Steps towards understanding variation for water and nitrogen uptake and use in Brassica napus

Non-Peer Reviewe

Changes in healthcare costs following genome-wide sequencing for children with developmental disorders and early onset seizures in England and Canada

Importance Etiologic diagnoses for rare diseases can involve a diagnostic odyssey, with repeated health care interactions and inconclusive diagnostics. Prior studies reported cost savings associated with genome-wide sequencing (GWS) compared with cytogenetic or molecular testing through rapid genetic diagnosis, but there is limited evidence on whether diagnosis from GWS is associated with reduced health care costs. Objective To measure changes in health care costs after diagnosis from GWS for Canadian and English children with suspected rare diseases. Design, Setting, and Participants This cohort study was a quasiexperimental retrospective analysis across 3 distinct English and Canadian cohorts, completed in 2023. Mixed-effects generalized linear regression was used to estimate associations between GWS and costs in the 2 years before and after GWS. Difference-in-differences regression was used to estimate associations of genetic diagnosis and costs. Costs are in 2019 US dollars. GWS was conducted in a research setting (Genomics England 100 000 Genomes Project [100KGP] and Clinical Assessment of the Utility of Sequencing and Evaluation as a Service [CAUSES] Research Clinic) or clinical outpatient setting (publicly reimbursed GWS in British Columbia [BC], Canada). Participants were children with developmental disorders, seizure disorders, or both undergoing GWS between 2014 and 2019. Data were analyzed from April 2021 to September 2023. Exposures GWS and genetic diagnosis. Main Outcomes and Measures Annual health care costs and diagnostic costs per child. Results Study cohorts included 7775 patients in 100KGP, among whom 788 children had epilepsy (mean [SD] age at GWS, 11.6 [11.1] years; 400 female [50.8%]) and 6987 children had an intellectual disability (mean [SD] age at GWS, 8.2 [8.4] years; 2750 female [39.4%]); 77 patients in CAUSES (mean [SD] age at GWS, 8.5 [4.4] years; 33 female [42.9%]); and 118 publicly reimbursed GWS recipients from BC (mean [SD] age at GWS, 5.5 [5.2] years; 58 female [49.2%]). GWS diagnostic yield was 143 children (18.1%) for those with epilepsy and 1323 children (18.9%) for those with an intellectual disability in 100KGP, 47 children (39.8%) in the BC publicly reimbursed setting, and 42 children (54.5%) in CAUSES. Mean annual per-patient spending over the study period was $5283 (95$5121-$5427) for epilepsy and$3373 (95% CI, $3322-$3424) for intellectual disability in the 100KGP, $724 (95$563-$886) in CAUSES, and$1573 (95% CI, $1372-$1773) in the BC reimbursed setting. Receiving a genetic diagnosis from GWS was not associated with changed costs in any cohort. Conclusions and Relevance In this study, receiving a genetic diagnosis was not associated with cost savings. This finding suggests that patient benefit and cost-effectiveness should instead drive GWS implementation

Non-thermal X-rays from the Ophiuchus galaxy cluster and dark matter annihilation

We investigate a scenario where the recently discovered non-thermal hard X-ray emission from the Ophiuchus cluster originates from inverse Compton scattering of energetic electrons and positrons produced in weakly interacting dark matter pair annihilations. We show that this scenario can account for both the X-ray and the radio emission, provided the average magnetic field is of the order of 0.1 microGauss. We demonstrate that GLAST will conclusively test the dark matter annihilation hypothesis. Depending on the particle dark matter model, GLAST might even detect the monochromatic line produced by dark matter pair annihilation into two photons.Comment: 6 pages, 4 figures, matches published versio

Non-Water-Suppressed 1H MR Spectroscopy with Orientational Prior Knowledge Shows Potential for Separating Intra- and Extramyocellular Lipid Signals in Human Myocardium

Conditions such as type II diabetes are linked with elevated lipid levels in the heart, and significantly increased risk of heart failure; however, metabolic processes underlying the development of cardiac disease in type II diabetes are not fully understood. Here we present a non-invasive method for in vivo investigation of cardiac lipid metabolism: namely, IVS-McPRESS. This technique uses metabolite-cycled, non-water suppressed 1H cardiac magnetic resonance spectroscopy with prospective and retrospective motion correction. High-quality IVS-McPRESS data acquired from healthy volunteers allowed us to investigate the frequency shift of extramyocellular lipid signals, which depends on the myocardial fibre orientation. Assuming consistent voxel positioning relative to myofibres, the myofibre angle with the magnetic field was derived from the voxel orientation. For separation and individual analysis of intra- and extramyocellular lipid signals, the angle myocardial fibres in the spectroscopy voxel take with the magnetic field should be within ±24.5°. Metabolite and lipid concentrations were analysed with respect to BMI. Significant correlations between BMI and unsaturated fatty acids in intramyocellular lipids, and methylene groups in extramyocellular lipids were found. The proposed IVS-McPRESS technique enables non-invasive investigation of cardiac lipid metabolism and may thus be a useful tool to study healthy and pathological conditions

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy

Ensuring competency in end-of-life care: controlling symptoms

BACKGROUND: Palliative medicine is assuming an increasingly important role in patient care. The Education for Physicians in End-of-life Care (EPEC) Project is an ambitious program to increase core palliative care skills for all physicians. It is not intended to transmit specialty level competencies in palliative care. METHOD: The EPEC Curriculum was developed to be a comprehensive syllabus including trainer notes, multiple approaches to teaching the material, slides, and videos of clinical encounters to trigger discussion are provided. The content was developed through a combination of expert opinion, participant feedback and selected literature review. Content development was guided by the goal of teaching core competencies not included in the training of generalist and non-palliative medicine specialist physicians. RESULTS: Whole patient assessment forms the basis for good symptom control. Approaches to the medical management of pain, depression, anxiety, breathlessness (dyspnea), nausea/vomiting, constipation, fatigue/weakness and the symptoms common during the last hours of life are described. CONCLUSION: While some physicians will have specialist palliative care services upon which to call, most in the world will need to provide the initial approaches to symptom control at the end-of-life

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: An individual patient data meta-analysis

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy. Conclusion Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies