Effects of 2-Chloroethyl-phosphonic Acid (Ethephon) As a Male Gametocide for Induction of Sterility in Wheat and Barley

Exploitation of induced male sterility has now become a potential tool in plant breeding. Ethephon (2-chloroethyl-phosphonic acid) has induced male sterility in winter cultivars of wheat and barley. The purpose of this research was to further elucidate the response of winter wheat (Triticum aestivum L. em Thell), and winter barley (Hordeum vulgate L.) to foliar application of ethephon. Ethephon was foliarly sprayed on winter cultivars of wheat and barley which were Arthur and Blueboy, and Barsoy and Volbar respectively, at 0.05, 0.10, and 0.20 and 0.40 percent active ingredient, when plants were in mid-boot and late boot stages in the field study at Knoxville, Tennessee. In the growth room wheat winter cultivars Arthur and Blueboy, and barley winter cultivars Keowee and Harrison were sprayed at 0.02 and 0.05 percent active ingredient at the late boot stage of development. The most effective level was 0.40 percent ethephon in mid-boot and late boot stages for both cultivars of wheat and barley in the field study. Concentration, replication, date, cultivar, date X concentration, date X cultivar, concentration X cultivar, date X concentration X cultivar effects were significant for all variables except seed weight, date headed, and date mature. No overall replication, date X concentration, date X cultivar, and concentration X cultivar effects occurred for seed weight. No overall date X concentration X cultivar effect occurred for date mature. Concentration and cultivar effects per plant were strongly and positively associated with induction of male sterility. Clearly female fertility was not impaired to any great extent from ethephon treatments from data obtained from open-pollinated spikes. Certain beneficial effects, such as reduced height and lodging, were accompanied by reduced yields. The successful utilization of this technique using ethephon in enhancing production of hybrid plants, however, depends on the economics of hybrid seed production. The results of this research project indicate the induction of male sterility with ethephon in wheat and barley appears feasible

Informing the design of a randomised controlled trial of an exercise-based programme for long term stroke survivors: lessons from a before-and-after case series study

Background: To inform the design of a randomised controlled trial (RCT) of an exercise-based programme for long term stroke survivors, we conducted a mixed methods before-and-after case series with assessment at three time points. We evaluated Action for Rehabilitation from Neurological Injury (ARNI), a personalised, functionally-focussed programme. It was delivered through 24 hours of one-to-one training by an Exercise Professional (EP), plus at least 2 hours weekly unsupervised exercise, over 12- 14 weeks. Assessment was by patient-rated questionnaires addressing function, physical activity, confidence, fatigue and health-related quality of life; objective assessment of gait quality and speed; qualitative individual interviews conducted with participants. Data were collected at baseline, 3 months and 6 months. Fidelity and acceptability was assessed by participant interviews, audit of participant and EP records, and observation of training. Findings: Four of six enrolled participants completed the exercise programme. Quantitative data demonstrated little change across the sample, but marked changes on some measures for some individuals. Qualitative interviews suggested that small benefits in physical outcomes could be of great psychological significance to participants. Participant-reported fatigue levels commonly increased, and non-completers said they found the programme too demanding. Most key components of the intervention were delivered, but there were several potentially important departures from intervention fidelity. Discussion: The study provided data and experience that are helping to inform the design of an RCT of this intervention. It suggested the need for a broader recruitment strategy; indicated areas that could be explored in more depth in the qualitative component of the trial; and highlighted issues that should be addressed to enhance and evaluate fidelity, particularly in the preparation and monitoring of intervention providers. The experience illustrates the value of even small sample before-and-after studies in the development of trials of complex interventions.PenCLAHRC; NIH

Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure?

AbstractObjectivesThis study examined the relative merits of digoxin, carvedilol, and their combination for the management of patients with atrial fibrillation (AF) and heart failure (HF).BackgroundIn patients with AF and HF, both digoxin and beta-blockers reduce the ventricular rate, and both may improve symptoms, but only beta-blockers have been shown to improve prognosis. If combined therapy is not superior to beta-blockers alone, treatment of patients with HF and AF could be simplified by stopping digoxin.MethodsWe enrolled 47 patients (29 males; mean age 68 years) with persistent AF and HF (mean left ventricular ejection fraction [LVEF] 24%) in a randomized, double-blinded, placebo-controlled study. In the first phase of the study, digoxin was compared with the combination of digoxin and carvedilol (four months). In the second phase, digoxin was withdrawn in a double-blinded manner in the carvedilol-treated arm, thus allowing a comparison between digoxin and carvedilol (six months). Investigations were undertaken at baseline and at the end of each phase.ResultsCompared with digoxin alone, combination therapy lowered the ventricular rate on 24-h ambulatory electrocardiographic monitoring (p < 0.0001) and during submaximal exercise (p < 0.05), whereas LVEF (p < 0.05) and symptom score (p < 0.05) improved. In phase 2, there was no significant difference between digoxin alone and carvedilol alone in any variable. The mean ventricular rate rose and LVEF fell when patients switched from combination therapy to carvedilol alone. Six-minute walk distance was not significantly influenced by any therapy.ConclusionsThe combination of carvedilol and digoxin appears generally superior to either carvedilol or digoxin alone in the management of AF in patients with HF

Older people presenting to the emergency department after a fall: a population with substantial recurrent healthcare use

ABSTRACT Objectives To document patient characteristics, care pathways, healthcare use and costs of fall-related emergency department (ED) presentations by older adults. Participants and methods All fallers aged $70 years, presenting to the ED of a 450-bed metropolitan university hospital in Sydney, Australia (1 April 2007 through 31 March 2009) were studied. Data were collected from the ED electronic information system, ED clinical records and the hospital electronic information system database. Population estimates for 2008 for the local areas served by the hospital were used to estimate ED presentation rates. Results Of 18 902 all-cause ED presentations, 3220 (17.0%) were due to a fall. Among fallers, 35.4% had one or more ED presentations and 20.3% had had one or more hospital admissions in the preceding 12 months. Fall-related ED presentation led directly to hospital admission in 42.7% of the cases, the majority of which (78.0%) received acute care only (length of stayd14.4 days for men and 13.7 days for women) and the remaining cases underwent further inpatient rehabilitation (length of stay 35.6 days for men and 3

Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers

The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes

Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis

Background: There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates. Methods: An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT.Results: 429 (69%) patients’ tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p&lt;0.001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).Conclusions: POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.<br/

Patient and public involvement in a study of multimedia clinical trial information for children, young people and families

© 2020 Sheridan, Preston, Stones, Ainsworth, Taylor, Challinor, Ainsworth, Martin-Kerry, Brady and Knapp. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY) 4.0. https://creativecommons.org/licenses/by/4.0/.There is increasing recognition of the need to involve the public in health research, but accounts of how best to achieve this are scarce. This article describes public involvement in the TRials Engagement in Children and Adolescents (TRECA) study, which is developing and evaluating multimedia information resources to inform children, young people and their familes about clinical trials. A dedicated group of young people with long-term health conditions and their parents met regularly throughout the study; further involvement was sought when specific input was required. Review of formal impact records and informal discussions highlighted how public involvement can positively influence research practice and the people involved. By detailing the methods of involvement used, this work also provides guidance for successfully implementing public involvement in research, and highlights challenges that should be considered in future research projects.Peer reviewe

Supporting meaningful participation of older people in core outcome set development

The use of core outcome sets (COS) by trials is widely accepted as best practice, aiming to improve research efficiency by enabling comparison and aggregation of results across trials for specific clinical areas.1 A COS is an agreed minimum set of standardized outcomes that should be reported in all trials for a specific clinical area.1 A COS should include only fundamental outcomes, that is, core to evaluating a treatment or intervention, rather than every relevant or important outcome.1, 2 Trials can additionally measure other outcomes.1, 3 Outcomes in a COS should be valid and important for all stakeholders. When developing a COS for hospital deprescribing trials,4 we involved stakeholders that would be affected by the intervention: older patients and their carers; healthcare professionals who care for older people in hospital; hospital managers; and academics researching older people's medicine/deprescribing. We followed COMET (Core Outcome Measures in Effectiveness Trials) guidance for COS development1; this summarizes available methods for COS development but provides limited guidance on how to ensure meaningful involvement of patients, who historically have not been involved in deciding which outcomes should be measured in trials. The INCLUDE framework highlights that older people are often explicitly or implicitly excluded from healthcare research.5 Despite anticipating some barriers to older people's participation in our COS study and addressing these in the study planning, we experienced several challenges to ensuring that the selection of outcomes for the COS included their views. We reflect on these challenges, discuss what worked to address them, and present further refinements that could better support equitable, meaningful participation of older people in COS development. Study registration: COMET (Core Outcome Measures in Effectiveness Trials) database (https://www.comet-initiative.org/Studies/Details/1825)

The genome sequence of <i>Trypanosoma brucei gambiense</i>, causative agent of chronic Human African Trypanosomiasis

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; &lt;i&gt;Trypanosoma brucei gambiense&lt;/i&gt; is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a &lt;i&gt;T. b. brucei&lt;/i&gt; isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between &lt;i&gt;T. b. gambiense&lt;/i&gt; and the reference genome. We sought to identify features that were uniquely associated with &lt;i&gt;T. b. gambiense&lt;/i&gt; and its ability to infect humans.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and findings:&lt;/b&gt; An improved high-quality draft genome sequence for the group 1 &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with &lt;i&gt;T. b. brucei&lt;/i&gt; showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972. A comparison of the variant surface glycoproteins (VSG) in &lt;i&gt;T. b. brucei&lt;/i&gt; with all &lt;i&gt;T. b. gambiense&lt;/i&gt; sequence reads showed that the essential structural repertoire of VSG domains is conserved across &lt;i&gt;T. brucei&lt;/i&gt;.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This study provides the first estimate of intraspecific genomic variation within &lt;i&gt;T. brucei&lt;/i&gt;, and so has important consequences for future population genomics studies. We have shown that the &lt;i&gt;T. b. gambiense&lt;/i&gt; genome corresponds closely with the reference, which should therefore be an effective scaffold for any &lt;i&gt;T. brucei&lt;/i&gt; genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in &lt;i&gt;T. b. brucei&lt;/i&gt;, no &lt;i&gt;T. b. gambiense&lt;/i&gt;-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.&lt;/p&gt

FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship