Peripheral artery disease causes consistent gait irregularities regardless of the location of leg claudication pain

Highlights Peripheral artery disease (PAD) is a multi-level disease. PAD diffusely impairs the performance of leg muscles. PAD causes similar irregularities in gait biomechanics regardless of where claudication pain is located in the leg. Abstract Background The most common symptom of peripheral artery disease (PAD) is intermittent claudication that involves the calf, thigh, and/or buttock muscles. How the specific location of this leg pain is related to altered gait, however, is unknown. Objectives We hypothesized that because the location of claudication symptoms uniquely affects different leg muscle groups in people with PAD, this would produce distinctive walking patterns. Methods A total of 105 participants with PAD and 35 age-matched older volunteers without PAD (CTRL) were recruited. Participants completed walking impairment questionnaires (WIQ), Gardner-Skinner progressive treadmill tests, the six-minute walk test, and we performed an advanced evaluation of the biomechanics of their overground walking. Participants with PAD were categorized into 4 groups according to their stated pain location(s): calf only (C, n = 43); thigh and calf (TC, n = 18); buttock and calf (BC, n = 15); or buttock, thigh, and calf (BTC, n = 29). Outcomes were compared between CTRL, C, TC, BC and BTC groups using a one-way ANOVA with post-hoc comparisons to identify and assess statistically significant differences. Results There were no significant differences between CTRL, C, TC, BC and BTC groups in distances walked or walking speed when either pain-free or experiencing claudication pain. Each participant with PAD had significantly dysfunctional biomechanical gait parameters, even when pain-free, when compared to CTRL (pain-free) walking data. During pain-free walking, out of the 18 gait parameters evaluated, we only identified significant differences in hip power generation during push-off (in C and TC groups) and in knee power absorption during weight acceptance (in TC and BC groups). There were no between-group differences in gait parameters while people with PAD were walking with claudication pain. Conclusions Our data demonstrate that PAD affects the ischemic lower extremities in a diffuse manner irrespective of the location of claudication symptoms. Database Registration ClinicalTrials.gov NCT01970332

A low-cost, wireless near-infrared spectroscopy device detects the presence of lower extremity atherosclerosis as measured by computed tomographic angiography and characterizes walking impairment in peripheral artery disease

Background Patients with peripheral artery disease (PAD) who experience intermittent claudication report a range of symptoms. Patients with symptoms other than classically described intermittent claudication may be at the highest risk for functional decline and mobility loss. Therefore, technologies allowing for characterization of PAD severity are desirable. Near-infrared spectroscopy (NIRS) allows for measurements of muscle heme oxygen saturation (StO2) during exercise. We hypothesized lower extremities affected by PAD would exhibit distinct NIRS profiles as measured by a low-cost, wireless NIRS device and that NIRS during exercise predicts walking limitation. Methods We recruited 40 patients with PAD and 10 control participants. All patients with PAD completed a computed tomographic angiography, 6-minute walk test, and a standardized treadmill test. Controls completed a 540-second treadmill test for comparison. StO2 measurements were continuously taken from the gastrocnemius during exercise. Variables were analyzed by Fischer\u27s exact, χ2, Wilcoxon rank-sum, and Kruskal-Wallis tests as appropriate. Correlations were assessed by partial Spearman correlation coefficients adjusted for occlusive disease pattern. Results Patients with PAD experienced claudication onset at a median of 108 seconds with a median peak walking time of 288 seconds. The baseline StO2 was similar between PAD and control. The StO2 of PAD and control participants dropped below baseline at a median of 1 and 104 seconds of exercise, respectively (P \u3c .0001). Patients with PAD reached minimum StO2 earlier than control participants (119 seconds vs 522 seconds, respectively; P \u3c .001) and experienced a greater change in StO2 at 1 minute of exercise (−73.2% vs 8.3%; P \u3c .0001) and a greater decrease at minimum exercise StO2 (−83.4% vs −16.1%; P \u3c .0001). For patients with PAD, peak walking time, and 6-minute walking distance correlated with percent change in StO2 at 1 minute of exercise (r = −0.76 and -0.67, respectively; P \u3c .001) and time to minimum StO2 (r = 0.79 and 0.70, respectively; P \u3c .0001). Conclusions In this initial evaluation of a novel, low-cost NIRS device, lower extremities affected by PAD exhibited characteristic changes in calf muscle StO2, which differentiated them from healthy controls and were strongly correlated with walking impairment. These findings confirm and expand on previous work demonstrating the potential clinical value of NIRS devices and the need for further research investigating the ability of low-cost NIRS technology to evaluate, diagnose, and monitor treatment response in PAD

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Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?

There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy

Optimizing computational kernels in quantum chemistry

Density fitting is a rank reduction technique popularly used in quantum chemistry in order to reduce the computational cost of evaluating, transforming, and processing the 4-center electron repulsion integrals (ERIs). By utilizing the resolution of the identity technique, density fitting reduces the 4-center ERIs into a 3-center form. Doing so not only alleviates the high storage cost of the ERIs, but it also reduces the computational cost of operations involving them. Still, these operations can remain as computational bottlenecks which commonly plague quantum chemistry procedures. The goal of this thesis is to investigate various optimizations for density-fitted version of computational kernels used ubiquitously throughout quantum chemistry. First, we detail the spatial sparsity available to the 3-center integrals and the application of such sparsity to various operations, including integral computation, metric contractions, and integral transformations. Next, we investigate sparse memory layouts and their implication on the performance of the integral transformation kernel. Next, we analyze two transformation algorithms and how their performance will vary depending on the context in which they are used. Then, we propose two sparse memory layouts and the resulting performance of Coulomb and exchange evaluations. Since the memory required for these tensors grows rapidly, we frame these discussions in the context of their in-core and disk performance. We implement these methods in the P SI 4 electronic structure package and reveal the optimal algorithm for the kernel should vary depending on whether a disk-based implementation must be used.M.S

Implementation and Evaluation of a Virtual Elective in Otolaryngology in the Time of COVID-19

To develop and evaluate a virtual otolaryngology medical student elective created during the COVID-19 crisis with the intention of teaching the basic tenets of otolaryngology and increasing exposure to the specialty. Cross-sectional survey. Emory University School of Medicine. A 1-week virtual otolaryngology curriculum was offered to third- and fourth-year medical students that centered on the American Academy of Otolaryngology-Head and Neck Surgery Foundation's handbook (fourth edition). The course covered a variety of topics and was conducted remotely via online video conferencing software. We applied multiple teaching modalities and surveyed students regarding the effectiveness of the course. Mixed methods analysis was employed to analyze the course data. Twelve students participated; 67% reported their baseline precourse understanding of otolaryngology in the "poor-fair" range. After the course, 92% of students reported increased understanding, with 42% and 58% reporting "good" and "very good" understanding, respectively. Following completion of the course, posttest scores on summative assessments were significantly higher than pretest scores ( < .001). Ninety-two percent of students reported either "increased" or "greatly increased" interest in otolaryngology postcourse. Qualitative survey results revealed students' appreciation of course organization, formative assessments, and case-based learning. An otolaryngology elective administered through a virtual format can be effective at providing an educational experience and garnering interest in the field. Positive exposure to otolaryngology can increase medical students' interest in pursuing the specialty and expand their general knowledge of consultation, diagnosis, and management in otolaryngology

Peripheral artery disease affects the function of the legs of claudicating patients in a diffuse manner irrespective of the segment of the arterial tree primarily involved

Different levels of arterial occlusive disease (aortoiliac, femoropopliteal, multi-level disease) can produce claudication symptoms in different leg muscle groups (buttocks, thighs, calves) in patients with peripheral artery disease (PAD). We tested the hypothesis that different locations of occlusive disease uniquely affect the muscles of PAD legs and produce distinctive patterns in the way claudicating patients walk. Ninety-seven PAD patients and 35 healthy controls were recruited. PAD patients were categorized to aortoiliac, femoropopliteal and multi-level disease groups using computerized tomographic angiography. Subjects performed walking trials both pain-free and during claudication pain and joint kinematics, kinetics, and spatiotemporal parameters were calculated to evaluate the net contribution of the calf, thigh and buttock muscles. PAD patients with occlusive disease affecting different segments of the arterial tree (aortoiliac, femoropopliteal, multi-level disease) presented with symptoms affecting different muscle groups of the lower extremity (calves, thighs and buttocks alone or in combination). However, no significant biomechanical differences were found between PAD groups during the pain-free conditions with minimal differences between PAD groups in the claudicating state. All statistical differences in the pain-free condition occurred between healthy controls and one or more PAD groups. A discriminant analysis function was able to adequately predict if a subject was a control with over 70% accuracy, but the function was unable to differentiate between PAD groups. In-depth gait analyses of claudicating PAD patients indicate that different locations of arterial disease produce claudication symptoms that affect different muscle groups across the lower extremity but impact the function of the leg muscles in a diffuse manner generating similar walking impairments

AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation

Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q (CoQ) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ biosynthesis, ADCK3 deficiency decreased cellular CoQ content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients