Field Performance and Quality of Hybrid Winter Wheat.

End of Project ReportAn assessment of hybrid winter wheat was carried out over three seasons to determine the commercial potential of hybrid varieties under Irish conditions. The studies examined the effects of reduced seeding rate on hybrid grain yield and quality in comparison to pure-line varieties. A comparison of the hybrid varieties available was also carried out and the higher yielding hybrids were then compared with the best pure-line varieties in terms of grain yield and quality, and response to fungicide. The results indicated that in good sowing conditions hybrids can give greater yields than pure-line varieties at reduced seeding rates, but the effect is not large or consistent. There was generally no effect of seeding rate on the grain quality of hybrid varieties but crop lodging occurred in one season at high seeding rates. Of the hybrid varieties examined, Mercury and Hyno Esta were the two better varieties in terms of grain yield; there was little difference between the hybrids examined in terms of grain quality. The best hybrid varieties did not give consistently higher yields or quality than the best pure-line varieties and exhibited a similar response to fungicide application as the pure-line varieties. It is concluded that when the price differential between seed of pure-line varieties and hybrid varieties is taken into account, the winter wheat hybrid varieties currently available do not offer any economic advantages to commercial growers at the present time

Developing a fluorescent, tumour-specific, molecular imaging platform for laparoscopic colorectal cancer surgery.

Background: Fluorescent laparoscopic imaging of primary colorectal tumours and lymph node metastases would improve localisation of early tumours and allow intra-operative staging, potentially facilitating intra-operative stratification of the extent of surgical resections thereby improving patient outcomes. I aimed to develop and test a fluorescent molecular probe capable of allowing localisation of tumours in vivo. Methods: Immunohistochemistry was used to identify the most appropriate colorectal cancer target from a panel of seven biomarkers in prospectively collected, matched normal and tumour tissue from 280 colorectal cancer patients. The availability of targets for antibody binding was assessed in live cells, fresh frozen tumour samples and ex vivo cancer specimens. Indocyanine green was conjugated to anti-CEA and control IgG antibodies, and CEA-specific fluorescence was quantified in live cancer cells. Dye-doped silica nanoparticles loaded with NIR664 dye were synthesised using a water-in-oil microemulsion technique. Anti-CEA IgGs or control IgGs were conjugated to nanoparticles using a variety of different chemical conjugation strategies and binding to cells was quantified in vitro. A murine xenograft model and live IVIS imaging were used to assess PAMAM-linked nanoparticles in vivo. Results: Of the biomarkers tested, CEA showed the greatest differential expression between normal and tumour samples (p<0.001) and the best sensitivity (93.7%) and specificity (96.1%) for colorectal cancer detection. ICG-anti-CEA exhibited CEA-specific fluorescence in all three cell lines tested (p<0.01) with fluorescence peaking at 24-36 hours. CEA-targeted, PAMAM dendrimer-conjugated nanoparticles allowed strong tumour-specific targeting, demonstrating up to 12.3-fold greater fluorescence than control nanoparticles when incubated with colorectal cancer cell lines (p<0.002). In LS174T xenografts, CEA-targeted nanoparticles demonstrated clear tumour-specific fluorescence from 6 to 72h after injection, as compared to only background fluorescence for control IgG-targeted nanoparticles at all time points (p<0.0001). Conclusions: CEA has the greatest potential to allow highly specific tumour imaging. ICG-conjugated anti-CEA antibodies allow CEA-specific imaging of colorectal cancer cells in vitro. Dye-doped silica nanoparticles conjugated to anti-CEA antibodies via PAMAM dendrimers have potential to allow intra-operative fluorescent visualisation of tumour cells. These findings are the first to demonstrate live tumour-specific fluorescent colorectal cancer imaging using an antibody-targeted nanoparticle in vivo

The impact of simulation-based mastery learning, booster session timing and clinical exposure on confidence in intercostal drain insertion:a survey of internal medicine trainees in Scotland

Background: Intercostal chest drain (ICD) insertion is a skill that medical trainees lack confidence in performing. This study explores the impact of a national programme of Simulation-Based Mastery Learning (SBML) on procedural confidence, including the impact of time intervals between booster sessions and interim clinical experience. Methods: Internal Medicine Trainees in Scotland were surveyed about confidence and clinical experience with ICD insertion before and immediately after SBML and booster session. Data were matched and analysed using paired sample t-tests. Short interval and long interval groups were compared using Student’s unpaired t-test. The impact of interim clinical experience was assessed using Analysis of Variance. Results: Mean confidence in ICD insertion rose following SBML, fell between initial and booster session, and increased again following booster session (P = &lt; 0.001). 33 of 74 trainees had successfully inserted an ICD between sessions. Fall in confidence was unaffected by the time interval between training sessions, but was mitigated by interim clinical experience. Conclusions: SBML boosts trainee confidence in ICD insertion. However, there is evidence of confidence decay, possibly due to a lack of clinical experience between sessions. More research is needed to explore barriers to transfer of skills from simulated to real-world environments.</p

Short-chain fatty acid level and field cancerization show opposing associations with enteroendocrine cell number and neuropilin expression in patients with colorectal adenoma

BACKGROUND: Previous reports have suggested that the VEGF receptor neuropilin-1 (NRP-1) is expressed in a singly dispersed subpopulation of cells in the normal colonic epithelium, but that expression becomes dysregulated during colorectal carcinogenesis, with higher levels in tumour suggestive of a poor prognosis. We noted that the spatial distribution and morphology if NRP-1 expressing cells resembles that of enteroendocrine cells (EEC) which are altered in response to disease state including cancer and irritable bowel syndrome (IBS). We have shown that NRP-1 is down-regulated by butyrate in colon cancer cell lines in vitro and we hypothesized that butyrate produced in the lumen would have an analogous effect on the colon mucosa in vivo. Therefore we sought to investigate whether NRP-1 is expressed in EEC and how NRP-1 and EEC respond to butyrate and other short-chain fatty acids (SCFA - principally acetate and propionate). Additionally we sought to assess whether there is a field effect around adenomas. METHODOLOGY: Biopsies were collected at the mid-sigmoid, at the adenoma and at the contralateral wall (field) of 28 subjects during endoscopy. Samples were fixed for IHC and stained for either NRP-1 or for chromogranin A (CgA), a marker of EEC. Stool sampling was undertaken to assess individuals' butyrate, acetate and propionate levels. RESULT: NRP-1 expression was inversely related to SCFA concentration at the colon landmark (mid-sigmoid), but expression was lower and not related to SCFA concentration at the field. Likewise CgA+ cell number was also inversely related to SCFA at the landmark, but was lower and unresponsive at the field. Crypt cellularity was unaltered by field effect. A colocalisation analysis showed only a small subset of NRP-1 localised with CgA. Adenomas showed extensive, weaker staining for NRP-1 which contrastingly correlated positively with butyrate level. Field effects cause this relationship to be lost. Adenoma tissue shows dissociation of the co-regulation of NRP-1 and EEC. CONCLUSION: NRP-1 is inversely associated with levels of butyrate and other SCFA in vivo and is expressed in a subset of CgA expressing cells. EEC number is related to butyrate level in the same way

Pulmonary embolism severity before and during the COVID-19 pandemic

OBJECTIVES: Early in the coronavirus 2019 (COVID-19) pandemic, a high frequency of pulmonary embolism was identified. This audit aims to assess the frequency and severity of pulmonary embolism in 2020 compared to 2019. METHODS: In this retrospective audit, we compared computed tomography pulmonary angiography (CTPA) frequency and pulmonary embolism severity in April and May 2020, compared to 2019. Pulmonary embolism severity was assessed with the Modified Miller score and the presence of right heart strain was assessed. Demographic information and 30-day mortality was identified from electronic health records. RESULTS: In April 2020, there was a 17% reduction in the number of CTPA performed and an increase in the proportion identifying pulmonary embolism (26%, n = 68/265 vs 15%, n = 47/320, p < 0.001), compared to April 2019. Patients with pulmonary embolism in 2020 had more comorbidities (p = 0.026), but similar age and sex compared to 2019. There was no difference in pulmonary embolism severity in 2020 compared to 2019, but there was an increased frequency of right heart strain in May 2020 (29 vs 12%, p = 0.029). Amongst 18 patients with COVID-19 and pulmonary embolism, there was a larger proportion of males and an increased 30 day mortality (28% vs 6%, p = 0.008). CONCLUSION: During the COVID-19 pandemic, there was a reduction in the number of CTPA scans performed and an increase in the frequency of CTPA scans positive for pulmonary embolism. Patients with both COVID-19 and pulmonary embolism had an increased risk of 30-day mortality compared to those without COVID-19. ADVANCES IN KNOWLEDGE: During the COVID-19 pandemic, the number of CTPA performed decreased and the proportion of positive CTPA increased. Patients with both pulmonary embolism and COVID-19 had worse outcomes compared to those with pulmonary embolism alone

Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids. METHODS: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716. FINDINGS: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics). INTERPRETATION: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL. FUNDING: NIHR Health Technology Assessment programme

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy

OBJECTIVES: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). METHODS: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αβ)42, Aβ40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aβ status. RESULTS: P-tau181 was elevated in MCI+AD compared with all other groups. Aβ42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-Aβ positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern. CONCLUSION: This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD

Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy.

OBJECTIVES: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). METHODS: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αβ)42, Aβ40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aβ status. RESULTS: P-tau181 was elevated in MCI+AD compared with all other groups. Aβ42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-Aβ positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern. CONCLUSION: This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD.b. Funding This study was funded by the Cambridge Centre for Parkinson-Plus, the National Institute for Health Research (NIHR) Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge and the NIHR Newcastle Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The UK Dementia Research Institute, receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the UK Dementia Research Institute at UCL, the Wellcome Trust and an anonymous donor

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Introduction: In addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). However, the prognostic value of the in vivo imaging markers for these processes in PSP remains unclear. We test the primary hypothesis that baseline in vivo imaging assessment of neuroinflammation in subcortical regions predicts clinical progression in patients with PSP. Methods: Seventeen patients with PSP–Richardson’s syndrome underwent a baseline multimodal imaging assessment, including [11C]PK11195 positron emission tomography (PET) to index microglial activation, [18F]AV-1451 PET for tau pathology and structural MRI. Disease severity was measured at baseline and serially up to 4 years with the Progressive Supranuclear Palsy Rating Scale (PSPRS) (average interval of 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three principal component analyses (PCAs). A linear mixed-effects model was applied to the longitudinal PSPRS scores. Single-modality imaging predictors were regressed against the individuals’ estimated rate of progression to identify the prognostic value of baseline imaging markers. Results: PCA components reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSPRS. PCA-derived PET markers of neuroinflammation and tau pathology correlated with regional brain volume in the same regions. However, MRI volumes alone did not predict the rate of clinical progression. Conclusions: Molecular imaging with PET for microglial activation and tau pathology can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP and the potential for PET to stratify patients in early phase clinical trials