Early diastolic heart sounds caused by the atrial kick.

An 81-year-old male with a history of coronary artery disease, hypertension, paroxysmal atrial fibrillation and chronic kidney disease presents with asymptomatic bradycardia. Examination was notable for an early diastolic heart sound. 12-lead electrocardiogram revealed sinus bradycardia with a markedly prolonged PR interval and second-degree atrioventricular block, type I Mobitz. We review the differential diagnosis of early diastolic heart sounds and present a case of Wenckebach associated with a variable early diastolic sound on physical exam.

Multispecies-targeting siRNAs for the modulation of JAK1 in the skin.

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.

Image Smart Segmentation Analysis Against Diabetic Foot Ulcer Using Internet of Things with Virtual Sensing.

Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. The image segmentation analysis of DFU identification plays a significant role. This will produce different segmentation of the same idea, incomplete, imprecise, and other problems. To address these issues, a method of image segmentation analysis of DFU through internet of things with the technique of virtual sensing for semantically similar objects, the analysis of four levels of range segmentation (region-based, edge-based, image-based, and computer-aided design-based range segmentation) for deeper segmentation of images is implemented. In this study, the multimodal is compressed with the object co-segmentation for semantical segmentation. The result is predicting the better validity and reliability assessment. The experimental results demonstrate that the proposed model can efficiently perform segmentation analysis, with a lower error rate, than the existing methodologies. The findings on the multiple-image dataset show that DFU obtains an average segmentation score of 90.85% and 89.03% correspondingly in two types of labeled ratios before DFU with virtual sensing and after DFU without virtual sensing (i.e., 25% and 30%), which is an increase of 10.91% and 12.22% over the previous best results. In live DFU studies, our proposed system improved by 59.1% compared with existing deep segmentation-based techniques and its average image smart segmentation improvements over its contemporaries are 15.06%, 23.94%, and 45.41%, respectively. Proposed range-based segmentation achieves interobserver reliability by 73.9% on the positive test namely likelihood ratio test set with only a 0.25 million parameters at the pace of labeled data.

Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice.

Nonalcoholic steatohepatitis (NASH) is a malady of multiple cell types associated with hepatocyte triglyceride (TG) accumulation, macrophage inflammation, and stellate cell-induced fibrosis, with no approved therapeutics yet available. Here, we report that stellate cell fatty acid synthase (FASN) in de novo lipogenesis drives the autophagic flux that is required for stellate cell activation and fibrotic collagen production. Further, we employ a dual targeting approach to NASH that selectively depletes collagen through selective stellate cell knockout of FASN (using AAV9-LRAT Cre in FASNfl/fl mice), while lowering hepatocyte triglyceride by depleting DGAT2 with a GalNac-conjugated, fully chemically modified siRNA. DGAT2 silencing in hepatocytes alone or in combination with stellate cell FASNKO reduced liver TG accumulation in a choline-deficient NASH mouse model, while FASNKO in hepatocytes alone (using AAV8-TBG Cre in FASNfl/fl mice) did not. Neither hepatocyte DGAT2 silencing alone nor FASNKO in stellate cells alone decreased fibrosis (total collagen), while loss of both DGAT2 plus FASN caused a highly significant attenuation of NASH. These data establish proof of concept that dual targeting of DGAT2 plus FASN alleviates NASH progression in mice far greater than targeting either gene product alone.

Predictors of help-seeking behavior in mothers of preschoolers.

Mental health difficulties in the preschool years require early intervention, but preschool children are underserved in mental healthcare. One explanation might be that parents do not seek services because their problem recognition, or labeling, ability is lacking. While previous research demonstrates that labeling is positively associated with help-seeking, interventions aimed at improving help-seeking by improving labeling are not always successful. Parental perceptions of severity, impairment, and stress also predict help-seeking, but have not been examined alongside labeling. Thus, it is unclear how much they add to the parental help-seeking process. The present study simultaneously examined labeling and parental perceptions of severity, impairment, and stress on help-seeking. Participants (82 adult mothers of children ages 3-5 years) read vignettes describing preschool-aged children with symptoms of depression, anxiety, and ADHD, and answered a series of questions to assess their labeling and likelihood of help-seeking for each of the problems presented. Help-seeking was found to be positively associated with labeling (r = .73; r = .60), severity (r = .66), impairment (r = .31), and stress (r = .25). Furthermore, severity, impairment, and stress predicted endorsements of help-seeking above and beyond what was predicted by labeling alone (R2 change = .12; χ2 (3) = 20.03, p < .01). These results underscore the importance of parental perceptions of children's behavior to the help-seeking process.

Internal Jugular Vein Fenestration: An Intraoperative Finding Without a Radiological Clue.

A comprehensive understanding of the anatomical variations of the internal jugular vein (IJV) is essential to prevent inadvertent injuries during neck procedures, particularly neck dissection. In addition, its relationship with the spinal accessory nerve in the upper part of the neck is relatively variable. IJV fenestration refers to bifurcation of the vein with reunion proximal to the subclavian vein, whereas IJV duplication refers to continued branching till joining the subclavian vein separately. We report a case of a fenestrated IJV identified intraoperatively with the spinal accessory nerve passing laterally to both divisions.

Meta-Heuristic Feature Optimization for ontology-based data security in a campus workplace with robotic assistance.

BACKGROUND: For campus workplace secure text mining, robotic assistance with feature optimization is essential. The space model of the vector is usually used to represent texts. Besides, there are still two drawbacks to this basic approach: the curse and lack of semantic knowledge. OBJECTIVES: This paper proposes a new Meta-Heuristic Feature Optimization (MHFO) method for data security in the campus workplace with robotic assistance. Firstly, the terms of the space vector model have been mapped to the concepts of data protection ontology, which statistically calculate conceptual frequency weights by term various weights. Furthermore, according to the designs of data protection ontology, the weight of theoretical identification is allocated. The dimensionality of functional areas is reduced significantly by combining standard frequency weights and weights based on data protection ontology. In addition, semantic knowledge is integrated into this process. RESULTS: The results show that the development of the characteristics of this process significantly improves campus workplace secure text mining. CONCLUSION: The experimental results show that the development of the features of the concept hierarchy structure process significantly enhances data security of campus workplace text mining with robotic assistance.

Understanding hormonal crosstalk in Arabidopsis root development via emulation and history matching.

A major challenge in plant developmental biology is to understand how plant growth is coordinated by interacting hormones and genes. To meet this challenge, it is important to not only use experimental data, but also formulate a mathematical model. For the mathematical model to best describe the true biological system, it is necessary to understand the parameter space of the model, along with the links between the model, the parameter space and experimental observations. We develop sequential history matching methodology, using Bayesian emulation, to gain substantial insight into biological model parameter spaces. This is achieved by finding sets of acceptable parameters in accordance with successive sets of physical observations. These methods are then applied to a complex hormonal crosstalk model for Arabidopsis root growth. In this application, we demonstrate how an initial set of 22 observed trends reduce the volume of the set of acceptable inputs to a proportion of 6.1 × 10-7 of the original space. Additional sets of biologically relevant experimental data, each of size 5, reduce the size of this space by a further three and two orders of magnitude respectively. Hence, we provide insight into the constraints placed upon the model structure by, and the biological consequences of, measuring subsets of observations.

The use of portable X-ray fluorescence spectrometry to measure apparent total tract digestibility in beef cattle and sheep.

The use of portable X-ray fluorescence (PXRF) spectrometry to detect external markers on processed or unprocessed cattle and sheep fecal specimens to estimate apparent total tract digestibility (ATTD) was evaluated. Exp. 1: ruminally cannulated Angus-crossbred steers (n = 7; BW = 520 ± 30 kg) were individually fed ad libitum for 21 d in a completely randomized design (CRD). Markers (Cr2O3 and TiO2) were placed inside the rumen twice daily (7.5 g of each marker). Fecal samples were collected twice daily from day 14 to 21. Exp. 2: crossbred wethers (n = 8; BW = 68 ± 3 kg) were individually fed ad libitum for 21 d in a CRD. During this period, 2 g of Cr2O3 and TiO2 were top-dressed onto the feed twice daily. Sheep were housed in metabolism crates for 5 d for total fecal collection. Concentration of markers was determined on diets, refusals, and fecal specimens (fresh, dry-only, and dried/ground) using atomic absorption to detect Cr and spectrophotometry for Ti. Concentration of both markers was also determined via the PXRF spectrometer. Delta between ATTD estimated by wet chemistry and PXRF was not different from zero (P ≥ 0.14) when using cattle fresh fecal specimens for both markers, whereas ATTD estimated by PXRF with dry-only and dried/ground fecal specimens were 3.6 and 1.1 percent units lower (P ≤ 0.04), respectively, than ATTD estimated by wet chemistry for Cr and Ti, respectively. Regardless of the fecal sample preparation method on cattle specimens, Ti concentration was similar (P = 0.39) among methodologies, while Cr was underestimated (P < 0.01) by 13% when PXRF was used in dry-only or dried/ground samples. The ATTD of sheep was underestimated (P < 0.01) by 2.4 percent units compared with control when Cr was measured by PXRF in dry-only samples. The Cr concentration in dry-only fecal specimens of sheep tended (P = 0.09) to be lower compared with wet chemistry analysis. Fresh and dry/ground sheep fecal samples assessed for Cr, and dry-only assessed for Ti were not (P ≥ 0.49) affected by detection method. The Cr fecal recovery tended (P = 0.10) to be the lowest for dry-only, the greatest for wet chemistry, intermediate for fresh and dry/ground sheep-fecal specimens; while not affected (P = 0.40) for Ti. The PXRF is an accurate technology to detect Cr and Ti in fresh cattle fecal samples to estimate ATTD. For fresh and dry/ground, the technology was effective for determining the concentration of Cr, or dry-only fecal specimens when detecting Ti in sheep specimens.

Neurofunctional test batteries in safety pharmacology - Current and emerging considerations for the drug development process.

Regulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned. A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as "the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment". The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others. A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety.

Nucleus Isthmi Is Required to Sustain Target Pursuit during Visually Guided Prey-Catching.

Animals must frequently perform a sequence of behaviors to achieve a specific goal. However, the neural mechanisms that promote the continuation and completion of such action sequences are not well understood. Here, we characterize the anatomy, physiology, and function of the nucleus isthmi (NI), a cholinergic nucleus thought to modulate tectal-dependent, goal-directed behaviors. We find that the larval zebrafish NI establishes reciprocal connectivity with the optic tectum and identify two distinct types of isthmic projection neuron that either connect ipsilaterally to retinorecipient laminae of the tectum and pretectum or bilaterally to both tectal hemispheres. Laser ablation of NI caused highly specific deficits in tectally mediated loom-avoidance and prey-catching behavior. In the context of hunting, NI ablation did not affect prey detection or hunting initiation but resulted in larvae failing to sustain prey-tracking sequences and aborting their hunting routines. Moreover, calcium imaging revealed elevated neural activity in NI following onset of hunting behavior. We propose a model in which NI provides state-dependent feedback facilitation to the optic tectum and pretectum to potentiate neural activity and increase the probability of consecutive prey-tracking maneuvers during hunting sequences.

Comparison between density functional theory and density functional tight binding approaches for finding the muon stopping site in organic molecular crystals.

Finding the possible stopping sites for muons inside a crystalline sample is a key problem of muon spectroscopy. In a previous study, we suggested a computational approach to this problem when dealing with muonium, the pseudoatom formed by a positive muon that has captured an electron, using density functional theory software in combination with a random structure searching approach that relies on a Poisson sphere distribution. In this work, we test this methodology further by applying it to muonium in three organic molecular crystal model systems: durene, bithiophene, and tetracyanoquinodimethane. Using the same sets of random structures, we compare the performance of density functional theory software CASTEP and the much faster lower level approximation of Density Functional Tight Binding provided by DFTB+ combined with the use of the 3ob-3-1 parameter set. We show the benefits and limitations of such an approach, and we propose the use of DFTB+ as a viable alternative to more cumbersome simulations for routine site-finding in organic materials. Finally, we introduce the Muon Spectroscopy Computational Project software suite, a library of Python tools meant to make these methods standardized and easy to use.

A programmable microscopic stage: Design and development.

Microscopes have become a significant part of pathological study. Currently, motorized microscopes are enabled with horizontal and vertical movements, with the facility of fast response in acquiring images or videos from the slide. During microbial screening, viewing the specimen needs following a directional path viz., zig-zag, inward spiral, meander, and so forth. Even though the motorized movements are built-in, human intervention is required while screening. This leads to time delay in the scanning process and may leave some portions of the specimen unattended. In this proposed system, a programmable framework to define the scanning direction for the specimen and a firmware to control the microscopic stage is implemented, to enable customization of the scanning pattern without any human intervention during complete course of screening. The user can define the customized scanning pattern using two-dimensional (2D) graphics drawing primitives. The final drawing is converted into preparatory codes through a micro-computer numeric controlled software, which extracts the address information relating to the movement and direction of the stage. These X, Y directional information are fed into the machine control unit for activating the linear driving system, which has servo drives and motors to power the spindle for precise microscopic stage movement. The proposed system is cost effective and reduces the reliance on technicians in examining the whole slide. The system is also portable and can be attached to any conventional or fluorescence microscope. Some pre-defined scanning patterns have been tested for the stage movements and validated in this work.

The use of human tissue in safety assessment.

INTRODUCTION: The safety-related failure of drugs during clinical phases of development is a significant contributor to drug attrition, wasting resources and preventing treatments from reaching patients. A lack of concordance between results from animal models and adverse events in the clinic has been identified as one potential cause of attrition. In vitro models using human tissue or cells have the potential to replace some animal models and improve predictivity to humans. METHODS: To gauge the current use of human tissue models in safety pharmacology and the barriers to greater uptake, an electronic survey of the international safety assessment community was carried out and a Safety Pharmacology Society European Regional Meeting was organised entitled 'The Use of Human Tissue in Safety Assessment'. RESULTS: A greater range of human tissue models is in use in safety assessment now than four years ago, although data is still not routinely included in regulatory submissions. The barriers to increased uptake of the models have not changed over that time, with inadequate supply and characterisation of tissue being the most cited blocks. DISCUSSION: Supporting biobanking, the development of new human tissue modelling technology, and raising awareness in the scientific and regulatory communities are key ways in which the barriers to greater uptake of human tissue models can be overcome. The development of infrastructure and legislation in the UK to support the use of post-mortem or surgical discard tissue will allow scientists to locally source tissue for research.

Race affects SVR12 in a large and ethnically diverse hepatitis C-infected patient population following treatment with direct-acting antivirals: Analysis of a single-center Department of Veterans Affairs cohort.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct-acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12 weeks (SVR12) after completion of therapy. Historically, African-Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non-CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA-treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single-center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African-American. Genotype 1 was the most common genotype (83.9%, N = 896). In the adjusted models, race/ethnicity and the presence of fibrosis were statistically significant predictors of non-SVR. African-Americans had 57% lower odds for reaching SVR12 (adj.OR = 0.43, 95% CI = 1.5-4.1) compared to White people. Advanced fibrosis (adj.OR = 0.40, 95% CI = 0.26-0.68) was also a significant predictor of non-SVR. In a single-center VA population on DAAs, African-Americans were less likely than White people to reach SVR12 when adjusting for covariates.

Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons.

Mitochondrial trafficking plays a central role in dorsal root ganglion (DRG) neuronal cell survival and neurotransmission by transporting mitochondria from the neuronal cell body throughout the bundles of DRG axons. In type 2 diabetes (T2DM), dyslipidemia and hyperglycemia damage DRG neurons and induce mitochondrial dysfunction; however, the impact of free fatty acids and glucose on mitochondrial trafficking in DRG neurons remains unknown. To evaluate the impact of free fatty acids compared to hyperglycemia on mitochondrial transport, primary adult mouse DRG neuron cultures were treated with physiologic concentrations of palmitate and glucose and assessed for alterations in mitochondrial trafficking, mitochondrial membrane potential, and mitochondrial bioenergetics. Palmitate treatment significantly reduced the number of motile mitochondria in DRG axons, but physiologic concentrations of glucose did not impair mitochondrial trafficking dynamics. Palmitate-treated DRG neurons also exhibited a reduction in mitochondrial velocity, and impaired mitochondrial trafficking correlated with mitochondrial depolarization in palmitate-treated DRG neurons. Finally, we found differential bioenergetic effects of palmitate and glucose on resting and energetically challenged mitochondria in DRG neurons. Together, these results suggest that palmitate induces DRG neuron mitochondrial depolarization, inhibiting axonal mitochondrial trafficking and altering mitochondrial bioenergetic capacity.-Rumora, A. E., Lentz, S. I., Hinder, L. M., Jackson, S. W., Valesano, A., Levinson, G. E., Feldman, E. L. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons.

Concurrent La and A-Site Vacancy Doping Modulates the Thermoelectric Response of SrTiO3: Experimental and Computational Evidence.

To help understand the factors controlling the performance of one of the most promising n-type oxide thermoelectric SrTiO3, we need to explore structural control at the atomic level. In Sr1-xLa2x/3TiO3 ceramics (0.0 ≤ x ≤ 0.9), we determined that the thermal conductivity can be reduced and controlled through an interplay of La-substitution and A-site vacancies and the formation of a layered structure. The decrease in thermal conductivity with La and A-site vacancy substitution dominates the trend in the overall thermoelectric response. The maximum dimensionless figure of merit is 0.27 at 1070 K for composition x = 0.50 where half of the A-sites are occupied with La and vacancies. Atomic resolution Z-contrast imaging and atomic scale chemical analysis show that as the La content increases, A-site vacancies initially distribute randomly (x < 0.3), then cluster (x ≈ 0.5), and finally form layers (x = 0.9). The layering is accompanied by a structural phase transformation from cubic to orthorhombic and the formation of 90° rotational twins and antiphase boundaries, leading to the formation of localized supercells. The distribution of La and A-site vacancies contributes to a nonuniform distribution of atomic scale features. This combination induces temperature stable behavior in the material and reduces thermal conductivity, an important route to enhancement of the thermoelectric performance. A computational study confirmed that the thermal conductivity of SrTiO3 is lowered by the introduction of La and A-site vacancies as shown by the experiments. The modeling supports that a critical mass of A-site vacancies is needed to reduce thermal conductivity and that the arrangement of La, Sr, and A-site vacancies has a significant impact on thermal conductivity only at high La concentration.

Human tissue models in cancer research: looking beyond the mouse.

Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of 'non-animal human tissue' models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks. A number of key factors limit the wide adoption of non-animal human tissue models in cancer research, including deficiencies in the infrastructure and the technical tools required to collect, transport, store and maintain human tissue for lab use. Another obstacle is the long-standing cultural reliance on animal models, which can make researchers resistant to change, often because of concerns about historical data compatibility and losing ground in a competitive environment while new approaches are embedded in lab practice. There are a wide range of initiatives that aim to address these issues by facilitating data sharing and promoting collaborations between organisations and researchers who work with human tissue. The importance of coordinating biobanks and introducing quality standards is gaining momentum. There is an exciting opportunity to transform cancer drug discovery by optimising the use of human tissue and reducing the reliance on potentially less predictive animal models.

Gastrointestinal Manifestations of Hereditary Hemorrhagic Telangiectasia (HHT): A Systematic Review of the Literature.

Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.