Diagnostic, Prognostic, and Therapeutic Implications of Genetic Testing for Hypertrophic Cardiomyopathy

Over the last 2 decades, the pathogenic basis for the most common heritable cardiovascular disease, hypertrophic cardiomyopathy (HCM), has been investigated extensively. Affecting approximately 1 in 500 individuals, HCM is the most common cause of sudden death in young athletes. In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM. The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that the modern-day cardiologist understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology.

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses

Design of Stabilizing Arm Mechanisms for Carrying and Positioning Loads

Stabilizing arm mechanisms are used to support and position a load with minimal force from the user. Further, stabilizing arm mechanisms enable operators to stabilize the motion of the load while walking or running over variable terrain. Although existing stabilizing arm mechanisms have reached fairly broad adoption over a range of applications, it remains unknown exactly how the spring properties and geometric parameters of the mechanism enable its overall performance. We developed a simplified model to analyze the vertical dynamics of stabilizing arms to determine how the spring properties and mechanism geometry affect the natural frequency of the load mass, the range of load masses that can be supported, and the equilibrium position of the load mass. We found that decreasing the unstretched spring free length is the most effective way to minimize the natural frequency; the spring lever arm can be used to adjust for a desired load mass range, and the linkage length can be used to adjust the range of motion of the stabilizing arm. The spring stiffness should be selected based on the other parameters. This work provides a systematic design study of how the parameters of a stabilizing arm mechanism affect its behavior and fundamental design principles that could be used to improve existing mechanisms, and enable the design of new mechanisms

Arctic cloud macrophysical characteristics from CloudSat and CALIPSO

The lidar and radar profiling capabilities of the CloudSat and Cloud-Aerosol Lidar and Infrared Pathfinder (CALIPSO) satellites provide opportunities to improve the characterization of cloud properties. An Arctic cloud climatology based on their observations may be fundamentally different from earlier Arctic cloud climatologies based on passive satellite observations, which have limited contrast between the cloud and underlying surface. Specifically, the Radar–Lidar Geometrical Profile product (RL-GEOPROF) provides cloud vertical profiles from the combination of active lidar and radar. Based on this data product for the period July 2006 to March 2011, this paper presents a new cloud macrophysical property characteristic analysis for the Arctic, including cloud occurrence fraction (COF), vertical distributions, and probability density functions (PDF) of cloud base and top heights. Seasonal mean COF shows maximum values in autumn, minimum values in winter, and moderate values in spring and summer; this seasonality ismore prominent over the Arctic Ocean on the Pacific side. The mean ratios of multi-layer cloud to total cloud over the ocean and land are between 24% and 28%. Low-level COFs are higher over ocean than over land. The ratio of low-level cloud to total cloud is also higher over ocean. Middle-level and high-level COFs are smaller over ocean than over land except in summer, and the ratios of middle-level and highlevel clouds to total cloud are also smaller over ocean. Over the central Arctic Ocean, PDFs of cloud top height and cloud bottomheight show (1) two cloud top height PDF peaks, one for cloud top heights lower than 1200 mand another between 7 and 9 km; and (2) high frequency for cloud base below 1000 m with the majority of cloud base heights lower than 2000 m

Novel Characteristics of Valveless Pumping

This study investigates the occurrence of valveless pumping in a fluidfilled system consisting of two open tanks connected by an elastic tube. We show that directional flow can be achieved by introducing a periodic pinching applied at an asymmetrical location along the tube, and that the flow direction depends on the pumping frequency. We propose a relation between wave propagation velocity, tube length, and resonance frequencies associated with shifts in the pumping direction using numerical simulations. The eigenfrequencies of the system are estimated from the linearized system, and we show that these eigenfrequencies constitute the resonance frequencies and the horizontal slope frequencies of the system; 'horizontal slope frequency' being a new concept. A simple model is suggested, explaining the effect of the gravity driven part of the oscillation observed in response to the tank and tube diameter changes. Results are partly compared with experimental findings.Art. no. 22450

Rapid Improvement Project: Improving Caregivers’ Understanding of Safety Recommendations for Neurosurgical Devices

There has been a proliferation in the development of indwelling neuromodulatory devices with varied safety recommendations, making it difficult for providers to remain up-to-date. This deficit presents an opportunity for significant improvement in patient safety. Methods: We performed a search for monopolar electrocautery and magnetic resonance imaging safety recommendations for several indwelling neuromodulatory devices. We developed a questionnaire followed by an educational compendium and a posttest for 50 care providers. Results: Overall, there was a poor performance on the pretest (mean 39%, SD 19%) but significant improvement on the posttest (mean 71%, SD 16%), P < 0.0001. We placed the educational compendium that included all manufacturer recommendations in the operating room for easy reference. A 2.4 times decrease in the case start times of vagus nerve stimulator cases is evidence of its effectiveness. Conclusions: The authors highlight the lack of knowledge about manufacturer safety recommendations for indwelling neurosurgical devices, which led to the creation of operating room supplements and educational devices

Patient-reported outcomes of periacetabular osteotomy from the prospective ANCHOR cohort study

BACKGROUND: Current literature describing the periacetabular osteotomy (PAO) is mostly limited to retrospective case series. Larger, prospective cohort studies are needed to provide better clinical evidence regarding this procedure. The goals of the current study were to (1) report minimum 2-year patient-reported outcomes (pain, hip function, activity, overall health, and quality of life), (2) investigate preoperative clinical and disease characteristics as predictors of clinical outcomes, and (3) report the rate of early failures and reoperations in patients undergoing contemporary PAO surgery. METHODS: A large, prospective, multicenter cohort of PAO procedures was established, and outcomes at a minimum of 2 years were analyzed. A total of 391 hips were included for analysis (79% of the patients were female, and the average patient age was 25.4 years). Patient-reported outcomes, conversion to total hip replacement, reoperations, and major complications were documented. Variables with a p value of ≤0.10 in the univariate linear regressions were included in the multivariate linear regression. The backward stepwise selection method was used to determine the final risk factors of clinical outcomes. RESULTS: Clinical outcome analysis demonstrated major clinically important improvements in pain, function, quality of life, overall health, and activity level. Increasing age and a body mass index status of overweight or obese were predictive of improved results for certain outcome metrics. Male sex and mild acetabular dysplasia were predictive of lesser improvements in certain outcome measures. Three (0.8%) of the hips underwent early conversion to total hip arthroplasty, 12 (3%) required reoperation, and 26 (7%) experienced a major complication. CONCLUSIONS: This large, prospective cohort study demonstrated the clinical success of contemporary PAO surgery for the treatment of symptomatic acetabular dysplasia. Patient and disease characteristics demonstrated predictive value that should be considered in surgical decision-making. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence