Time to publication for NIHR HTA programme-funded research: a cohort study

ObjectiveTo assess the time to publication of primary research and evidence syntheses funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme published as a monograph in Health Technology Assessment and as a journal article in the wider biomedical literature.Study designRetrospective cohort study.SettingPrimary research and evidence synthesis projects funded by the HTA Programme were included in the cohort if they were registered in the NIHR research programmes database and was planned to submit the draft final report for publication in Health Technology Assessment on or before 9 December 2011.Main outcome measuresThe median time to publication and publication at 30?months in Health Technology Assessment and in an external journal were determined by searching the NIHR research programmes database and HTA Programme website.ResultsOf 458 included projects, 184 (40.2%) were primary research projects and 274 (59.8%) were evidence syntheses. A total of 155 primary research projects had a completion date; the median time to publication was 23?months (26.5 and 35.5?months to publish a monograph and to publish in an external journal, respectively) and 69% were published within 30?months. The median time to publication of HTA-funded trials (n=126) was 24?months and 67.5% were published within 30?months. Among the evidence syntheses with a protocol online date (n=223), the median time to publication was 25.5?months (28?months to publication as a monograph), but only 44.4% of evidence synthesis projects were published in an external journal. 65% of evidence synthesis studies had been published within 30.0?months.ConclusionsResearch funded by the HTA Programme publishes promptly. The importance of Health Technology Assessment was highlighted as the median time to publication was 9?months shorter for a monograph than an external journal article

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.This study was funded by Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), Medical Research Council (UK) (G0601943), and Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). Funding bodies had no influence on study design or data interpretation.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/NXG.000000000000011

Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia.

Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation

The neuroregenerative effects of topical decorin on the injured mouse cornea

BACKGROUND: The cornea is innervated with a rich supply of sensory nerves that play important roles in ocular surface health. Any injury or pathology of the corneal nerves increases the risk of dry eye disease and infection. This study aims to evaluate the therapeutic potential of topical decorin to improve corneal nerve regeneration in a mouse model of sterile epithelial abrasion injury. METHODS: Bilateral central corneal epithelial abrasions (2-mm, Alger Brush) were performed on young C57BL/6 J mice to remove the corneal sensory nerves. Decorin, or vehicle, was applied topically, three times per day for 1 week or every 2 h for 6 h. Spectral-domain optical coherence tomography was performed to measure the abrasion area and corneal thickness. Wholemount immunofluorescence staining was used to assess sensory nerve regeneration (β-tubulin III) and immune cell density (CD45, Iba1, CD11c). To investigate the specific role of dendritic cells (DCs), Cx3cr1gfp/gfp mice, which spontaneously lack resident corneal epithelial DCs, were also investigated. The effect of prophylactic topical administration of recombinant human decorin (applied prior to the abrasion) was also investigated. Nerve tracing (NeuronJ software) was performed to compare recovery of basal nerve axons and superficial nerve terminals in the central and peripheral cornea. RESULTS: At 6 h after injury, topical decorin application was associated with greater intraepithelial DC recruitment but no change in re-epithelialisation or corneal thickness, compared to the vehicle control. One week after injury, sub-basal nerve plexus and superficial nerve terminal density were significantly higher in the central cornea in the decorin-treated eyes. The density of corneal stromal macrophages in the decorin-treated eyes and their contralateral eyes was significantly lower compared to saline-treated corneas. No significant improvement in corneal nerve regeneration was observed in Cx3cr1gfp/gfp mice treated with decorin. CONCLUSIONS: Decorin promotes corneal epithelial nerve regeneration after injury. The neuroregenerative effect of topical decorin was associated with a higher corneal DC density during the acute phase, and fewer macrophages at the study endpoint. The corneal neuroregenerative effects of decorin were absent in mice lacking intraepithelial DCs. Together, these findings support a role for decorin in DC-mediated neuroregeneration following corneal abrasion injury

Precession of a Freely Rotating Rigid Body. Inelastic Relaxation in the Vicinity of Poles

When a solid body is freely rotating at an angular velocity ${\bf \Omega}$, the ellipsoid of constant angular momentum, in the space $\Omega_1, \Omega_2, \Omega_3$, has poles corresponding to spinning about the minimal-inertia and maximal-inertia axes. The first pole may be considered stable if we neglect the inner dissipation, but becomes unstable if the dissipation is taken into account. This happens because the bodies dissipate energy when they rotate about any axis different from principal. In the case of an oblate symmetrical body, the angular velocity describes a circular cone about the vector of (conserved) angular momentum. In the course of relaxation, the angle of this cone decreases, so that both the angular velocity and the maximal-inertia axis of the body align along the angular momentum. The generic case of an asymmetric body is far more involved. Even the symmetrical prolate body exhibits a sophisticated behaviour, because an infinitesimally small deviation of the body's shape from a rotational symmetry (i.e., a small difference between the largest and second largest moments of inertia) yields libration: the precession trajectory is not a circle but an ellipse. In this article we show that often the most effective internal dissipation takes place at twice the frequency of the body's precession. Applications to precessing asteroids, cosmic-dust alignment, and rotating satellites are discussed.Comment: 47 pages, 1 figur

Dynamical system analysis and forecasting of deformation produced by an earthquake fault

We present a method of constructing low-dimensional nonlinear models describing the main dynamical features of a discrete 2D cellular fault zone, with many degrees of freedom, embedded in a 3D elastic solid. A given fault system is characterized by a set of parameters that describe the dynamics, rheology, property disorder, and fault geometry. Depending on the location in the system parameter space we show that the coarse dynamics of the fault can be confined to an attractor whose dimension is significantly smaller than the space in which the dynamics takes place. Our strategy of system reduction is to search for a few coherent structures that dominate the dynamics and to capture the interaction between these coherent structures. The identification of the basic interacting structures is obtained by applying the Proper Orthogonal Decomposition (POD) to the surface deformations fields that accompany strike-slip faulting accumulated over equal time intervals. We use a feed-forward artificial neural network (ANN) architecture for the identification of the system dynamics projected onto the subspace (model space) spanned by the most energetic coherent structures. The ANN is trained using a standard back-propagation algorithm to predict (map) the values of the observed model state at a future time given the observed model state at the present time. This ANN provides an approximate, large scale, dynamical model for the fault.Comment: 30 pages, 12 figure

Childhood-onset Leber hereditary optic neuropathy

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor

Childhood-onset Leber hereditary optic neuropathy

Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m. 3460G>A, m. 11778G>A or m. 14484T>C. Results In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m. 3460G>A and m. 14484T>C mutations compared with the m. 11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) >= 0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA Conclusions Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.Peer reviewe