by the slab shallowing related to a younging of the subducting slab as the ridge approaches. Furthermore, the obliquity of the arcs formed at stages 1 and 3 is explained by a 20° clockwise rotation of the inner zone of southwest Japan during the ridge-subduction phase. Oceanic plate reconstructions show counterclockwise rotation in the subduction direction after the ridge subduction phase, and coupling of the subducting oceanic plate with the upper plate would support microplate rotation in the inner zone. The new proposed tectonic reconstructions provide a framework to related Paleogene subduction of an active spreading ridge along the east Asia margin not only to the distribution of granitic bodies but also to rift-related basin formation on the eastern margin of the Eurasian continent and to rotation of crustal blocks indicated by paleomagnetic data of Cretaceous terranes.

The current generation of total-body positron emission tomography (PET) scanners offer significant sensitivity increase with an extended axial imaging extent. With the large volume of lutetium-based scintillation crystals that are used as detector elements in these scanners, there is an increased flux of background radiation originating from 176Lu decay in the crystals and higher sensitivity for detecting it. Combined with the ability of scanning the entire body in a single bed position, this allows more effective utilization of the lutetium background as a transmission source for estimating 511 keV attenuation coefficients. In this study, utilization of the lutetium background radiation for attenuation correction in total-body PET was studied using Monte Carlo simulations of a 3D whole-body XCAT phantom in the uEXPLORER PET scanner, with particular focus on ultralow-dose PET scans that are now made possible with these scanners. Effects of an increased acceptance angle, reduced scan durations, and Compton scattering on PET quantification were studied. Furthermore, quantification accuracy of lutetium-based attenuation correction was compared for a 20-min scan of the whole body on the uEXPLORER, a one-meter-long, and a conventional 24-cm-long scanner. Quantification and lesion contrast were minimally affected in both long axial field-of-view scanners and in a whole-body 20-min scan, the mean bias in all analyzed organs of interest were within a ±10% range compared to ground-truth activity maps. Quantification was affected in certain organs, when scan duration was reduced to 5 min or a reduced acceptance angle of 17° was used. Analysis of the Compton scattered events suggests that implementing a scatter correction method for the transmission data will be required, and increasing the energy threshold from 250 keV to 290 keV can reduce the computational costs and data rates, with negligible effects on PET quantification. Finally, the current results can serve as groundwork for transferring lutetium-based attenuation correction into research and clinical practice.