HaploCatcher: An R package for prediction of haplotypes.

Wheat (Triticum aestivum L.) is crucial to global food security but is often threatened by diseases, pests, and environmental stresses. Wheat-stem sawfly (Cephus cinctus Norton) poses a major threat to food security in the United States, and solid-stem varieties, which carry the stem-solidness locus (Sst1), are the main source of genetic resistance against sawfly. Marker-assisted selection uses molecular markers to identify lines possessing beneficial haplotypes, like that of the Sst1 locus. In this study, an R package titled "HaploCatcher" was developed to predict specific haplotypes of interest in genome-wide genotyped lines. A training population of 1056 lines genotyped for the Sst1 locus, known to confer stem solidness, and genome-wide markers was curated to make predictions of the Sst1 haplotypes for 292 lines from the Colorado State University wheat breeding program. Predicted Sst1 haplotypes were compared to marker-derived haplotypes. Our results indicated that the training set was substantially predictive, with kappa scores of 0.83 for k-nearest neighbors and 0.88 for random forest models. Forward validation on newly developed breeding lines demonstrated that a random forest model, trained on the total available training data, had comparable accuracy between forward and cross-validation. Estimated group means of lines classified by haplotypes from PCR-derived markers and predictive modeling did not significantly differ. The HaploCatcher package is freely available and may be utilized by breeding programs, using their own training populations, to predict haplotypes for whole-genome sequenced early generation material.

Artificial intelligence methods for improved detection of undiagnosed heart failure with preserved ejection fraction.

AIM: Heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria. METHODS AND RESULTS: In a retrospective cohort study, we used an NLP pipeline applied to the electronic health record (EHR) to identify patients with a clinical diagnosis of HF between 2010 and 2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorized according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥50% were further categorized based on whether they had a clinician-assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre. We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalized more frequently; however the ESC criteria group had a higher 5-year mortality, despite being less comorbid and experiencing fewer acute cardiovascular events. CONCLUSIONS: This study demonstrates that patients with undiagnosed HFpEF are an at-risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms.

Multi-target genome editing reduces polyphenol oxidase activity in wheat (Triticum aestivum L.) grains.

Introduction: Polyphenol oxidases (PPO) are dual activity metalloenzymes that catalyse the production of quinones. In plants, PPO activity may contribute to biotic stress resistance and secondary metabolism but is undesirable for food producers because it causes the discolouration and changes in flavour profiles of products during post-harvest processing. In wheat (Triticum aestivum L.), PPO released from the aleurone layer of the grain during milling results in the discolouration of flour, dough, and end-use products, reducing their value. Loss-of-function mutations in the PPO1 and PPO2 paralogous genes on homoeologous group 2 chromosomes confer reduced PPO activity in the wheat grain. However, limited natural variation and the proximity of these genes complicates the selection of extremely low-PPO wheat varieties by recombination. The goal of the current study was to edit all copies of PPO1 and PPO2 to drive extreme reductions in PPO grain activity in elite wheat varieties. Results: A CRISPR/Cas9 construct with one single guide RNA (sgRNA) targeting a conserved copper binding domain was used to edit all seven PPO1 and PPO2 genes in the spring wheat cultivar 'Fielder'. Five of the seven edited T1 lines exhibited significant reductions in PPO activity, and T2 lines had PPO activity up to 86.7% lower than wild-type. The same construct was transformed into the elite winter wheat cultivars 'Guardian' and 'Steamboat', which have five PPO1 and PPO2 genes. In these varieties PPO activity was reduced by >90% in both T1 and T2 lines. In all three varieties, dough samples from edited lines exhibited reduced browning. Discussion: This study demonstrates that multi-target editing at late stages of variety development could complement selection for beneficial alleles in crop breeding programs by inducing novel variation in loci inaccessible to recombination.

Patient randomised controlled trial of technology enabled strategies to promote treatment adherence in liver transplantation: rationale and design of the TEST trial.

BACKGROUND AND AIMS: Liver transplantation is a life-saving procedure for end-stage liver disease. However, post-transplant medication regimens are complex and non-adherence is common. Post-transplant medication non-adherence is associated with graft rejection, which can have long-term adverse consequences. Transplant centres are equipped with clinical staff that monitor patients post-transplant; however, digital health tools and proactive immunosuppression adherence monitoring has potential to improve outcomes. METHODS AND ANALYSIS: This is a patient-randomised prospective clinical trial at three transplant centres in the Northeast, Midwest and South to investigate the effects of a remotely administered adherence programme compared with usual care. The programme monitors potential non-adherence largely levering text message prompts and phenotypes the nature of the non-adhere as cognitive, psychological, medical, social or economic. Additional reminders for medications, clinical appointments and routine self-management support are incorporated to promote adherence to the entire medical regimen. The primary study outcome is medication adherence via 24-hour recall; secondary outcomes include additional medication adherence (ASK-12 self-reported scale, regimen knowledge scales, tacrolimus values), quality of life, functional health status and clinical outcomes (eg, days hospitalised). Study implementation, acceptability, feasibility, costs and potential cost-effectiveness will also be evaluated. ETHICS AND DISSEMINATION: The University of Pennsylvania Review Board has approved the study as the single IRB of record (protocol # 849575, V.1.4). Results will be published in peer-reviewed journals and summaries will be provided to study funders. TRIAL REGISTRATION NUMBER: NCT05260268.

Utilization of a publicly available diversity panel in genomic prediction of Fusarium head blight resistance traits in wheat.

Fusarium head blight (FHB) is an economically and environmentally concerning disease of wheat (Triticum aestivum L). A two-pronged approach of marker-assisted selection coupled with genomic selection has been suggested when breeding for FHB resistance. A historical dataset comprised of entries in the Southern Uniform Winter Wheat Scab Nursery (SUWWSN) from 2011 to 2021 was partitioned and used in genomic prediction. Two traits were curated from 2011 to 2021 in the SUWWSN: percent Fusarium damaged kernels (FDK) and deoxynivalenol (DON) content. Heritability was estimated for each trait-by-environment combination. A consistent set of check lines was drawn from each year in the SUWWSN, and k-means clustering was performed across environments to assign environments into clusters. Two clusters were identified as FDK and three for DON. Cross-validation on SUWWSN data from 2011 to 2019 indicated no outperforming training population in comparison to the combined dataset. Forward validation for FDK on the SUWWSN 2020 and 2021 data indicated a predictive accuracy r ≈ 0.58 $r \approx 0.58$ and r ≈ 0.53 $r \approx 0.53$ , respectively. Forward validation for DON indicated a predictive accuracy of r ≈ 0.57 $r \approx 0.57$ and r ≈ 0.45 $r \approx 0.45$ , respectively. Forward validation using environments in cluster one for FDK indicated a predictive accuracy of r ≈ 0.65 $r \approx 0.65$ and r ≈ 0.60 $r \approx 0.60$ , respectively. Forward validation using environments in cluster one for DON indicated a predictive accuracy of r ≈ 0.67 $r \approx 0.67$ and r ≈ 0.60 $r \approx 0.60$ , respectively. These results indicated that selecting environments based on check performance may produce higher forward prediction accuracies. This work may be used as a model for utilizing public resources for genomic prediction of FHB resistance traits across public wheat breeding programs.

Utilizing genomics and historical data to optimize gene pools for new breeding programs: A case study in winter wheat.

With the rapid generation and preservation of both genomic and phenotypic information for many genotypes within crops and across locations, emerging breeding programs have a valuable opportunity to leverage these resources to 1) establish the most appropriate genetic foundation at program inception and 2) implement robust genomic prediction platforms that can effectively select future breeding lines. Integrating genomics-enabled breeding into cultivar development can save costs and allow resources to be reallocated towards advanced (i.e., later) stages of field evaluation, which can facilitate an increased number of testing locations and replicates within locations. In this context, a reestablished winter wheat breeding program was used as a case study to understand best practices to leverage and tailor existing genomic and phenotypic resources to determine optimal genetics for a specific target population of environments. First, historical multi-environment phenotype data, representing 1,285 advanced breeding lines, were compiled from multi-institutional testing as part of the SunGrains cooperative and used to produce GGE biplots and PCA for yield. Locations were clustered based on highly correlated line performance among the target population of environments into 22 subsets. For each of the subsets generated, EMMs and BLUPs were calculated using linear models with the 'lme4' R package. Second, for each subset, TPs representative of the new SC breeding lines were determined based on genetic relatedness using the 'STPGA' R package. Third, for each TP, phenotypic values and SNP data were incorporated into the 'rrBLUP' mixed models for generation of GEBVs of YLD, TW, HD and PH. Using a five-fold cross-validation strategy, an average accuracy of r = 0.42 was obtained for yield between all TPs. The validation performed with 58 SC elite breeding lines resulted in an accuracy of r = 0.62 when the TP included complete historical data. Lastly, QTL-by-environment interaction for 18 major effect genes across three geographic regions was examined. Lines harboring major QTL in the absence of disease could potentially underperform (e.g., Fhb1 R-gene), whereas it is advantageous to express a major QTL under biotic pressure (e.g., stripe rust R-gene). This study highlights the importance of genomics-enabled breeding and multi-institutional partnerships to accelerate cultivar development.

Profiling of Fusarium head blight resistance QTL haplotypes through molecular markers, genotyping-by-sequencing, and machine learning.

KEY MESSAGE: Marker-assisted selection is important for cultivar development. We propose a system where a training population genotyped for QTL and genome-wide markers may predict QTL haplotypes in early development germplasm. Breeders screen germplasm with molecular markers to identify and select individuals that have desirable haplotypes. The objective of this research was to investigate whether QTL haplotypes can be accurately predicted using SNPs derived by genotyping-by-sequencing (GBS). In the SunGrains program during 2020 (SG20) and 2021 (SG21), 1,536 and 2,352 lines submitted for GBS were genotyped with markers linked to the Fusarium head blight QTL: Qfhb.nc-1A, Qfhb.vt-1B, Fhb1, and Qfhb.nc-4A. In parallel, data were compiled from the 2011-2020 Southern Uniform Winter Wheat Scab Nursery (SUWWSN), which had been screened for the same QTL, sequenced via GBS, and phenotyped for: visual Fusarium severity rating (SEV), percent Fusarium damaged kernels (FDK), deoxynivalenol content (DON), plant height, and heading date. Three machine learning models were evaluated: random forest, k-nearest neighbors, and gradient boosting machine. Data were randomly partitioned into training-testing splits. The QTL haplotype and 100 most correlated GBS SNPs were used for training and tuning of each model. Trained machine learning models were used to predict QTL haplotypes in the testing partition of SG20, SG21, and the total SUWWSN. Mean disease ratings for the observed and predicted QTL haplotypes were compared in the SUWWSN. For all models trained using the SG20 and SG21, the observed Fhb1 haplotype estimated group means for SEV, FDK, DON, plant height, and heading date in the SUWWSN were not significantly different from any of the predicted Fhb1 calls. This indicated that machine learning may be utilized in breeding programs to accurately predict QTL haplotypes in earlier generations.

Predicting Fusarium Head Blight Resistance for Advanced Trials in a Soft Red Winter Wheat Breeding Program With Genomic Selection.

Many studies have evaluated the effectiveness of genomic selection (GS) using cross-validation within training populations; however, few have looked at its performance for forward prediction within a breeding program. The objectives for this study were to compare the performance of naïve GS (NGS) models without covariates and multi-trait GS (MTGS) models by predicting two years of F4: 7 advanced breeding lines for three Fusarium head blight (FHB) resistance traits, deoxynivalenol (DON) accumulation, Fusarium damaged kernels (FDK), and severity (SEV) in soft red winter wheat and comparing predictions with phenotypic performance over two years of selection based on selection accuracy and response to selection. On average, for DON, the NGS model correctly selected 69.2% of elite genotypes, while the MTGS model correctly selected 70.1% of elite genotypes compared with 33.0% based on phenotypic selection from the advanced generation. During the 2018 breeding cycle, GS models had the greatest response to selection for DON, FDK, and SEV compared with phenotypic selection. The MTGS model performed better than NGS during the 2019 breeding cycle for all three traits, whereas NGS outperformed MTGS during the 2018 breeding cycle for all traits except for SEV. Overall, GS models were comparable, if not better than phenotypic selection for FHB resistance traits. This is particularly helpful when adverse environmental conditions prohibit accurate phenotyping. This study also shows that MTGS models can be effective for forward prediction when there are strong correlations between traits of interest and covariates in both training and validation populations.

Analysis of the primary sources of quantitative adult plant resistance to stripe rust in U.S. soft red winter wheat germplasm.

Stripe rust, or yellow rust (Puccinia striiformis Westend. f. sp. tritic), is a disease of wheat (Triticum aestivum L.) historically causing significant economic losses in cooler growing regions. Novel isolates of stripe rust with increased tolerance for high temperatures were detected in the United States circa 2000. This increased heat tolerance puts geographic regions, such as the soft red winter wheat (SRWW) growing region of the southeastern United States, at greater risk of stripe rust induced losses. In order to identify sources of stripe rust resistance in contemporary germplasm, we conducted genome-wide association (GWA) studies on stripe rust severity measured in two panels. The first consisted of 273 older varieties, landraces, and some modern elite breeding lines and was evaluated in environments in the U.S. Pacific Northwest and the southeastern United States. The second panel consisted of 588 modern, elite SRWW breeding lines and was evaluated in four environments in Arkansas and Georgia. The analyses identified three major resistance loci on chromosomes: 2AS (presumably the 2NS:2AS alien introgression from Aegilops ventricosa Tausch; syn. Ae. caudata L.), 3BS, and 4BL. The 4BL locus explained a greater portion of variance in resistance than either the 2AS or 3BS loci in southeastern environments. However, its effects were unstable across different environments and sets of germplasm, possibly a result of its involvement in epistatic interactions. Relatively few lines carry resistance alleles at all three loci, suggesting that there is a pre-existing reservoir of enhanced stripe rust resistance that may be further exploited by regional breeding programs.

Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites.

Patients with well-controlled low-density lipoprotein cholesterol levels, but persistent high triglycerides, remain at increased risk for cardiovascular events as evidenced by multiple genetic and epidemiologic studies, as well as recent clinical outcome trials. While many trials of low-dose ω3-polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown mixed results to reduce cardiovascular events, recent trials with high-dose ω3-PUFAs have reignited interest in ω3-PUFAs, particularly EPA, in cardiovascular disease (CVD). REDUCE-IT demonstrated that high-dose EPA (4 g/day icosapent-ethyl) reduced a composite of clinical events by 25% in statin-treated patients with established CVD or diabetes and other cardiovascular risk factors. Outcome trials in similar statin-treated patients using DHA-containing high-dose ω3 formulations have not yet shown the benefits of EPA alone. However, there are data to show that high-dose ω3-PUFAs in patients with acute myocardial infarction had reduced left ventricular remodelling, non-infarct myocardial fibrosis, and systemic inflammation. ω3-polyunsaturated fatty acids, along with their metabolites, such as oxylipins and other lipid mediators, have complex effects on the cardiovascular system. Together they target free fatty acid receptors and peroxisome proliferator-activated receptors in various tissues to modulate inflammation and lipid metabolism. Here, we review these multifactorial mechanisms of ω3-PUFAs in view of recent clinical findings. These findings indicate physico-chemical and biological diversity among ω3-PUFAs that influence tissue distributions as well as disparate effects on membrane organization, rates of lipid oxidation, as well as various receptor-mediated signal transduction pathways and effects on gene expression.

Rumination as a Mediator of the Associations Between Moral Injury and Mental Health Problems in Combat-Wounded Veterans.

Moral injury is hypothesized to develop from witnessing or engaging in events that violate one's beliefs about themselves and has been shown to be associated with negative mental health symptoms. Although there has been an increase in research examining moral injury among military veterans, mechanisms that link moral injury to mental health outcomes are not well understood. The present study examined rumination subcomponents (problem-focused thoughts, counterfactual thinking, repetitive thoughts, and anticipatory thoughts) as possible mediators of the associations between moral injury (both self-directed and other-directed symptoms) and negative mental health symptoms (i.e., depression, anxiety, suicidality, sleep disturbance, memory problems, and posttraumatic stress disorder symptoms). Participants were 189 combat wounded veterans (180 men; Mean age = 43.14 years) who had experienced one or more deployments (defined as 90 days or more). Nearly all participants reported a service-connected disability (n = 176, 93.1%), with the average participant reporting a 90% total VA disability ranking, and most participants had received a purple heart (n = 163, 86.2%). Within our comprehensive mediation model, we found eight significant mediation effects with the most consistent mediator being problem-focused thoughts. Specifically, both self-directed and other- directed moral injury were associated with increased problem-focused thoughts, which in turn was associated with higher reported symptoms of depression, anxiety, and posttraumatic stress disorder. Taken together, rumination, and in particular, problem-focused thoughts, is relevant to understand the increased vulnerability of military veterans to exhibit poor mental health outcomes when experiencing moral injury.

Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study.

BACKGROUND: Optimal prophylactic and therapeutic management of thromboembolic disease in patients with COVID-19 remains a major challenge for clinicians. The aim of this study was to define the incidence of thrombotic and haemorrhagic complications in critically ill patients with COVID-19. In addition, we sought to characterise coagulation profiles using thromboelastography and explore possible biological differences between patients with and without thrombotic complications. METHODS: We conducted a multicentre retrospective observational study evaluating all the COVID-19 patients received in four intensive care units (ICUs) of four tertiary hospitals in the UK between March 15, 2020, and May 05, 2020. Clinical characteristics, laboratory data, thromboelastography profiles and clinical outcome data were evaluated between patients with and without thrombotic complications. RESULTS: A total of 187 patients were included. Their median (interquartile (IQR)) age was 57 (49-64) years and 124 (66.3%) patients were male. Eighty-one (43.3%) patients experienced one or more clinically relevant thrombotic complications, which were mainly pulmonary emboli (n = 42 (22.5%)). Arterial embolic complications were reported in 25 (13.3%) patients. ICU length of stay was longer in patients with thrombotic complications when compared with those without. Fifteen (8.0%) patients experienced haemorrhagic complications, of which nine (4.8%) were classified as major bleeding. Thromboelastography demonstrated a hypercoagulable profile in patients tested but lacked discriminatory value between those with and without thrombotic complications. Patients who experienced thrombotic complications had higher D-dimer, ferritin, troponin and white cell count levels at ICU admission compared with those that did not. CONCLUSION: Critically ill patients with COVID-19 experience high rates of venous and arterial thrombotic complications. The rates of bleeding may be higher than previously reported and re-iterate the need for randomised trials to better understand the risk-benefit ratio of different anticoagulation strategies.

Identification of QTLs for Resistance to Fusarium Head Blight Using a Doubled Haploid Population Derived from Southeastern United States Soft Red Winter Wheat Varieties AGS 2060 and AGS 2035.

Fusarium head blight (FHB), caused primarily by the fungus Fusarium graminearum, is one of the most damaging diseases of wheat, causing significant loss of yield and quality worldwide. Warm and wet conditions during flowering, a lack of resistant wheat varieties, and high inoculum pressure from corn stubble contribute to frequent FHB epidemics in the southern United States. The soft red winter wheat variety AGS 2060 is moderately susceptible (as opposed to susceptible) to FHB and regularly found in pedigrees of resistant breeding lines. AGS 2060 does not carry any known resistance genes or quantitative trait loci (QTL). A QTL mapping study was conducted to determine the location and genetic effect of its resistance using a doubled haploid mapping population produced from a cross between wheat varieties AGS 2060 and AGS 2035 (FHB susceptible). The population was genotyped using the Illumina iSelect single nucleotide polymorphism (SNP) array for wheat and phenotyped in Baton Rouge and Winnsboro, Louisiana and Newport, Arkansas in 2018 and 2019. The effect of genotype was significant for Fusarium damaged kernels (FDK) and deoxynivalenol (DON) content across all locations and years, indicating genetic variation in the population. The study detected 13 QTLs (one each on chromosome 1A, 1B, 1D, 2A, 2B, 6A, 6B, 7A, and 7B, and two each on 5A and 5B) responsible for the reduction of FDK and/or DON. Of these, nine QTLs for FHB resistance were identified in Winnsboro, Louisiana, in 2019. QTLs on chromosomes 2A and 7A could be valuable sources of resistance to both DON and FDK over several environments and were likely the best candidates for use in marker-assisted selection. Consistently expressed QTLs on chromosomes 5A, 6B, and 7A were potentially newly identified sources of resistance to FHB in soft red winter wheat.

Prevalence of cardiovascular events in genetically confirmed versus unconfirmed familial hypercholesterolaemia.

Introduction: Genetic testing for familial hypercholesterolaemia (FH) is not yet established for widespread use internationally to provide diagnostic confirmation, in part due to high cost and resource requirement. We need to establish whether genetic testing is clinically justified in terms of risk stratification and prediction of cardiovascular events. Methods:We performed a single tertiary cardiac centre retrospective evaluation of patients with FH managed within our genetic screening service. We evaluated the prevalence of cardiovascular events in genetically confirmed cases of FH compared to those unconfirmed upon genetic testing, to assess whether gene positivity confers a higher risk phenotype. We also compared the clinical characteristics of the genetically confirmed and unconfirmed group. Results:Amongst adult patients (≥18 years) with genetically confirmed heterozygous FH (n=87), 34% (30/87) had one or more documented CV events. In comparison a lower event rate was observed in adult patients with genetically unconfirmed FH (n=170) with 25% (42/170) experiencing one or more documented CV events. Additional cardiovascular risk factors were more prevalent in the unconfirmed group including hypertension, co-morbidities, higher age and body mass index which may have modified the difference in cardiovascular risk. Conclusion:Genetic testing in FH may be clinically justified and appears to identify a subset of patients with higher risk of cardiovascular events. However, the risk difference is modified by alternative cardiovascular risk factors and co-morbidities which may be more prevalent in genetically unconfirmed FH.

Understanding the Genetic Basis of Spike Fertility to Improve Grain Number, Harvest Index, and Grain Yield in Wheat Under High Temperature Stress Environments.

Moderate heat stress accompanied by short episodes of extreme heat during the post-anthesis stage is common in most US wheat growing areas and causes substantial yield losses. Sink strength (grain number) is a key yield limiting factor in modern wheat varieties. Increasing spike fertility (SF) and improving the partitioning of assimilates can optimize sink strength which is essential to improve wheat yield potential under a hot and humid environment. A genome-wide association study (GWAS) allows identification of novel quantitative trait loci (QTLs) associated with SF and other partitioning traits that can assist in marker assisted breeding. In this study, GWAS was performed on a soft wheat association mapping panel (SWAMP) comprised of 236 elite lines using 27,466 single nucleotide polymorphisms (SNPs). The panel was phenotyped in two heat stress locations over 3 years. GWAS identified 109 significant marker-trait associations (MTAs) (p ≤ 9.99 x 10-5) related to eight phenotypic traits including SF (a major component of grain number) and spike harvest index (SHI, a major component of grain weight). MTAs detected on chromosomes 1B, 3A, 3B, and 5A were associated with multiple traits and are potentially important targets for selection. More than half of the significant MTAs (60 out of 109) were found in genes encoding different types of proteins related to metabolism, disease, and abiotic stress including heat stress. These MTAs could be potential targets for further validation study and may be used in marker-assisted breeding for improving wheat grain yield under post-anthesis heat stress conditions. This is the first study to identify novel QTLs associated with SF and SHI which represent the major components of grain number and grain weight, respectively, in wheat.

Development of the Self Optimising Kohonen Index Network (SKiNET) for Raman Spectroscopy Based Detection of Anatomical Eye Tissue.

Raman spectroscopy shows promise as a tool for timely diagnostics via in-vivo spectroscopy of the eye, for a number of ophthalmic diseases. By measuring the inelastic scattering of light, Raman spectroscopy is able to reveal detailed chemical characteristics, but is an inherently weak effect resulting in noisy complex signal, which is often difficult to analyse. Here, we embraced that noise to develop the self-optimising Kohonen index network (SKiNET), and provide a generic framework for multivariate analysis that simultaneously provides dimensionality reduction, feature extraction and multi-class classification as part of a seamless interface. The method was tested by classification of anatomical ex-vivo eye tissue segments from porcine eyes, yielding an accuracy >93% across 5 tissue types. Unlike traditional packages, the method performs data analysis directly in the web browser through modern web and cloud technologies as an open source extendable web app. The unprecedented accuracy and clarity of the SKiNET methodology has the potential to revolutionise the use of Raman spectroscopy for in-vivo applications.

Coronary artery bypass confers intermediate-term survival benefit over percutaneous coronary intervention with new-generation stents in real-world patients with multivessel coronary artery disease, including left main disease: a retrospective analysis of 6383 patients.

OBJECTIVES: The intermediate-term all-cause mortality rate of real-world patients with multivessel disease (MVD) treated with percutaneous coronary intervention (PCI) with new-generation drug-eluting stents or coronary artery bypass grafting (CABG) remains unknown. We sought to compare the intermediate-term all-cause mortality rates of real-world patients with MVD including left main stem disease, treated with CABG or PCI. METHODS: All consecutive all-comer patients with MVD undergoing CABG or PCI with second/third generation drug-eluting stents from 2007 to 2015 in Harefield Hospital, UK were included in this study. The revascularization modality was based on heart team discussions. Primary outcome was all-cause mortality. Mean follow-up of the study was 3.3 years. Cox regression analysis and propensity matching were used. RESULTS: Of 6383 patients with MVD, 4230 underwent CABG, whereas 2153 had PCI with new-generation stents. In the CABG group, the mean age was 66.4 ± 10 years, whereas in the PCI group it was 65.3 ± 12.1 years (P < 0.001). Fewer female patients with MVD were treated with CABG than were treated with PCI (18.5% vs 20.5%; P = 0.026). There was a higher 5-year estimated survival rate among patients having CABG (88% vs 78.3%; Plog-rank < 0.001). The adjusted hazard ratio (HR) for PCI over CABG was 1.74 [95% confidence interval (CI) 1.41-2.16; P < 0.001]. A total of 653 patients having CABG and 653 having PCI were included in the propensity-matched groups. At mean follow-up, PCI was associated with a higher adjusted HR for all-cause mortality (2.18, 95% CI 1.54-3.1; P < 0.001). CONCLUSIONS: In this contemporary cohort of real-world patients with MVD, CABG was associated with increased intermediate-term survival compared to PCI with new-generation drug-eluting stents.

Training population selection and use of fixed effects to optimize genomic predictions in a historical USA winter wheat panel.

KEY MESSAGE: The optimization of training populations and the use of diagnostic markers as fixed effects increase the predictive ability of genomic prediction models in a cooperative wheat breeding panel. Plant breeding programs often have access to a large amount of historical data that is highly unbalanced, particularly across years. This study examined approaches to utilize these data sets as training populations to integrate genomic selection into existing pipelines. We used cross-validation to evaluate predictive ability in an unbalanced data set of 467 winter wheat (Triticum aestivum L.) genotypes evaluated in the Gulf Atlantic Wheat Nursery from 2008 to 2016. We evaluated the impact of different training population sizes and training population selection methods (Random, Clustering, PEVmean and PEVmean1) on predictive ability. We also evaluated inclusion of markers associated with major genes as fixed effects in prediction models for heading date, plant height, and resistance to powdery mildew (caused by Blumeria graminis f. sp. tritici). Increases in predictive ability as the size of the training population increased were more evident for Random and Clustering training population selection methods than for PEVmean and PEVmean1. The selection methods based on minimization of the prediction error variance (PEV) outperformed the Random and Clustering methods across all the population sizes. Major genes added as fixed effects always improved model predictive ability, with the greatest gains coming from combinations of multiple genes. Maximum predictabilities among all prediction methods were 0.64 for grain yield, 0.56 for test weight, 0.71 for heading date, 0.73 for plant height, and 0.60 for powdery mildew resistance. Our results demonstrate the utility of combining unbalanced phenotypic records with genome-wide SNP marker data for predicting the performance of untested genotypes.

Mid-to-long term mortality following surgical versus percutaneous coronary revascularization stratified according to stent subtype: An analysis of 6,682 patients with multivessel disease.

BACKGROUND: Studies comparing coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) have largely been performed in the bare-metal stent (BMS) and first-generation drug eluting stent (F-DES) era. Second-generation DES (S-DES) have shown improved outcomes when compared to F-DES, but data comparing CABG with PCI using S-DES is limited. We compared mortality following CABG versus PCI for patients with multivessel disease and analyzed different stent types. METHODS: A total of 6,682 patients underwent multivessel revascularization at Harefield Hospital, UK. We stratified CABG patients into single arterial graft (SAG) or multiple arterial grafts (MAG); and PCI patients into BMS, F-DES or S-DES groups. We analyzed all-cause mortality at 5 years. RESULTS: 4,388 patients had CABG (n[SAG] = 3,358; n[MAG] = 1,030) and 2,294 patients had PCI (n[BMS] = 416; n[F-DES] = 752; n[S-DES] = 1,126). PCI had higher 5-year mortality with BMS (HR = 2.27, 95% CI:1.70-3.05, p<0.001); F-DES (HR = 1.52, 95% CI:1.14-2.01, p = 0.003); and S-DES (HR = 1.84, 95% CI:1.42-2.38, p<0.001). This was confirmed in inverse probability treatment weighted analyses. When adjusting for both measured and unmeasured factors using instrumental variable analyses, PCI had higher 5-year mortality with BMS (Δ = 15.5, 95% CI:3.6,27.5, p = 0.011) and FDES (Δ = 16.5, 95% CI:6.6,26.4, p<0.001), but had comparable mortality with CABG for PCI with SDES (Δ = 0.9, 95% CI: -9.6,7.9, p = 0.844), and when exclusively compared to CABG patients with SAG (Δ = 0.4, 95% CI: -8.0,8.7, p = 0.931) or MAG (Δ = 4.6, 95% CI: -0.4,9.6, p = 0.931). CONCLUSIONS: In this real-world analysis, when adjusting for measured and unmeasured confounding, PCI with SDES had comparable 5-year mortality when compared to CABG. This warrants evaluation in adequately-powered randomized controlled trials.