INTRODUCTION: A key determinant of prosthesis use is the quality of fit of the prosthetic socket. The socket surrounds the residual limb and applies the appropriate force distribution to the soft tissues to maintain suspension, support, and stabilization as well as translate limb movement to prosthesis movement. The challenge in socket fabrication lays in achieving geometry that provides the appropriate force distribution at physiologically appropriate locations; a task dependent on the understanding of interface tissue-mechanics. AREAS COVERED: In the last 20 years substantial advancements in sensor innovation and computational power have allowed researchers to quantify the socket-residual limb interface; this paper reviews prominent measurement and sensing techniques described in literature over this time frame. Advantages and short comings of each technique are discussed with a focus on translation to clinical environments. EXPERT OPINION: Prosthetic sockets directly influence comfort, device use, user satisfaction, and tissue health. Advancements in instrumentation technology have unlocked the possibility of sophisticated measurement systems providing quantitative data that may work in tandem with a clinicians heuristic expertise during socket fabrication. If validated, many of the emerging sensing technologies could be implemented into a clinical setting to better characterize how patients interact with their device and help inform prosthesis fabrication and assessment techniques.

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G₁/S checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell-cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low-molecular-weight cyclin E (LMW-E) isoforms were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21^CIP1 and p27^KIP1 LMW-E is predominantly generated by neutrophil elastase-mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E's accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by IHC, is prognostic of poor survival and predicts resistance to standard therapies in patients with cancer. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities. Cancer Res; 78(19); 5481-91. ©2018 AACR.

Background

Strategic vibration of musculotendinous regions of a limb elicits illusionary sensations of movement. As a rehabilitation technique, this 'kinesthetic illusion' has demonstrated beneficial results for numerous sensory-motor disorders. However, literature shows little consistency in the vibration parameters or body positioning used, and their effects have yet to be comprehensively investigated.

Objective

To characterize the effects of the vibration amplitude, frequency, and limb position on the kinesthetic illusion.

Methods

Movement illusions were induced in 12 participants' biceps and triceps. The effect of amplitude (0.1 to 0.5 mm), frequency (70 to 110 Hz), and two limb positions were quantified on the strength of illusion (SOI), range of motion (ROM) and velocity.

Results

Amplitude significantly affected the illusionary SOI, ROM and velocity in the biceps and triceps (p< 0.05). Increasing amplitude resulted in an increase of all three output variables. Limb position showed an effect on illusionary velocity in the biceps as well as ROM and velocity in the triceps (p< 0.05). Frequency demonstrated no statistical effect.

Conclusions

Amplitude demonstrated the most profound impact on the kinesthetic illusion in the experimental ranges tested. This work may help guide clinicians and researchers in selecting appropriate vibratory parameters and body positions to consistently elicit and manipulate the kinesthetic illusion.

The aim of this paper was to demonstrate the functionality of an inexpensive mechanotactile sensory feedback system for transhumeral myoelectric prostheses. We summarize the development of a tactile-integrated prosthesis, including 1) evaluation of sensors that were retrofit onto existing commercial terminal devices; 2) design of two custom mechanotactile tactors that were integrated into a socket without compromising suction suspension; 3) design of a modular controller which translated sensor input to tactor output, was wirelessly adjusted, and fit within a prosthetic forearm; and 4) evaluation of the system with a single transhumeral participant. Prosthesis functionality was demonstrated over three test sessions; the participant was able to identify tactor stimulation location and demonstrated a reduction in grasp force with the mechanotactile stimulation. This system offers an inexpensive and modular solution for integration of a mechanotactile sensory feedback system into a prosthetic socket without compromising the suction seal. These principles can be applied in future studies to investigate the direct impact of sensory feedback on tangible outcomes for prosthetic users, thereby reducing barriers to clinical translation.

Force Sensitive Resistors (FSRs) are commercially available thin film polymer sensors commonly employed in a multitude of biomechanical measurement environments. Reasons for such wide spread usage lie in the versatility, small profile, and low cost of these sensors. Yet FSRs have limitations. It is commonly accepted that temperature, curvature and biological tissue compliance may impact sensor conductance and resulting force readings. The effect of these variables and degree to which they interact has yet to be comprehensively investigated and quantified. This work systematically assesses varying levels of temperature, sensor curvature and surface compliance using a full factorial design-of-experiments approach. Three models of Interlink FSRs were evaluated. Calibration equations under 12 unique combinations of temperature, curvature and compliance were determined for each sensor. Root mean squared error, mean absolute error, and maximum error were quantified as measures of the impact these thermo/mechanical factors have on sensor performance. It was found that all three variables have the potential to affect FSR calibration curves. The FSR model and corresponding sensor geometry are sensitive to these three mechanical factors at varying levels. Experimental results suggest that reducing sensor error requires calibration of each sensor in an environment as close to its intended use as possible and if multiple FSRs are used in a system, they must be calibrated independently.

One of the most important factors in successful upper limb prostheses is the socket design. Sockets must be individually fabricated to arrive at a geometry that suits the user's morphology and appropriately distributes the pressures associated with prosthetic use across the residual limb. In higher levels of amputation, such as transhumeral, this challenge is amplified as prosthetic weight and the physical demands placed on the residual limb are heightened. Yet, in the upper limb, socket fabrication is largely driven by heuristic practices. An analytical understanding of the interactions between the socket and residual limb is absent in literature. This work describes techniques, adapted from lower limb prosthetic research, to empirically characterize the pressure distribution occurring between the residual limb and well-fit transhumeral prosthetic sockets. A case series analyzing the result of four participants with transhumeral amputation is presented. A Tekscan VersaTek pressure measurement system and FaroArm Edge coordinate measurement machine were employed to capture socket-residual limb interface pressures and geometrically register these values to the anatomy of participants. Participants performed two static poses with their prosthesis under two separate loading conditions. Surface pressure maps were constructed from the data, highlighting pressure distribution patterns, anatomical locations bearing maximum pressure, and the relative pressure magnitudes. Pressure distribution patterns demonstrated unique characteristics across the four participants that could be traced to individual socket design considerations. This work presents a technique that implements commercially available tools to quantitatively characterize upper limb socket-residual limb interactions. This is a fundamental first step toward improved socket designs developed through informed, analytically-based design tools.

To effortlessly complete an intentional movement, the brain needs feedback from the body regarding the movement's progress. This largely nonconscious kinesthetic sense helps the brain to learn relationships between motor commands and outcomes to correct movement errors. Prosthetic systems for restoring function have predominantly focused on controlling motorized joint movement. Without the kinesthetic sense, however, these devices do not become intuitively controllable. We report a method for endowing human amputees with a kinesthetic perception of dexterous robotic hands. Vibrating the muscles used for prosthetic control via a neural-machine interface produced the illusory perception of complex grip movements. Within minutes, three amputees integrated this kinesthetic feedback and improved movement control. Combining intent, kinesthesia, and vision instilled participants with a sense of agency over the robotic movements. This feedback approach for closed-loop control opens a pathway to seamless integration of minds and machines.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.