764 research outputs found
The SENCO role in post-primary schools in Ireland: victims or agents of change?
This paper considers the role of Special Educational Needs Coordinators (SENCOs) in mainstream post-primary schools (12–18 years) in Ireland. Little is known of the role in the Irish context and it is hoped that this research will inform policy. The Irish educational landscape has witnessed seismic change recently with further transformation imminent. The SENCO role is a recent phenomenon in Irish schools and while much is known of the role internationally, Irish SENCOs tend to operate in a policy vacuum. This paper draws on research with a purposive sample of twenty-seven SENCOs. A lengthy postal questionnaire served as the method of data collection, where both quantitative and qualitative data were collected. Findings reveal the complexity of the role in an evolving education system. SENCOs continue to fulfil largely operational roles and are limited in their capacity to effect change in inclusive practice from a whole-school perspective. Lack of formal recognition of the SENCO role has led to its ad-hoc development. This research makes the case for the formalisation of the role at policy level and recognition of the need to develop the SENCO as strategic leader, firmly situated within school management. Otherwise, Irish SENCOs risk being victims rather than agents of change
FDG‐PET/CT after two cycles of R‐CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome – final result of a UK National Cancer Research Institute prospective study
The UK National Cancer Research Institute initiated a prospective study (UKCRN‐ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/computed tomography (CT) in diffuse large B‐cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post‐cycle‐2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end‐of‐treatment CT, progression‐free (PFS) and overall survival (OS) was explored. The end‐of‐treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUVmax) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow‐up, the 5‐year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1–5 (P = 0·01); and 72·6% and 57·1% by ∆SUVmax of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1–3) at interim PET/CT after two cycles of R‐CHOP in DLBCL was associated with a higher end‐of‐treatment complete and overall response rate; however, only DS‐5 patients had inferior PFS and OS
Assessing the coherence in biological and environmental drivers of young sea bass abundance across important estuarine nursery areas of the northern European sea bass stock
Year class strength is an important determinant of fish population size, but the drivers are often unknown. The northern stock of European sea bass (Dicentrarchus labrax) is an important target species for both commercial and recreational fisheries. Scientific assessments showed a rapid decline in spawning stock biomass from 2010-18 attributed to a combination of fishing mortality and poor year class strength. Recruitment to the adult stock is linked to the abundance and temporal dynamics of young bass in estuarine nursery areas, but little is known about the relative importance of environmental and biological drivers on the survival of these young life stages. In this study, we use Generalised Linear Models to attempt to identify important local environmental (sea surface temperature and river flow) and biological (chlorophyll-a concentration and predator abundance) drivers of young sea bass abundance. We focus on seven British and Irish estuarine areas that are important to the northern stock of European sea bass. In four English estuarine areas there were good model fits to the abundance of young sea bass, but predictors differed amongst these suggesting that drivers of abundance may differ among individual nursery areas. This was further demonstrated by poor fits of models generated for English estuaries to interannual patterns of abundance in the Irish nursery areas tested. The differences found in the most important abundance drivers amongst areas highlight the complex and differing dynamics between estuaries. If the number of young bass that eventually join the adult stock is dependent on survivors from a diverse set of unique nursery area conditions, then endeavours to incorporate this knowledge into fisheries management should be further explored
Comparison of variables associated with cerebrospinal fluid neurofilament, total-tau, and neurogranin
INTRODUCTION: Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total-tau [T-tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging-Alzheimer's Association Research Framework. METHODS: We examined, in a community-based population (N = 777, aged 50-95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T-tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in-house enzyme-linked immunosorbent assays. RESULTS: Multiple variables were differentially associated with CSF NfL and T-tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T-tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. DISCUSSION: Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice
Dynamic coupling of fast channel gating with slow ATP-turnover underpins protein transport through the Sec translocon.
The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA. We show that the SecYEG channel fluctuations between open and closed states are much faster (~20-fold during translocation) than ATP turnover, and that the nucleotide status of SecA modulates the rates of opening and closure. The SecY variant PrlA4, which exhibits faster transport but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore and thereby enhancing translocation efficiency. Thus, rapid SecYEG channel dynamics are allosterically coupled to SecA via modulation of the energy landscape, and play an integral part in protein transport. Loose coupling of ATP-turnover by SecA to the dynamic properties of SecYEG is compatible with a Brownian-rachet mechanism of translocation, rather than strict nucleotide-dependent interconversion between different static states of a power stroke
Search algorithms as a framework for the optimization of drug combinations
Combination therapies are often needed for effective clinical outcomes in the
management of complex diseases, but presently they are generally based on
empirical clinical experience. Here we suggest a novel application of search
algorithms, originally developed for digital communication, modified to
optimize combinations of therapeutic interventions. In biological experiments
measuring the restoration of the decline with age in heart function and
exercise capacity in Drosophila melanogaster, we found that search algorithms
correctly identified optimal combinations of four drugs with only one third of
the tests performed in a fully factorial search. In experiments identifying
combinations of three doses of up to six drugs for selective killing of human
cancer cells, search algorithms resulted in a highly significant enrichment of
selective combinations compared with random searches. In simulations using a
network model of cell death, we found that the search algorithms identified the
optimal combinations of 6-9 interventions in 80-90% of tests, compared with
15-30% for an equivalent random search. These findings suggest that modified
search algorithms from information theory have the potential to enhance the
discovery of novel therapeutic drug combinations. This report also helps to
frame a biomedical problem that will benefit from an interdisciplinary effort
and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio
Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial
Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34
Gene Function Classification Using Bayesian Models with Hierarchy-Based Priors
We investigate the application of hierarchical classification schemes to the
annotation of gene function based on several characteristics of protein
sequences including phylogenic descriptors, sequence based attributes, and
predicted secondary structure. We discuss three Bayesian models and compare
their performance in terms of predictive accuracy. These models are the
ordinary multinomial logit (MNL) model, a hierarchical model based on a set of
nested MNL models, and a MNL model with a prior that introduces correlations
between the parameters for classes that are nearby in the hierarchy. We also
provide a new scheme for combining different sources of information. We use
these models to predict the functional class of Open Reading Frames (ORFs) from
the E. coli genome. The results from all three models show substantial
improvement over previous methods, which were based on the C5 algorithm. The
MNL model using a prior based on the hierarchy outperforms both the
non-hierarchical MNL model and the nested MNL model. In contrast to previous
attempts at combining these sources of information, our approach results in a
higher accuracy rate when compared to models that use each data source alone.
Together, these results show that gene function can be predicted with higher
accuracy than previously achieved, using Bayesian models that incorporate
suitable prior information
Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom
PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud
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PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud
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RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud
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CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud
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