Sex-Related Differences in Motor Unit Firing Rate and Pennation Angle.

Motor unit firing rate (MUFR) and pennation angle were measured concurrently in males and females from submaximal to maximal intensities. Thirty participants, (16F and 14M) performed isometric dorsiflexion contractions at 20%, 40%, 60%, 80% and 100% of maximal voluntary contraction (MVC). During each contraction, measures of MUFR were obtained via surface electromyography decomposition, and muscle fiber pennation angle and fascicle length were obtained via ultrasound.

No influence of steady-state postural changes on cerebrovascular compliance in humans.

The aim of this study was to determine the effect of posture changes on vascular compliance in intracranial (brain) versus extracranial vascular beds (forearm). Eighteen young adults (nine females) performed a supine-to-seated-to-standing protocol involving 5 min of rest in each position. Continuous blood pressure, middle cerebral artery (MCA) blood velocity, and brachial artery blood velocity were recorded at each posture.

Escalating Surgical Treatment for Left Ventricular Assist Device Infection and Expected Mortality: Clinical Risk Prediction Score.

Background: Left ventricular assist devices (LVAD) improve survival for patients with cardiac failure, but LVAD-specific infection (VSI) remains a challenge with poorly understood predictive risk factors. The indications and use of escalating medical treatment to surgical debridement and potential flap reconstruction are not well characterized.

Study Design: A retrospective review of consecutive patients undergoing primary LVAD implantation at a tertiary academic center was performed.

Identifying Opportunities for Impact of Community-Based Pharmacist-Led Biometric Health Screenings on ASCVD Risk.

Introduction: Community-based pharmacists are positioned uniquely to assist in the early detection of underlying cardiovascular disease (CVD) which affects approximately 50% of adults in the United States. Organizations utilize community-based pharmacists to conduct annual biometric health screenings to help employees identify health risks previously undetected. The goal of this study was to evaluate how community-based pharmacists could impact lifetime atherosclerotic cardiovascular disease (ASCVD) risk for a large population.

Gamification educational intervention improves pediatric nurses' comfort and speed drawing up code-dose epinephrine.

Purpose: Drawing up weight-based doses of epinephrine is a vital skill for pediatric nurses; however, non-intensive care unit (ICU) nurses may not routinely perform this skill and may not be as efficient or comfortable doing so during pediatric resuscitations. This study aimed to evaluate the impact of a gamification program on non-ICU pediatric nurses' knowledge and skills regarding epinephrine for pediatric cardiac arrest.

Design And Methods: Comfort and time to draw up three doses of epinephrine during out-of-ICU in-hospital pediatric cardiac arrest were measured pre- and post- a gamification-centered educational intervention.

Variational kinetic clustering of complex networks.

Efficiently identifying the most important communities and key transition nodes in weighted and unweighted networks is a prevalent problem in a wide range of disciplines. Here, we focus on the optimal clustering using variational kinetic parameters, linked to Markov processes defined on the underlying networks, namely, the slowest relaxation time and the Kemeny constant. We derive novel relations in terms of mean first passage times for optimizing clustering via the Kemeny constant and show that the optimal clustering boundaries have equal round-trip times to the clusters they separate.

Spare Part Reconstruction of Distal Pediatric Thumb Amputation.

Thumb tip amputations can be reconstructive challenges, particularly in pediatric patients. Reconstruction using composite grafting and local flap options has been described for tip amputations in the adult population. The authors describe the use of a spare part reconstruction using autologous bone graft and a reverse cross finger flap to preserve length and function for a distal thumb tip amputation in a young man.

Comparative Insecticide Uptake Characteristics of Chlorfenapyr Suggests an Additional Reason Why Bed Bugs (Hemiptera: Cimicidae) are so Difficult to Control.

Insecticides interact with biochemical sites, disrupting homeostasis, leading to moribundity and death. Considering this process of intoxication, investigating insecticide uptake ensures an understanding of exposure profile. This study evaluated insecticide uptake by bed bugs, Cimex lectularius L.

Efficient and Precise Processing of the Optimized Primary Artificial MicroRNA in a Huntingtin-Lowering Adeno-Associated Viral Gene Therapy and in Mice and Nonhuman Primates.

Huntington's disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin () gene comprising an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat sequence that results in a pathogenic huntingtin protein. Adeno-associated viral (AAV) gene therapy containing a primary artificial microRNA (pri-amiRNA) specifically targeting messenger RNA (mRNA) has the potential to provide long-lasting therapeutic benefit, through durable reduction of mutant expression after a single administration. The efficiency and precision of processing of the pri-amiRNA precursor to the mature guide (G) strand by transduced cells are critical for specific and potent mRNA lowering.

Pedicled Myocutaneous Flap Breast Reconstruction in the Community Hospital Setting: An Analysis of Cost and Complications.

Background Free tissue transfer breast reconstruction is an option for breast cancer patients that is precluded by a number of factors. The authors' objective was to assess the use of pedicled myocutaneous breast reconstruction in the community hospital setting, with more limited resources, as a viable option with comparable rates of complications, cost, and outcomes. Methods The authors performed a retrospective cohort review of pedicled myocutaneous breast reconstructions of a single surgeon at a community-based institution from 2015 to 2019.

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2 (AAV2)-human GDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8 × 10, 6.

Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration.

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN).

Correlation functions, mean first passage times, and the Kemeny constant.

Markov processes are widely used models for investigating kinetic networks. Here, we collate and present a variety of results pertaining to kinetic network models in a unified framework. The aim is to lay out explicit links between several important quantities commonly studied in the field, including mean first passage times (MFPTs), correlation functions, and the Kemeny constant.

Can One Trust Kinetic and Thermodynamic Observables from Biased Metadynamics Simulations?: Detailed Quantitative Benchmarks on Millimolar Drug Fragment Dissociation.

Understanding ligand dissociation mechanisms at an atomic resolution is a highly desired but difficult to achieve objective in experiments as well as in computer simulations. Structural details of the dissociation process are in general hard to capture in experiments, while the relevant time scales are far beyond molecular dynamics (MD) simulations even with the most powerful supercomputers. As such, many different specialized enhanced sampling methods have been proposed that make it possible to efficiently calculate the dissociation mechanisms in protein-ligand systems.

Mean first passage times in variational coarse graining using Markov state models.

Markov state models (MSMs) provide some of the simplest mathematical and physical descriptions of dynamical and thermodynamical properties of complex systems. However, typically, the large dimensionality of biological systems studied makes them prohibitively expensive to work in fully Markovian regimes. In this case, coarse graining can be introduced to capture the key dynamical processes-slow degrees of the system-and reduce the dimension of the problem.

Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

Objective: To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.

Methods: Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.

Development of a novel frameless skull-mounted ball-joint guide array for use in image-guided neurosurgery.

Objective: Successful convection-enhanced delivery of therapeutic agents to subcortical brain structures requires accurate cannula placement. Stereotactic guiding devices have been developed to accurately target brain nuclei. However, technologies remain limited by a lack of MRI compatibility, or by devices' size, making them suboptimal for direct gene delivery to brain parenchyma.

Calculating Kinetic Rates and Membrane Permeability from Biased Simulations.

We present a simple approach to calculate the kinetic properties of lipid membrane crossing processes from biased molecular dynamics simulations. We demonstrate that by using biased simulations, one can obtain highly accurate kinetic information with significantly reduced computational time with respect to unbiased simulations. We describe how to conveniently calculate the transition rates to enter, cross, and exit the membrane in terms of the mean first passage times.

Limiting relaxation times from Markov state models.

Markov state models (MSMs) are more and more widely used in the analysis of molecular simulations to incorporate multiple trajectories together and obtain more accurate time scale information of the slowest processes in the system. Typically, however, multiple lagtimes are used and analyzed as input parameters, yet convergence with respect to the choice of lagtime is not always possible. Here, we present a simple method for calculating the slowest relaxation time (RT) of the system in the limit of very long lagtimes.

Dynamic Histogram Analysis To Determine Free Energies and Rates from Biased Simulations.

We present an algorithm to calculate free energies and rates from molecular simulations on biased potential energy surfaces. As input, it uses the accumulated times spent in each state or bin of a histogram and counts of transitions between them. Optimal unbiased equilibrium free energies for each of the states/bins are then obtained by maximizing the likelihood of a master equation (i.

Peptide dimerization-dissociation rates from replica exchange molecular dynamics.

We show how accurate rates of formation and dissociation of peptide dimers can be calculated using direct transition counting (DTC) from replica-exchange molecular dynamics (REMD) simulations. First, continuous trajectories corresponding to system replicas evolving at different temperatures are used to assign conformational states. Second, we analyze the entire REMD data to calculate the corresponding rates at each temperature directly from the number of transition counts.

Widespread optogenetic expression in macaque cortex obtained with MR-guided, convection enhanced delivery (CED) of AAV vector to the thalamus.

Background: In non-human primate (NHP) optogenetics, infecting large cortical areas with viral vectors is often a difficult and time-consuming task. Previous work has shown that parenchymal delivery of adeno-associated virus (AAV) in the thalamus by convection-enhanced delivery (CED) can lead to large-scale transduction via axonal transport in distal areas including cortex. We used this approach to obtain widespread cortical expression of light-sensitive ion channels.

Recurrent Compartment Syndrome Leading to the Diagnosis of McArdle Disease: Case Report.

Glycogen storage disorders are rare diseases of metabolism that are usually diagnosed when a patient presents with recurrent fatigue, muscle pains, and exercise intolerance. In this case report, we describe a patient who presented with the second episode of nontraumatic compartment syndrome over a 10-year span. Because of the obscure presentation, we performed a muscle biopsy, which on muscle phosphorylase staining revealed McArdle disease (glycogen storage disease type V).

Slow AAV2 clearance from the brain of nonhuman primates and anti-capsid immune response.

Adeno-associated virus serotype 2 (AAV2) has previously been reported to be a slowly uncoating virus in peripheral tissues, but persistence of intact vector in primate brain has not been explored. Because some neurological gene therapies may require re-administration of the same vector to patients, it seems important to understand the optimal timeframe in which to consider such repeat intervention. Surprisingly, convection-enhanced delivery of AAV2 into the thalamus of nonhuman primates (NHPs) resulted in robust staining of neurons with A20 antibody that detected intact AAV2 particles at ∼1.