Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5–9 (months)) was available in 3,773 and age at onset (median:67, IQR:61–73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10−6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Exoskeletons that assist in ankle plantarflexion can improve energy economy in locomotion. Characterizing the joint-level mechanisms behind these reductions in energy cost can lead to a better understanding of how people interact with these devices, as well as to improved device design and training protocols. We examined the biomechanical responses to exoskeleton assistance in exoskeleton users trained with a lengthened protocol. Kinematics at unassisted joints were generally unchanged by assistance, which has been observed in other ankle exoskeleton studies. Peak plantarflexion angle increased with plantarflexion assistance, which led to increased total and biological mechanical power despite decreases in biological joint torque and whole-body net metabolic energy cost. Ankle plantarflexor activity also decreased with assistance. Muscles that act about unassisted joints also increased activity for large levels of assistance, and this response should be investigated over long-term use to prevent overuse injuries.

From industrial exoskeletons to implantable medical devices, robots that interact closely with people are poised to improve every aspect of our lives. Yet designing these systems is very challenging; humans are incredibly complex and, in many cases, we respond to robotic devices in ways that cannot be modelled or predicted with sufficient accuracy. A new approach, human-in-the-loop optimization, can overcome these challenges by systematically and empirically identifying the device characteristics that result in the best objective performance for a specific user and application. This approach has enabled substantial improvements in human-robot performance in research settings and has the potential to speed development and enhance products. In this Perspective, we describe methods for applying human-in-the-loop optimization to new human-robot interaction problems, addressing each key decision in a variety of contexts. We also identify opportunities to develop new optimization techniques and answer underlying scientific questions. We anticipate that our readers will advance human-in-the-loop optimization and use it to design robotic devices that truly enhance the human experience.

Lower-limb exoskeletons could improve the mobility of people with disabilities, older adults, workers, first responders, and military personnel. Despite recent advances, few products are commercially available and exoskeleton research is still often limited by hardware constraints. Many promising multi-joint assistance strategies, especially those with high-torque and high-power components, have yet to be tested because they are beyond the capabilities of current devices. To study these untested assistance strategies, we present a hip–knee–ankle exoskeleton emulator that can apply high torques and powers that match or exceed those observed in uphill running. The system has powerful off-board motors that actuate a 13.5 kg exoskeleton end effector worn by the user. It can apply up to 200 Nm of torque in hip flexion, hip extension, and ankle plantarflexion, 250 Nm of torque in knee extension, and 140 Nm of torque in knee flexion, with over 4.5 kW of power at each joint and a closed-loop torque bandwidth of at least 18 Hz in each direction of actuation. The exoskeleton is compliant in unactuated directions, adjustable for a wide range of users and comfortable during walking and running. When paired with human-in-the-loop optimization, we expect that this system will identify new assistance strategies to improve human mobility. A complete computer-aided design (CAD) model of the exoskeleton and a bill of materials are included and available for download.