Constraining the number of compact remnants near Sgr A*

Due to dynamical friction stellar mass black holes and neutron stars are expected to form high density cusps in the inner parsec of our Galaxy. These compact remnants, expected to number around 20000, may be accreting cold dense gas present there, and give rise to potentially observable X-ray emission. Here we build a simple but detailed time-dependent model of such emission. We find that at least several X-ray sources of this nature should be detectable with Chandra at any one time. Turning this issue around, we also ask a question of what current observational constraints might be telling us about the total number of compact remnants. A cusp with ~ 40 thousand black holes over-predicts the number of discrete sources and the total X-ray luminosity of the inner parsec, and is hence ruled out. Future observations of the distribution and orbits of the cold ionised gas in the inner parsec of Sgr A* will put tighter constraints on the cusp of compact remnants.Comment: 9 pages, 3 Postscript figure

Imiglucerase in the treatment of Gaucher disease: a history and perspective

The scientific and therapeutic development of imiglucerase (Cerezyme®) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.NIHR BRC and NIHR Senior Investigator, Rosetrees fundin

Nutrient enrichment induces dormancy and decreases diversity of active bacteria in salt marsh sediments

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 7 (2016): 12881, doi:10.1038/ncomms12881.Microorganisms control key biogeochemical pathways, thus changes in microbial diversity, community structure and activity can affect ecosystem response to environmental drivers. Understanding factors that control the proportion of active microbes in the environment and how they vary when perturbed is critical to anticipating ecosystem response to global change. Increasing supplies of anthropogenic nitrogen to ecosystems globally makes it imperative that we understand how nutrient supply alters active microbial communities. Here we show that nitrogen additions to salt marshes cause a shift in the active microbial community despite no change in the total community. The active community shift causes the proportion of dormant microbial taxa to double, from 45 to 90%, and induces diversity loss in the active portion of the community. Our results suggest that perturbations to salt marshes can drastically alter active microbial communities, however these communities may remain resilient by protecting total diversity through increased dormancy

The outburst duration and duty-cycle of GRS 1915+105

The extraordinarily long outburst of GRS 1915+105 makes it one of the most remarkable low-mass X-ray binaries (LMXBs). It has been in a state of constant outburst since its discovery in 1992, an eruption which has persisted ~100 times longer than those of more typical LXMBs. The long orbital period of GRS 1915+105 implies that it contains large and massive accretion disc which is able to fuel its extreme outburst. In this paper, we address the longevity of the outburst and quiescence phases of GRS 1915+105 using Smooth Particle Hydrodynamics (SPH) simulations of its accretion disc through many outburst cycles. Our model is set in the two-alpha framework and includes the effects of the thermo-viscous instability, tidal torques, irradiation by central X-rays and wind mass loss. We explore the model parameter space and the examine the impact of the various ingredients. We predict that the outburst of GRS 1915+105 should last a minimum of 20 years and possibly up to ~100 years if X-ray irradiation is very significant. The predicted recurrence times are of the order of 10^4 years, making the X-ray duty cycle a few 0.1%. Such a low duty cycle may mean that GRS 1915+105 is not an anomaly among the more standard LMXBs and that many similar, but quiescent, systems could be present in the Galaxy.Comment: 10 pages, 9 figures, accepted for publication by MNRA

Training to enhance psychiatrist communication with patients with psychosis (TEMPO): cluster randomised controlled trial

Background A better therapeutic relationship predicts better outcomes. However, there is no trial-based evidence on how to improve therapeutic relationships in psychosis. Aims To test the effectiveness of communication training for psychiatrists on improving shared understanding and the therapeutic relationship (trial registration: ISRCTN94846422). Method In a cluster randomised controlled trial in the UK, 21 psychiatrists were randomised. Ninety-seven (51% of those approached) out-patients with schizophrenia/schizoaffective disorder were recruited, and 64 (66% of the sample recruited at baseline) were followed up after 5 months. The intervention group received four group and one individualised session. The primary outcome, rated blind, was psychiatrist effort in establishing shared understanding (self-repair). Secondary outcome was the therapeutic relationship. Results Psychiatrists receiving the intervention used 44% more self-repair than the control group (adjusted difference in means 6.4, 95% CI 1.46–11.33, P<0.011, a large effect) adjusting for baseline self-repair. Psychiatrists rated the therapeutic relationship more positively (adjusted difference in means 0.20, 95% CI 0.03–0.37, P = 0.022, a medium effect), as did patients (adjusted difference in means 0.21, 95% CI 0.01–0.41, P = 0.043, a medium effect). Conclusions Shared understanding can be successfully targeted in training and improves relationships in treating psychosis

The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients.

Funder: Sanofi Genzyme; doi: http://dx.doi.org/10.13039/100013995BACKGROUND: Fractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated. METHODS: Inclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk. RESULTS: Patients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI). CONCLUSIONS: The GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed

A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease:The role of implantable loop recorders (RaILRoAD) compared with current standard practice

Background: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. Aim: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. Methods: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations - blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging - at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. Discussion: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. Trial registration: ClinicalTrials.gov (NCT03305250). Registered on 9 October 2017

Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy

Background: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation. Methods: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control). Results: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation: 29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size. Conclusions: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation

Improving the quantitative classification of Erlenmeyer flask deformities

Abstract: The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher’s disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson’s correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4–6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone