Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia, anterior frontal and parietal cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest clinical duration had an atypical synaptic deposition of abnormal prion protein and no kuru plaques. Taken together, these data provide a remarkable example of the interplay between the strain of the pathogen and host prion protein genotype. Based on extensive modelling of human prion transmission barriers in transgenic mice expressing human prion protein on a mouse prion protein null background, the temporal distribution of codon 129 genotypes within the cohort of patients with iatrogenic Creutzfeldt-Jakob disease in the UK suggests that there was a point source of infecting prion contamination of growth hormone derived from a patient with Creutzfeldt-Jakob disease expressing prion protein valine 129

Evidence for widespread hydrated minerals on asteroid (101955) Bennu

Early spectral data from the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission reveal evidence for abundant hydrated minerals on the surface of near-Earth asteroid (101955) Bennu in the form of a near-infrared absorption near 2.7 µm and thermal infrared spectral features that are most similar to those of aqueously altered CM-type carbonaceous chondrites. We observe these spectral features across the surface of Bennu, and there is no evidence of substantial rotational variability at the spatial scales of tens to hundreds of metres observed to date. In the visible and near-infrared (0.4 to 2.4 µm) Bennu’s spectrum appears featureless and with a blue (negative) slope, confirming previous ground-based observations. Bennu may represent a class of objects that could have brought volatiles and organic chemistry to Earth

The dynamic geophysical environment of (101955) Bennu based on OSIRIS-REx measurements

The top-shaped morphology characteristic of asteroid (101955) Bennu, often found among fast-spinning asteroids and binary asteroid primaries, may have contributed substantially to binary asteroid formation. Yet a detailed geophysical analysis of this morphology for a fast-spinning asteroid has not been possible prior to the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission. Combining the measured Bennu mass and shape obtained during the Preliminary Survey phase of the OSIRIS-REx mission, we find a notable transition in Bennu’s surface slopes within its rotational Roche lobe, defined as the region where material is energetically trapped to the surface. As the intersection of the rotational Roche lobe with Bennu’s surface has been most recently migrating towards its equator (given Bennu’s increasing spin rate), we infer that Bennu’s surface slopes have been changing across its surface within the last million years. We also find evidence for substantial density heterogeneity within this body, suggesting that its interior is a mixture of voids and boulders. The presence of such heterogeneity and Bennu’s top shape are consistent with spin-induced failure at some point in its past, although the manner of its failure cannot yet be determined. Future measurements by the OSIRIS-REx spacecraft will provide insight into and may resolve questions regarding the formation and evolution of Bennu’s top-shape morphology and its link to the formation of binary asteroids

Properties of Rubble-Pile Asteroid (101955) Bennu from OSIRIS-REx Imaging and Thermal Analysis

Establishing the abundance and physical properties of regolith and boulders on asteroids is crucial for understanding the formation and degradation mechanisms at work on their surfaces. Using images and thermal data from NASA's Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft, we show that asteroid (101955) Bennu's surface is globally rough, dense with boulders, and low in albedo. The number of boulders is surprising given Bennu's moderate thermal inertia, suggesting that simple models linking thermal inertia to particle size do not adequately capture the complexity relating these properties. At the same time, we find evidence for a wide range of particle sizes with distinct albedo characteristics. Our findings imply that ages of Bennu's surface particles span from the disruption of the asteroid's parent body (boulders) to recent in situ production (micrometre-scale particles)

Clinical trial simulations based on genetic stratification and the natural history of a functional outcome measure in Creutzfeldt-Jakob disease

A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease.To establish a more powerful and meaningful clinical trial method in sCJD.A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs.A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type).Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided α = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale decline as the primary outcome could be conducted with only 120 participants assessed every 10 days and only 90 participants assessed daily, providing considerably more power than using survival as the primary outcome. Restricting to VV or MV codon 129 genotypes increased power even further. Alternatively, single-arm intervention studies (half the total sample size) could provide similar power in comparison to the natural history cohort.Functional end points in neurodegeneration need not require long and very large clinical studies to be adequately powered for efficacy. Patients with sCJD may be an efficient and cost-effective group for testing disease-modifying therapeutics. Stratified medicine and natural history cohort approaches may transform the feasibility of clinical trials in orphan diseases