Label-free fibre optic Raman spectroscopy with bounded simplex-structured matrix factorization for the serial study of serum in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease in urgent need of disease biomarkers for the assessment of promising therapeutic candidates in clinical trials. Raman spectroscopy is an attractive technique for identifying disease related molecular changes due to its simplicity. Here, we describe a fibre optic fluid cell for undertaking spontaneous Raman spectroscopy studies of human biofluids that is suitable for use away from a standard laboratory setting. Using this system, we examined serum obtained from patients with ALS at their first presentation to our centre (n = 66) and 4 months later (n = 27). We analysed Raman spectra using bounded simplex-structured matrix factorization (BSSMF), a generalisation of non-negative matrix factorisation which uses the distribution of the original data to limit the factorisation modes (spectral patterns). Biomarkers associated with ALS disease such as measures of symptom severity, respiratory function and inflammatory/immune pathways (C3/C-reactive protein) correlated with baseline Raman modes. Between visit spectral changes were highly significant (p = 0.0002) and were related to protein structure. Comparison of Raman data with established ALS biomarkers as a trial outcome measure demonstrated a reduction in required sample size with BSSMF Raman. Our portable, simple to use fibre optic system allied to BSSMF shows promise in the quantification of disease-related changes in ALS over short timescales

An X-ray spectral survey of the disc of M31 with XMM-Newton

We present the results of a complete spectral survey of the X-ray point sources detected in five XMM-Newton observations along the major axis of M31 but avoiding the central bulge, aimed at establishing the population characteristics of X-ray sources in this galaxy. We obtained background subtracted spectra and lightcurves for each of the 335 X-ray point sources detected across the five observations from 2002. We also correlate our source list with those of earlier X-ray surveys and radio, optical and infra-red catalogues. Sources with more than 50 source counts are individually spectrally fit in order to create the most accurate luminosity functions of M31 to date. Based on the spectral fitting of these sources with a power law model, we observe a broad range of best fit photon index. From this distribution of best fit index, we identify 16 strong high mass X-ray binary system candidates in M31. We show the first cumulative luminosity functions created using the best fit spectral model to each source with more than 50 source counts in the disc of M31. The cumulative luminosity functions show a prominent, statistically significant flattening in the X-ray luminosity LX interval 37.0 \lesssim log LX erg s-1 \lesssim 37.5. Such a feature may also be present in the X-ray populations of several other galaxies, but at a much lower statistical significance. We investigate the number of AGN present in our source list and find that above LX ~1.4x1036 erg s-1 the observed population is statistically dominated by the point source population of M31.Comment: accepted by A&A. 24 pages, 6 figures, 7 table

Reflections on a 'virtual' practice development unit: changing practice through identity development

Aims. This paper draws together the personal thoughts and critical reflections of key people involved in the establishment of a ‘virtual’ practice development unit of clinical nurse specialists in the south of England. Background. This practice development unit is ‘virtual’ in that it is not constrained by physical or specialty boundaries. It became the first group of Trust-wide clinical nurse specialists to be accredited in the UK as a practice development unit in 2004. Design and methods. The local university was asked to facilitate the accreditation process via 11 two-hour audio-recorded learning sessions. Critical reflections from practice development unit members, leaders and university staff were written 12 months after successful accreditation, and the framework of their content analysed. Findings and discussion. Practice development was seen as a way for the clinical nurse specialists to realize their potential for improving patient care by transforming care practice in a collaborative, interprofessional and evolutionary manner. The practice development unit provided a means for these nurses to analyse their role and function within the Trust. Roberts’ identity development model for nursing serves as a useful theoretical underpinning for the reflections contained in this paper. Conclusions. These narratives provide another example of nurses making the effort to shape and contribute to patient care through organizational redesign. This group of nurses began to realize that the structure of the practice development unit process provided them with the means to analyse their role and function within the organization and, as they reflected on this structure, their behaviour began to change. Relevance to clinical practice. Evidence from these reflections supports the view that practice development unit participants have secured a positive and professional identity and are, therefore, better able to improve the patient experience

Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment

Objective: In people living with HIV (PLHIV), we sought to test the hypothesis that long term anti-retroviral therapy restores the normal T cell repertoire, and investigate the functional relationship of residual repertoire abnormalities to persistent immune system dysregulation. Methods: We conducted a case-control study in PLHIV and HIV-negative volunteers, of circulating T cell receptor repertoires and whole blood transcriptomes by RNA sequencing, complemented by metadata from routinely collected health care records. Results: T cell receptor sequencing revealed persistent abnormalities in the clonal T cell repertoire of PLHIV, characterized by reduced repertoire diversity and oligoclonal T cell expansion correlated with elevated CD8 T cell counts. We found no evidence that these expansions were driven by cytomegalovirus or another common antigen. Increased frequency of long CDR3 sequences and reduced frequency of public sequences among the expanded clones implicated abnormal thymic selection as a contributing factor. These abnormalities in the repertoire correlated with systems level evidence of persistent T cell activation in genome-wide blood transcriptomes. Conclusions: The diversity of T cell receptor repertoires in PLHIV on long term anti-retroviral therapy remains significantly depleted, and skewed by idiosyncratic clones, partly attributable to altered thymic output and associated with T cell mediated chronic immune activation. Further investigation of thymic function and the antigenic drivers of T cell clonal selection in PLHIV are critical to efforts to fully re-establish normal immune function

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery

Prospects for progress on health inequalities in England in the post-primary care trust era : professional views on challenges, risks and opportunities

Background - Addressing health inequalities remains a prominent policy objective of the current UK government, but current NHS reforms involve a significant shift in roles and responsibilities. Clinicians are now placed at the heart of healthcare commissioning through which significant inequalities in access, uptake and impact of healthcare services must be addressed. Questions arise as to whether these new arrangements will help or hinder progress on health inequalities. This paper explores the perspectives of experienced healthcare professionals working within the commissioning arena; many of whom are likely to remain key actors in this unfolding scenario. Methods - Semi-structured interviews were conducted with 42 professionals involved with health and social care commissioning at national and local levels. These included representatives from the Department of Health, Primary Care Trusts, Strategic Health Authorities, Local Authorities, and third sector organisations. Results - In general, respondents lamented the lack of progress on health inequalities during the PCT commissioning era, where strong policy had not resulted in measurable improvements. However, there was concern that GP-led commissioning will fare little better, particularly in a time of reduced spending. Specific concerns centred on: reduced commitment to a health inequalities agenda; inadequate skills and loss of expertise; and weakened partnership working and engagement. There were more mixed opinions as to whether GP commissioners would be better able than their predecessors to challenge large provider trusts and shift spend towards prevention and early intervention, and whether GPs’ clinical experience would support commissioning action on inequalities. Though largely pessimistic, respondents highlighted some opportunities, including the potential for greater accountability of healthcare commissioners to the public and more influential needs assessments via emergent Health & Wellbeing Boards. Conclusions - There is doubt about the ability of GP commissioners to take clearer action on health inequalities than PCTs have historically achieved. Key actors expect the contribution from commissioning to address health inequalities to become even more piecemeal in the new arrangements, as it will be dependent upon the interest and agency of particular individuals within the new commissioning groups to engage and influence a wider range of stakeholders.</p

A study of the interplay between ionized gas and star clusters in the central region of NGC 5253 with 2D spectroscopy

ABRIDGED: A detailed 2D study of the central region of NGC5253 has been performed to characterize the stellar and ionized gas structure as well as the extinction distribution, physical properties and kinematics of the ionized gas in the central ~210pc x 130pc. We utilized optical integral field spectroscopy (IFS) data obtained with FLAMES. A detailed extinction map for the ionized gas in NGC5253 shows that the largest extinction is associated with the prominent Giant HII region. There is an offset of ~0.5" between the peak of the optical continuum and the extinction peak in agreement with findings in the infrared. We found that stars suffer less extinction than gas by a factor of 0.33. The [SII]l6717/[SII]l6731 map shows an electron density (N_e) gradient declining from the peak of emission in Ha (790cm^-3) outwards, while the argon line ratio traces areas with $N_e~4200 - 6200cm^(-3). The area polluted with extra nitrogen, as deduced from the excess [NII]/Ha, extends up to distances of 3.3" (~60pc) from the maximum pollution, which is offset by ~1.5" from the peak of continuum emission. Wolf-Rayet features are distributed in an irregular pattern over a larger area (~100pc x 100pc) and associated with young stellar clusters. We measured He^+ abundances over most of the field of view and values of He^++/H^+<~0.0005 in localized areas which do not coincide, in general, with the areas presenting W-R emission or extra nitrogen. The line profiles are complex. Up to three emission components were needed to reproduce them. One of them, associated with the giant HII region, presents supersonic widths and [NII] and [SII] emission lines shifted up to 40km/s with respect to Ha. Similarly, one of the narrow components presents offsets in the [NII] line of <~20km/s. This is the first time that maps with such velocity offsets for a starburst galaxy have been presented.Comment: accepted in Astronomy & Astrophysics. 21 pages, 22 figure

The Orbital Solution and Spectral Classification of the High-Mass X-Ray Binary IGR J01054-7253 in the Small Magellanic Cloud

We present X-ray and optical data on the Be/X-ray binary (BeXRB) pulsar IGR J01054-7253 = SXP11.5 in the Small Magellanic Cloud (SMC). Rossi X-ray Timing Explorer (RXTE) observations of this source in a large X-ray outburst reveal an 11.483 +/- 0.002s pulse period and show both the accretion driven spin-up of the neutron star and the motion of the neutron star around the companion through Doppler shifting of the spin period. Model fits to these data suggest an orbital period of 36.3 +/- 0.4d and Pdot of (4.7 +/- 0.3) x 10^{-10} ss^{-1}. We present an orbital solution for this system, making it one of the best described BeXRB systems in the SMC. The observed pulse period, spin-up and X-ray luminosity of SXP11.5 in this outburst are found to agree with the predictions of neutron star accretion theory. Timing analysis of the long-term optical light curve reveals a periodicity of 36.70 +/- 0.03d, in agreement with the orbital period found from the model fit to the X-ray data. Using blue-end spectroscopic observations we determine the spectral type of the counterpart to be O9.5-B0 IV-V. This luminosity class is supported by the observed V-band magnitude. Using optical and near-infrared photometry and spectroscopy, we study the circumstellar environment of the counterpart in the months after the X-ray outburst.Comment: 12 pages, 13 figures and 3 tables. This paper has been accepted for publication in MNRA

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research