From dawn till dusk: Time-adaptive bayesian optimization for neurostimulation.

Stimulation optimization has garnered considerable interest in recent years in order to efficiently parametrize neuromodulation-based therapies. To date, efforts focused on automatically identifying settings from parameter spaces that do not change over time. A limitation of these approaches, however, is that they lack consideration for time dependent factors that may influence therapy outcomes. Disease progression and biological rhythmicity are two sources of variation that may influence optimal stimulation settings over time. To account for this, we present a novel time-varying Bayesian optimization (TV-BayesOpt) for tracking the optimum parameter set for neuromodulation therapy. We evaluate the performance of TV-BayesOpt for tracking gradual and periodic slow variations over time. The algorithm was investigated within the context of a computational model of phase-locked deep brain stimulation for treating oscillopathies representative of common movement disorders such as Parkinson's disease and Essential Tremor. When the optimal stimulation settings changed due to gradual and periodic sources, TV-BayesOpt outperformed standard time-invariant techniques and was able to identify the appropriate stimulation setting. Through incorporation of both a gradual "forgetting" and periodic covariance functions, the algorithm maintained robust performance when a priori knowledge differed from observed variations. This algorithm presents a broad framework that can be leveraged for the treatment of a range of neurological and psychiatric conditions and can be used to track variations in optimal stimulation settings such as amplitude, pulse-width, frequency and phase for invasive and non-invasive neuromodulation strategies.

Providing occupational and physical therapy services in a free community-based interprofessional primary care clinic.

Interprofessional care provided in a free community-based clinic that focuses on chronic health conditions and health promotion provides an innovative solution to improve societal health. Many existing clinics provide a range of professions, but few include allied health services such as occupational and physical therapy. This paper provides a description of the development and implementation of an expanded faculty-guided student-led community-based primary care clinic that includes occupational and physical therapists as part of an interprofessional collaborative practice model. A detailed description and explanation of the partners involved, the institutional missions that drive this work, the logistics completed that enabled the 'doors to open,' faculty and student roles, and initial outcomes will be provided. A review of the service delivery model, lessons learned, and future directions for the clinic will also be offered.

Trends in Snakebites Related to Texas Tropical Storms and Hurricanes, 2000-2017.

INTRODUCTION: Anecdotal media reports suggest an increase in snakebites after hurricanes. After Hurricane Harvey, several households called Texas poison control centers to report snakebites that occurred when rising water flooded homes. Patterns of snakebite before and after hurricane landfalls have not been well studied. METHODS: We reviewed retrospective surveillance data from the Texas Poison Control Network to examine snakebites possibly related to tropical storms/hurricanes that hit Texas between 2000 and 2017. For that assessment, we compared 2 groups of counties: those designated for individual assistance (impact counties) by the Federal Emergency Management Agency and all others (nonimpact counties). Typically, counties with individual assistance declarations are those in which damage is worse and resident return may be delayed. RESULTS: Eleven named tropical storms/hurricanes struck Texas between 2000 and 2017; 9 received individual assistance declarations. During the 18 y, 2037 snakebites were reported in the 30 d after and the 30 d before landfalls in 9 storms; 132 (6%) occurred poststorm in impact counties, and 13 of 132 (9%) of the case narratives mentioned hurricanes as a contributing factor. Impact counties were not statistically more likely to report snakebites in the 30 d after landfall for any of the 9 storms or overall, nor did we find differences in patient demographic characteristics, type of snake, and care patterns post- and prestorm. CONCLUSIONS: There was no evidence of increases in snakebites after hurricanes in Texas during the study period. More detailed evaluations may be warranted in other regions that experience hurricanes and have venomous snake populations.

Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

BACKGROUND: The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive. OBJECTIVE: To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO). METHODS: A total of 16 disease-modifying treatment (DMT) naive RRMS subjects were studied in a baseline versus treatment (BVT) controlled prospective study. MRI scans were performed during 5 months of screening-observation, 10 months of treatment, and 4 months of post-treatment surveillance. RESULTS: No serious symptoms or adverse events occurred during treatment. For the cohort, there was a trend consistent with a 35% diminution in active lesions when observation MRIs were compared to treatment MRIs ( p = 0.08), and at the level of individuals, 12 of 16 subjects improved during TSO treatment. T regulatory lymphocytes were increased during TSO treatment. CONCLUSION: TSO is safe in RRMS subjects. Potentially favorable MRI outcomes and immunoregulatory changes were observed during TSO treatment; however, the magnitude of these effects was modest, and there was considerable variation among the responses of individual subjects.

Biomechanical comparison of fixation stability using a Lisfranc plate versus transarticular screws.

BACKGROUND: To obtain adequate fixation in treating Lisfranc soft tissue injuries, the joint is commonly stabilized using multiple transarticular screws; however iatrogenic injury is a concern. Alternatively, two parallel, longitudinally placed plates, can be used to stabilize the 1st and 2nd tarsometatarsal joints; however this may not provide adequate stability along the Lisfranc ligament. Several biomechanical studies have compared earlier methods of fixation using plates to the standard transarticular screw fixation method, highlighting the potential issue of transverse stability using plates. A novel dorsal plate is introduced, intended to provide transverse and longitudinal stability, without injury to the articular cartilage. METHODS: A biomechanical cadaver model was developed to compare the fixation stability of a novel Lisfranc plate to that of traditional fixation, using transarticular screws. Thirteen pairs of cadaveric specimens were tested intact, after a simulated Lisfranc injury, and then following implant fixation, using one method of fixation randomly assigned, on either side of each pair. Optical motion tracking was used to measure the motion between each of the following four bones: 1st metatarsal, 2nd metatarsal, 1st cuneiform, and 2nd cuneiform. Testing included both cyclic abduction loading and cyclic axial loading. RESULTS: Both the Lisfranc plate and screw fixation method provided stability such that the average 3D motions across the Lisfranc joint (between 2nd metatarsal and 1st cuneiform), were between 0.2 and 0.4mm under cyclic abduction loading, and between 0.4 and 0.5mm under cyclic axial loading. Comparing the stability of fixation between the Lisfranc plate and the screws, the differences in motion were all 0.3mm or lower, with no clinically significant differences (p>0.16). CONCLUSIONS: Diastasis at the Lisfranc joint following fixation with a novel plate or transarticular screw fixation were comparable. Therefore, the Lisfranc plate may provide adequate support without risk of iatrogenic injury to the articular cartilage.

Helminths in the gastrointestinal tract as modulators of immunity and pathology.

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract.

Online Evaluative Conditioning Did Not Alter Internalized Homonegativity or Self-Esteem in Gay Men.

OBJECTIVE: Internalized homonegativity is linked to psychological distress in sexual minorities and is thus a potential treatment target in this population. Previous studies have shown that evaluative conditioning (EC) can modify self-esteem, another self-directed attitude. The present study aimed to determine if EC deployed over the Internet could modify self-esteem and internalized homonegativity. METHOD: Gay men recruited online (N = 184) were randomly assigned to a control group or an experimental condition. Participants completed self-reports and measures of implicit attitudes before and after being exposed to control or experimental tasks. The study was administered online. RESULTS: There were no significant between-group differences on implicit or explicit self-esteem (ps > .49) or internalized homonegativity (ps > .28). CONCLUSION: Despite past laboratory success, Internet-based EC did not produce significant effects in implicit or explicit self-directed attitudes. Post hoc analyses did not support any of several potential explanations for these results. Alternative explanations are discussed.

Acute Cardiopulmonary and Metabolic Responses to High-Intensity Interval Training Protocols Using 60 s of Work and 60 s Recovery.

Rozenek, R, Salassi III, JW, Pinto, NM, and Fleming, JD. Acute cardiopulmonary and metabolic responses to high-intensity interval training protocols using 60 s of work and 60 s recovery. J Strength Cond Res 30(11): 3014-3023, 2016-Low-volume, high-intensity interval training (HIIT) consisting of 60 s work and 60 s recovery (60 s/60 s) repeated for 10 times has previously been found to produce beneficial cardiopulmonary, cellular, and metabolic adaptations in healthy and at-risk populations. There is currently relatively little information pertaining to the acute changes that take place during individual training sessions. The purpose of this study was to examine the acute physiological responses to 60 s/60 s × 10 HIIT protocols using several combinations of work and recovery intensities. Eleven healthy adults (mean age ± SD = 26.0 ± 5.3 years) performed 4 HIIT trials on separate days at varying percentages of peak power output that consisted of the following work/recovery intensities: (a) 80% PPO/0% PPO (80/0); (b) 80% PPO/50% PPO (80/50); (c) 100% PPO/0% PPO (100/0); and (d) 100% PPO/50% PPO (100/50). Compared with the other protocols, 100/50 produced higher (p ≤ 0.05) peak, average, and nadir %V[Combining Dot Above]O2peak. Other than the nadir values resulting from the 80/0 trial, all trials produced average, peak, and nadir %V[Combining Dot Above]O2peak and %HRpeak values that were within exercise intensity ranges (≈45-90% V[Combining Dot Above]O2max; ≈65-90% HRmax) recommended by the American College of Sports Medicine for improvement of cardiopulmonary function. Similar average HR and peak HR, RPE, blood lactate, and %V[Combining Dot Above]O2peak values were produced by 80/50 and 100/0 protocols. However, the average %V[Combining Dot Above]O2peak was significantly higher (∼9.3% absolute) in 80/50. It appeared that use of the 80/0, 80/50, and 100/0 protocols would be appropriate for individuals who are at the low to moderate end of the cardiopulmonary fitness spectrum.

Distal fibula fracture fixation: Biomechanical evaluation of three different fixation implants.

BACKGROUND: The goal of this study was to evaluate the biomechanical performance of three distal fibula fracture fixation implants in a matched pair cadaveric fibula model: (1) a 5-hole compression plate with lag screw, (2) a 5-hole locking plate with lag screw, and (3) the 6-hole tabbed-plate with locking screws. METHODS: Three-dimensional motions between the proximal and distal fibular segments were measured under cyclic valgus bending, cyclic compressive axial loading, and cyclic torsional external-rotation loading. During loading, strains were measured on the surfaces of each fibula near the simulated fracture site, and on the plate, to assess load transfer. Bone quality was quantified globally for each donor using bone mineral density (BMD) measured using Dual X-ray absorptiometry (DEXA) and locally at the fracture site using bone mineral content (BMC) measured using peripheral quantitative computed tomography (pQCT). RESULTS: Mean failure loads were below 0.2Nm of valgus bending and below 4Nm of external-rotational torque. Mean failure angulation was below 1degree for valgus bending, and failure rotation was below 7degrees for external-rotation. In the compression plate group, significant correlations were observed between bone quality (global BMD and local BMC) and strain in every one of the five locations (Pearson correlation coefficients >0.95, p<0.05). In contrast, in the locking and tabbed-plate groups, BMD and BMC correlated with far fewer strain locations. CONCLUSIONS: Overall, the tabbed-plate had similar construct stability and strength to the compression and locking plates. However, the distribution of load with the locking and tabbed-plates was not as heavily dependent on bone quality.

Clathrin and AP-1 regulate apical polarity and lumen formation during C. elegans tubulogenesis.

Clathrin coats vesicles in all eukaryotic cells and has a well-defined role in endocytosis, moving molecules away from the plasma membrane. Its function on routes towards the plasma membrane was only recently appreciated and is thought to be limited to basolateral transport. Here, an unbiased RNAi-based tubulogenesis screen identifies a role of clathrin (CHC-1) and its AP-1 adaptor in apical polarity during de novo lumenal membrane biogenesis in the C. elegans intestine. We show that CHC-1/AP-1-mediated polarized transport intersects with a sphingolipid-dependent apical sorting process. Depleting each presumed trafficking component mislocalizes the same set of apical membrane molecules basolaterally, including the polarity regulator PAR-6, and generates ectopic lateral lumens. GFP::CHC-1 and BODIPY-ceramide vesicles associate perinuclearly and assemble asymmetrically at polarized plasma membrane domains in a co-dependent and AP-1-dependent manner. Based on these findings, we propose a trafficking pathway for apical membrane polarity and lumen morphogenesis that implies: (1) a clathrin/AP-1 function on an apically directed transport route; and (2) the convergence of this route with a sphingolipid-dependent apical trafficking path.

Differential processing of mammalian L-histidine decarboxylase enzymes.

In the mammalian species studied so far, the L-histidine decarboxylase (HDC) enzyme responsible for histamine biosynthesis has been shown to undergo post-translational processing. The processing is best characterized for the mouse enzyme, where di-asparate DD motifs mediate the production of active ~55 and ~60 kDa isoforms from the ~74 kDa precursor in a caspase-9 dependent manner. The identification of conserved di-aspartate motifs at similar locations in the rat and human HDC protein sequences has led to proposals that these may represent important processing sites in these species also. Here we used transfected Cos7 cells to demonstrate that the rat and human HDC proteins undergo differential processing compared to each other, and found no evidence to suggest that conserved di-aspartate motifs are required absolutely for processing in this cell type. Instead we identified SKD and EEAPD motifs that are important for caspase-6 dependent production of ~54 and ~59 kDa isoforms in the rat and human proteins, respectively. The addition of staurosporine, which is known to pharmacologically activate caspase enzymes, increased processing of the human HDC protein. We propose that caspase-dependent processing is a conserved feature of mammalian HDC enzymes, but that proteolysis may involve different enzymes and occur at diverse sites and sequences.

The human ubiquitin conjugating enzyme UBE2J2 (Ubc6) is a substrate for proteasomal degradation.

The human Ube2J2 enzyme functions in the ubiquitination of proteins at the ER. Here we demonstrate that it, and a second ubiquitin conjugating (Ubc) enzyme Ube2G2, are unstable, and incubation of transfected cells with proteasome inhibitors increased steady-state protein levels. For Ube2J2, pharmacological induction of the unfolded protein response (UPR) did not significantly alter ectopic protein levels, however the effect of proteasomal inhibition was abolished if the enzyme was inactivated or truncated to disrupt its ER-localization. These results suggest for the first time that the steady state expression of Ubcs' may be important in regulating the degradation of ER proteins in mammalian cells.

Use of the BacT/alert system for rapid detection of microbial contamination in a pilot study using pancreatic islet cell products.

At the Islet Isolation Laboratory of the Scottish National Blood Transfusion Service, manual sterility testing data show that contamination rates are 57.7% for pancreas transport fluid, 4.3% for postpurification islet samples, and 0% for pretransplant islet samples. This pilot study presents the BacT/Alert System as an alternative to manual testing to provide more rapid and sensitive sterility results for islet cell products.

Determination of regional lung air volume distribution at mid-tidal breathing from computed tomography: a retrospective study of normal variability and reproducibility.

BACKGROUND: Determination of regional lung air volume has several clinical applications. This study investigates the use of mid-tidal breathing CT scans to provide regional lung volume data. METHODS: Low resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects, each on two separate occasions. A 3D map of air volume was derived, and total lung volume calculated. The regional distribution of air volume from centre to periphery of the lung was analysed using a radial transform and also using one dimensional profiles in three orthogonal directions. RESULTS: The total air volumes for the right and left lungs were 1035 +/- 280 ml and 864 +/- 315 ml, respectively (mean and SD). The corresponding fractional air volume concentrations (FAVC) were 0.680 +/- 0.044 and 0.658 +/- 0.062. All differences between the right and left lung were highly significant (p < 0.0001). The coefficients of variation of repeated measurement of right and left lung air volumes and FAVC were 6.5% and 6.9% and 2.5% and 3.6%, respectively. FAVC correlated significantly with lung space volume (r = 0.78) (p < 0.005). FAVC increased from the centre towards the periphery of the lung. Central to peripheral ratios were significantly higher for the right (0.100 +/- 0.007 SD) than the left (0.089 +/- 0.013 SD) (p < 0.0001). CONCLUSION: A technique for measuring the distribution of air volume in the lung at mid-tidal breathing is described. Mean values and reproducibility are described for healthy male control subjects. Fractional air volume concentration is shown to increase with lung size.

Validated respiratory drug deposition predictions from 2D and 3D medical images with statistical shape models and convolutional neural networks.

For the one billion sufferers of respiratory disease, managing their disease with inhalers crucially influences their quality of life. Generic treatment plans could be improved with the aid of computational models that account for patient-specific features such as breathing pattern, lung pathology and morphology. Therefore, we aim to develop and validate an automated computational framework for patient-specific deposition modelling. To that end, an image processing approach is proposed that could produce 3D patient respiratory geometries from 2D chest X-rays and 3D CT images. We evaluated the airway and lung morphology produced by our image processing framework, and assessed deposition compared to in vivo data. The 2D-to-3D image processing reproduces airway diameter to 9% median error compared to ground truth segmentations, but is sensitive to outliers of up to 33% due to lung outline noise. Predicted regional deposition gave 5% median error compared to in vivo measurements. The proposed framework is capable of providing patient-specific deposition measurements for varying treatments, to determine which treatment would best satisfy the needs imposed by each patient (such as disease and lung/airway morphology). Integration of patient-specific modelling into clinical practice as an additional decision-making tool could optimise treatment plans and lower the burden of respiratory diseases.

Airway deposition of nebulized gene delivery nanocomplexes monitored by radioimaging agents.

Receptor-targeted nanocomplexes are nonviral vectors developed for gene delivery to the airway epithelium for the treatment of pulmonary disease associated with cystic fibrosis. The present study aimed to optimize the delivery of the nanocomplex by nebulization, and to monitor the in vivo deposition of radiolabeled vector in the airways of a large animal model by γ-camera scintigraphy. Large White weaner pigs were nebulized with nanocomplexes mixed with technetium-99m radiopharmaceuticals. The aerosol deposition scans suggested that the nebulized radiovectors were deposited mainly in the trachea-main bronchi and in the midregion of the lungs. The plasmid biodistribution, assessed by real-time PCR, correlated with the scintigraphy images. The highest plasmid copy numbers were found in the bronchial areas and in the tissues proximal to the main bronchi bifurcation. Immunohistochemistry detected transgene expression in the tracheal and bronchial ciliated epithelium. Histological analysis of lung tissue showed no evidence of inflammation, and no increase in inflammatory cytokines or inflammatory cells was detected in the bronchoalveolar lavage. The deposition of nebulized nanocomplexes coassociated with technetium-99m can be monitored by nuclear medicine techniques. The use of a noninvasive strategy to follow the delivery of the vector could improve the clinical management of patients undergoing cystic fibrosis gene therapy.

Targeted gene alteration in Caenorhabditis elegans by gene conversion.

Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using standard transposon insertion-deletion approaches. We also targeted an engineered green fluorescent protein insertion-replacement cassette to one of these genes, thereby confirming that custom alleles of different types can be created in vitro to make the corresponding mutations in vivo. This approach should also be applicable to heterologous transposons in C. elegans and other organisms, including vertebrates.

The Use of Single Photon Emission Computed Tomography in Aerosol Medicine.

Imaging of radiolabeled aerosols provides useful in vivo data on both the initial site of deposition and its subsequent transport by mucociliary clearance and epithelial permeability. Single Photon Emission Computed Tomography (SPECT) uses a gamma camera with multiple rotating heads to produce three-dimensional (3D) images of inhaled radioaerosol labeled with technetium-99m. This enables total lung deposition and its 3D regional distribution to be quantified. Aligned 3D images of lung structure allow deposition data to be related to lung anatomy. Mucociliary clearance or epithelial permeability can be assessed from a time series of SPECT aerosol images. SPECT is slightly superior to planar imaging for measuring total lung deposition. However, it is more complex to use, and for studies where total lung deposition is the endpoint, planar imaging is recommended. However, SPECT has been shown to be clearly superior to planar imaging for assessing regional distribution of aerosol and is the method of choice for this purpose. It therefore has applications in studying the influence of regional deposition on clinical effectiveness and also in validating computer models of deposition. The inability to directly radiolabel drug molecules with 99mTc is a clear disadvantage of SPECT and limits its potential use for pharmacokinetic studies. SPECT provides a wealth of data on aerosol deposition, which has been relatively underused at present. Optimal methods of analyzing and interpreting the data need to be developed. SPECT can also, in principle, provide detailed information of mucociliary clearance and has the potential to significantly improve knowledge of this process and hence clarify the role of clearance as a biomarker.

Multivariable closed-loop control of deep brain stimulation for Parkinson's disease.

Objective. Closed-loop deep brain stimulation (DBS) methods for Parkinson's disease (PD) to-date modulate either stimulation amplitude or frequency to control a single biomarker. While good performance has been demonstrated for symptoms that are correlated with the chosen biomarker, suboptimal regulation can occur for uncorrelated symptoms or when the relationship between biomarker and symptom varies. Control of stimulation-induced side-effects is typically not considered.Approach.A multivariable control architecture is presented to selectively target suppression of either tremor or subthalamic nucleus beta band oscillations. DBS pulse amplitude and duration are modulated to maintain amplitude below a threshold and avoid stimulation of distal large diameter axons associated with stimulation-induced side effects. A supervisor selects between a bank of controllers which modulate DBS pulse amplitude to control rest tremor or beta activity depending on the level of muscle electromyographic (EMG) activity detected. A secondary controller limits pulse amplitude and modulates pulse duration to target smaller diameter axons lying close to the electrode. The control architecture was investigated in a computational model of the PD motor network which simulated the cortico-basal ganglia network, motoneuron pool, EMG and muscle force signals.Main results.Good control of both rest tremor and beta activity was observed with reduced power delivered when compared with conventional open loop stimulation, The supervisor avoided over- or under-stimulation which occurred when using a single controller tuned to one biomarker. When DBS amplitude was constrained, the secondary controller maintained the efficacy of stimulation by increasing pulse duration to compensate for reduced amplitude. Dual parameter control delivered effective control of the target biomarkers, with additional savings in the power delivered.Significance.Non-linear multivariable control can enable targeted suppression of motor symptoms for PD patients. Moreover, dual parameter control facilitates automatic regulation of the stimulation therapeutic dosage to prevent overstimulation, whilst providing additional power savings.