Genome-wide association analysis of bean fly resistance and agromorphological traits in common bean

The bean fly (Ophiomyia spp) is a key insect pest causing significant crop damage and yield loss in common bean (Phaseolus vulgaris L., 2n = 2x = 22). Development and deployment of agronomic superior and bean fly resistant common bean varieties aredependent on genetic variation and the identification of genes and genomic regions controlling economic traits. This study’s objective was to determine the population structure of a diverse panel of common bean genotypes and deduce associations between bean fly resistance and agronomic traits based on single nucleotide polymorphism (SNP) markers. Ninety-nine common bean genotypes were phenotyped in two seasons at two locations and genotyped with 16 565 SNP markers. The genotypes exhibited significant variation for bean fly damage severity (BDS), plant mortality rate (PMR), and pupa count (PC). Likewise, the genotypes showed significant variation for agro-morphological traits such as days to flowering (DTF), days to maturity (DTM), number of pods per plant (NPP), number of seeds per pod (NSP), and grain yield (GYD). The genotypes were delineated into two populations, which were based on the Andean and Mesoamerican gene pools. The genotypes exhibited a minimum membership coefficient of 0.60 to their respective populations. Eighty-three significant (P<0.01) markers were identified with an average linkage disequilibrium of 0.20 at 12Mb across the 11 chromosomes. Three markers were identified, each having pleiotropic effects on two traits: M100049197 (BDS and NPP), M3379537 (DTF and PC), and M13122571 (NPP and GYD). The identified markers are useful for marker-assisted selection in the breeding program to develop common bean genotypes with resistance to bean fly damage

safety and efficacy of fidaxomicin and vancomycin in children and adolescents with clostridioides clostridium difficile infection a phase 3 multicenter randomized single blind clinical trial sunshine

Abstract Background Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children. Methods Patients aged &lt;18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured. Results Of 148 patients randomized, 142 were treated (30 &lt;2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%–35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high. Conclusions Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI. ClinicalTrials.gov identifier NCT0221837

Comprehensive geriatric assessment, multifactorial interventions and nurse-led care coordination to prevent functional decline in community-dwelling older persons: protocol of a cluster randomized trial

<p>Abstract</p> <p>Background</p> <p>Functional decline in community-dwelling older persons is associated with the loss of independence, the need for hospital and nursing-home care and premature death. The effectiveness of multifactorial interventions in preventing functional decline remains controversial. The aim of this study is to investigate whether functional decline in community-dwelling older persons can be delayed or prevented by a comprehensive geriatric assessment, multifactorial interventions and nurse-led care coordination.</p> <p>Methods/Design</p> <p>In a cluster randomized controlled trial, with the general practice as the unit of randomization, 1281 participants from 25 general practices will be enrolled in each condition to compare the intervention with usual care. The intervention will focus on older persons who are at increased risk for functional decline, identified by an Identification of Seniors at Risk Primary Care (ISAR-PC) score (≥ 2). These older persons will receive a comprehensive geriatric assessment, an individually tailored care and treatment plan, consisting of multifactorial, evidence-based interventions and subsequent nurse-led care coordination. The control group will receive 'care as usual' by the general practitioner (GP). The main outcome after 12 months is the level of physical functioning on the modified Katz-15 index score. The secondary outcomes are health-related quality of life, psychological and social functioning, healthcare utilization and institutionalization. Furthermore, a process evaluation and cost-effectiveness analysis will be performed.</p> <p>Discussion</p> <p>This study will provide new knowledge regarding the effectiveness and feasibility of a comprehensive geriatric assessment, multifactorial interventions and nurse-led elderly care in general practice.</p> <p>Trial registration</p> <p><a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2653">NTR2653</a></p> <p>Grant</p> <p>Unrestricted grant 'The Netherlands Organisation for Health Research and development' no 313020201</p

Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

Dravet syndrome is an archetypal rare severe epilepsy, considered “monogenic”, typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Funder: University of Cambridge; FundRef: http://dx.doi.org/10.13039/501100000735Funder: Alzheimer's Society; FundRef: http://dx.doi.org/10.13039/501100000320Funder: Leverhulme Trust; FundRef: http://dx.doi.org/10.13039/501100000275Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276Funder: Evelyn Trust; FundRef: http://dx.doi.org/10.13039/501100004282Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Abstract: Objective: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. Design: Cohort study. Setting: National Health Service, England, including secondary and tertiary care. Participants: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. Intervention: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. Main outcome measure: Definite or probable genetic diagnosis. Results: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. Conclusion: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Funder: Galderma; doi: http://dx.doi.org/10.13039/501100009754Funder: NIHR-BRC Cambridge core grantFunder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272Funder: NHS EnglandAbstract: T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma

Genotypic Response of Dry Bean (Phaseolus vulgaris L.) to Natural Field Infection of Ascochyta Blight (Phoma exigua var. diversispora (Bubak) Boerema) under Diverse Environmental Conditions in Rwanda

Ascochyta blight, caused by Phoma exigua var. diversispora (Bubak) Boerema, is a serious constraint in the cultivation of the common bean (Phaseolus vulgaris L.) in Rwanda, particularly in the cool and wet highland production areas. In order to identify resistant genotypes, a germplasm evaluation study was conducted to quantify the impact of the disease on phenotypic and agronomic traits under natural conditions. Field screening trials of 39 bush (Types I, II and III) and 36 climbing (Type IV) genotypes from different accessions within and outside the country were conducted at three sites, namely, Rwerere, Nyamagabe and Musanze Research Stations, for two seasons. The relative area under the disease progress curve (RAUDPC) based on evaluations of the disease severity (percentage leaf area infected), was used to evaluate the genotypes. Thirteen genotypes were identified with some level of ascochyta resistance. The study revealed Rwandan genotypes G 2333 and SMC 18 as new sources of resistance to Ascochyta blight. Additional results showed a negative relationship (r = −0.42 and −0.51 for Seasons A and B, respectively) between ascochyta infection and yield. Further relationships were identified between the plant flower colour and seed size to ascochyta resistance. Some of the identified resistant genotypes can be used to introgress ascochyta resistance into susceptible Rwandan market classes of common bean genotypes

Genotype × environment interaction effects on early fresh storage root yield and related traits in cassava

Cassava (Manihot esculenta Crantz) is an important root crop worldwide. It exhibits substantial differential genotypic responses to varying environmental conditions, a phenomenon termed genotype × environment interaction (GEI). A significant GEI presents challenges in the selection of superior genotypes. The objective of this study was to examine the effect of genotype, environment and GEI on early fresh storage root yield (FSRY) and related traits in cassava. Accordingly, 12 cassava genotypes were evaluated in a randomised complete block design at three contrasting locations (Jinja, Nakasongola and Namulonge) in Uganda. Trials were harvested nine months after planting and the data collected were analysed using the additive main effects and multiplicative interaction (AMMI) model. The AMMI analysis of variance showed significant variation among genotypes for early FSRY and all other traits assessed. Locations were significantly different for all traits except for cassava brown streak disease root necrosis. The GEI effect was non-significant for early FSRY, but significant for other traits. For early FSRY, 48.5% of the treatment sum of squares was attributable to genotypes, 27.3% to environments, and 24.1% to GEI, indicating a predominance of genotypic variation for this trait. Predominance of genotypic variation was also observed for all the other traits. A majority of the genotypes (67%) had low interaction effects with locations for early FSRY, with Akena, CT2, CT4 and NASE14 being the most stable genotypes for the trait. Significant negative correlation was observed between cassava mosaic disease severity and early FSRY and storage root number, indicating significant negative effects of cassava mosaic disease on early FSRY and stability in cassava. The information generated will inform future selection initiatives for superior early-yielding cassava genotypes combining resistance to cassava mosaic and brown streak diseases in Uganda