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Background: Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference. Methods: Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients. Results: Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02). Conclusions: Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage. [ABSTRACT FROM AUTHOR]

Microbial fuel cells (MFCs) can evolve in a viable technology if environmentally sound materials are developed and became available at low cost for these devices. This is especially important not only for the designing of large wastewater treatment systems, but also for the fabrication of low-cost, single-use devices. In this work we synthesized membranes by a simple procedure involving easily-biodegradable and economic materials such as poly (vinyl alcohol) (PVA), chitosan (CS) and the composite PVA:CS. Membranes were chemical and physically characterized and compared to Nafion®. Performance was studied using the membrane as separator in a typical H-Type MFCs showing that PVA:CS membrane outperform Nafion® 4 times (power production) while being 75 times more economic. We found that performance in MFC depends over interactions among several membrane characteristics such as oxygen permeability and ion conductivity. Moreover, we design a paper-based micro-scale MFC, which was used as a toxicity assay using 16 μL samples containing formaldehyde as a model toxicant. The PVA:CS membrane presented here can offer low environmental impact and become a very interesting option for point of need single-use analytical devices, especially in low-income countries where burning is used as disposal method, and toxic fluoride fumes (from Nafion®) can be released to the environment. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty. [ABSTRACT FROM AUTHOR]

Nanoparticles in polluted air or aerosolized drug nanoparticles predominantly settle in the alveolar lung. Here, we describe a novel, highly effective pathway for the particles to cross the alveolar epithelium and reach the lymph and bloodstream. Amorphous silica nanoparticles, suspended in perfluorocarbon, were instilled into the lungs of mice for intravital microscopy. Particles formed agglomerates that settled on the alveolar wall, half of which were removed from the lung within 30 minutes. TEM histology showed agglomerates in stages of crossing the alveolar epithelium, in large compartments inside the epithelial cells and crossing the basal membrane into the interstitium. This pathway is consistent with published kinetic studies in rats and mice, using a host of (negatively) charged and polar nanoparticles. [ABSTRACT FROM AUTHOR]

To confirm that neoplastic monocyte-derived collagen- and fibronectin-producing fibrocytes induce bone marrow (BM) fibrosis in primary myelofibrosis (PMF), we injected PMF BM-derived fibrocyte-precursor CD14+/CD34- monocytes into the tail vein of NOD-SCID-γ (NSG) mice. PMF BM-derived CD14+/CD34- monocytes engrafted and induced a PMF-like phenotype with splenomegaly, myeloid hyperplasia with clusters of atypical megakaryocytes, persistence of the JAK2V617F mutation, and BM and spleen fibrosis. As control we used normal human BM-derived CD14+/CD34- monocytes. These monocytes also engrafted and gave rise to normal megakaryocytes that, like PMF CD14+/CD34--derived megakaryocytes, expressed HLA-ABC and human CD42b antigens. Using 2 clonogenic assays we confirmed that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte colony-forming cells, suggesting that a subpopulation BM monocytes harbors megakaryocyte progenitor capacity. Taken together, our data suggest that PMF monocytes induce myelofibrosis-like phenotype in immunodeficient mice and that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte progenitor cells. [ABSTRACT FROM AUTHOR]

Open data science and algorithm development competitions offer a unique avenue for rapid discovery of better computational strategies. We highlight three examples in computational biology and bioinformatics research in which the use of competitions has yielded significant performance gains over established algorithms. These include algorithms for antibody clustering, imputing gene expression data, and querying the Connectivity Map (CMap). Performance gains are evaluated quantitatively using realistic, albeit sanitized, data sets. The solutions produced through these competitions are then examined with respect to their utility and the prospects for implementation in the field. We present the decision process and competition design considerations that lead to these successful outcomes as a model for researchers who want to use competitions and non-domain crowds as collaborators to further their research. [ABSTRACT FROM AUTHOR]

Purpose: To provide population-based reference values for cervical spinal canal parameters and vertebral body (VB) width and to study their associations with sex, age, body height, body weight and body mass index (BMI) using MRI. Methods: Cross-sectional analyses included data from 2,453 participants, aged 21–89 years, of the population-based Study of Health in Pomerania (SHIP) who underwent whole-body MRI at 1.5 Tesla between July 2008 and March 2011. A standardised reading was performed for the C2-C7 cervical spine levels at sagittal T2 TSE weighted sequences. Results: Reference intervals for spinal canal parameters were similar in males and females, while VB width was on average 2.1–2.2 mm larger in males. Age effects were only substantial regarding VB width with a 0.5 mm per ten-year age increase. Body height effects were only substantial regarding the osseous spinal canal and VB width. Body weight and BMI effects are mostly not substantial. Conclusions: Our study provides MRI-based reference values for the cervical spinal canal parameters in an adult Caucasian population. Except for VB width, associations with sex, age and somatometric measures are mostly small and thus have only limited clinical implications. Some available cut-off values may need a revision because they likely overestimate risks. [ABSTRACT FROM AUTHOR]

Raman chemometric urinalysis (Rametrix™) was used to analyze 235 urine specimens from healthy individuals. The purpose of this study was to establish the “range of normal” for Raman spectra of urine specimens from healthy individuals. Ultimately, spectra falling outside of this range will be correlated with kidney and urinary tract disease. Rametrix™ analysis includes direct comparisons of Raman spectra but also principal component analysis (PCA), discriminant analysis of principal components (DAPC) models, multivariate statistics, and it is available through GitHub as the Rametrix™ LITE Toolbox for MATLAB®. Results showed consistently overlapping Raman spectra of urine specimens with significantly larger variances in Raman shifts, found by PCA, corresponding to urea, creatinine, and glucose concentrations. A 2-way ANOVA test found that age of the urine specimen donor was statistically significant (p < 0.001) and donor sex (female or male identification) was less so (p = 0.0526). With DAPC models and blind leave-one-out build/test routines using the Rametrix™ PRO Toolbox (also available through GitHub), an accuracy of 71% (sensitivity = 72%; specificity = 70%) was obtained when predicting whether a urine specimen from a healthy unknown individual was from a female or male donor. Finally, from female and male donors (n = 4) who contributed first morning void urine specimens each day for 30 days, the co-occurrence of menstruation was found statistically insignificant to Rametrix™ results (p = 0.695). In addition, Rametrix™ PRO was able to link urine specimens with the individual donor with an average of 78% accuracy. Taken together, this study established the range of Raman spectra that could be expected when obtaining urine specimens from healthy individuals and analyzed by Rametrix™ and provides the methodology for linking results with donor characteristics. [ABSTRACT FROM AUTHOR]

PCR inhibition is frequent in medical microbiology routine practice and may lead to false-negative results; however there is no consensus on how to detect it. Pathogen-specific and human gene amplifications are widely used to detect PCR inhibition. We aimed at comparing the value of PCR inhibitor detection using these two methods. We analysed Cp shifts (ΔCp) obtained from qPCRs targeting either the albumin gene or the pathogen-specific sequence used in two laboratory-developed microbiological qPCR assays. 3152 samples including various matrixes were included. Pathogen-specific amplification and albumin qPCR identified 62/3152 samples (2.0%), and 409/3152 (13.0%) samples, respectively, as inhibited. Only 16 samples were detected using both methods. In addition, the use of the Youden's index failed to determine adequate Cp thresholds for albumin qPCR, even when we distinguished among the different sample matrixes. qPCR targeting the albumin gene therefore appears not adequate to identify the presence of PCR inhibitors in microbiological PCR assays. Our data may be extrapolated to other heterologous targets and should discourage their use to assess the presence of PCR inhibition in microbiological PCR assays. [ABSTRACT FROM AUTHOR]

This paper brings advances in weather data collection and modeling, and developments in socioeconomic climate microsimulations to bear on the analysis of the implications of climate change (CC) in the design of public policies to combat food insecurity. It uses new downscaled predictions of future climate in 2050, derived from three Earth System Models calibrated with a new historical weather station dataset for Peru. This climate data is used in a three-stage socioeconomic microsimulation model that includes climate risk, and deals with the endogeneity of incomes and simultaneity of expected food consumption and its variability. We estimate the impact of CC on agricultural yields, and find results consistent and fully bounded within what the global simulations literature has found, with yields falling up to 13% in some regions. However, we show that these drops (and increases) in yields translate to much smaller changes in food consumption, and also surprisingly, to very minor impacts on vulnerability to food insecurity. The document explores what explains this surprising result, showing that in addition to characteristics that are specific to Peru, there are household and market mediating mechanisms that are available in all countries, which explain how changes in yields, and corresponding farm incomes have a reduced impact in vulnerability to food insecurity. Finally, in light of these findings, we explore which policies might have greater impact in reducing food insecurity in contexts of hunger prevalence. [ABSTRACT FROM AUTHOR]

The alteration of the microbial community in the upper respiratory tract (URT) can contribute to the colonization and invasion of respiratory pathogens. However, there are no studies regarding whether the characteristics of the URT microbiota can be affected by infections in lower respiratory tract (LRT). To elucidate the microbial profiles of the URT during pneumonia, the oral, nasal, and lung microbiota was evaluated at the early phase in a murine pneumonia model by direct intratracheal inoculation of Klebsiella pneumoniae. The meta 16S rRNA sequencing of bronchoalveolar lavage fluid after K. pneumoniae inoculation presented alterations in the beta diversity of the microbes, but not in the alpha diversity. At this point, a significant increase in microbial alpha diversity was observed in the oral cavity, but not in the nasal cavity. The significant increase was observed in the family Carnobacteriaceae and family Enterococcaceae. These results suggest that characterizing the microbial community of the respiratory tract may not just involve a simple downstream relationship from the URT to the LRT. The health status of the LRT may influence the oral microbiota. Thus, evaluation of the oral microbiota may contribute towards monitoring lung health; the oral microbiota may act as a diagnostic marker of pneumonia. [ABSTRACT FROM AUTHOR]

Collapse of the lateral cerebral ventricles after ventriculo-peritoneal drainage is a fatal complication in dogs with internal hydrocephalus. It occurs due to excessive outflow of cerebrospinal fluid into the peritoneal cavity (overshunting). In most shunt systems, one-way valves with different pressure settings regulate flow into the distal catheter to avoid overshunting. The rationale for the choice of an appropriate opening pressure is a setting at the upper limit of normal intracranial pressure in dogs. However, physiological intraventricular pressure in normal dogs vary between 5 and 12 mm Hg. Furthermore, we hypothesise that intraventricular pressure in hydrocephalic dogs might differ from pressure in normal dogs and we also consider that normotensive hydrocephalus exists in dogs, as in humans. In order to evaluate intraventricular pressure in hydrocephalic dogs, twenty-three client owned dogs with newly diagnosed communicating internal hydrocephalus were examined before implantation of a ventriculo-peritoneal shunt using a single use piezo-resistive strain-gauge sensor (MicroSensor ICP probe). Ventricular volume and brain volume were measured before surgery, based on magnetic resonance images. Total ventricular volume was calculated and expressed in relation to the total volume of the brain, including the cerebrum, cerebellum, and brainstem (ventricle-brain index). Multiple logistic regression analysis was performed to assess the influence of the covariates “age”, “gender”, “duration of clinical signs”, “body weight”, and “ventricle-brain index” on intraventricular pressure. The mean cerebrospinal fluid pressure in the hydrocephalic dogs was 8.8 mm Hg (standard deviation 4.22), ranging from 3–18 mm Hg. The covariates “age”, (P = 0.782), “gender” (P = 0.162), “body weight”, (P = 0.065), or ventricle-brain index (P = 0.27)” were not correlated with intraventricular pressure. The duration of clinical signs before surgery, however, was correlated with intraventricular pressure (P< 0.0001). Dogs with internal hydrocephalus do not necessarily have increased intraventricular pressure. Normotensive communicating hydrocephalus exists in dogs. [ABSTRACT FROM AUTHOR]

To prepare for an impending event of unknown temporal distribution, humans internally increase the perceived probability of event onset as time elapses. This effect is termed the hazard rate of events. We tested how the neural encoding of hazard rate changes by providing human participants with prior information on temporal event probability. We recorded behavioral and electroencephalographic (EEG) data while participants listened to continuously repeating five-tone sequences, composed of four standard tones followed by a non-target deviant tone, delivered at slow (1.6 Hz) or fast (4 Hz) rates. The task was to detect a rare target tone, which equiprobably appeared at either position two, three or four of the repeating sequence. In this design, potential target position acts as a proxy for elapsed time. For participants uninformed about the target’s distribution, elapsed time to uncertain target onset increased response speed, displaying a significant hazard rate effect at both slow and fast stimulus rates. However, only in fast sequences did prior information about the target’s temporal distribution interact with elapsed time, suppressing the hazard rate. Importantly, in the fast, uninformed condition pre-stimulus power synchronization in the beta band (Beta 1, 15–19 Hz) predicted the hazard rate of response times. Prior information suppressed pre-stimulus power synchronization in the same band, while still significantly predicting response times. We conclude that Beta 1 power does not simply encode the hazard rate, but—more generally—internal estimates of temporal event probability based upon contextual information. [ABSTRACT FROM AUTHOR]

Understanding cell differentiation—the process of generation of distinct cell-types—plays a pivotal role in developmental and evolutionary biology. Transcriptomic information and epigenetic marks are useful to elucidate hierarchical developmental relationships among cell-types. Standard phylogenetic approaches such as maximum parsimony, maximum likelihood and neighbor joining have previously been applied to ChIP-Seq histone modification data to infer cell-type trees, showing how diverse types of cells are related. In this study, we demonstrate the applicability and suitability of quartet-based phylogenetic tree estimation techniques for constructing cell-type trees. We propose two quartet-based pipelines for constructing cell phylogeny. Our methods were assessed for their validity in inferring hierarchical differentiation processes of various cell-types in H3K4me3, H3K27me3, H3K36me3, and H3K27ac histone mark data. We also propose a robust metric for evaluating cell-type trees. [ABSTRACT FROM AUTHOR]

The benefits and efficacy of control programs for herds infected with Mycobacterium avium subsp. paratuberculosis (MAP) have been investigated under various contexts. However, most previous research investigated paratuberculosis control programs in isolation, without modeling the potential association with other dairy diseases. This paper evaluated the benefits of MAP control programs when the herd is also affected by mastitis, a common disease causing the largest losses in dairy production. The effect of typically suggested MAP controls were estimated under the assumption that MAP infection increased the rate of clinical mastitis. We evaluated one hundred twenty three control strategies comprising various combinations of testing, culling, and hygiene, and found that the association of paratuberculosis with mastitis alters the ranking of specific MAP control programs, but only slightly alters the cost-benefit difference of particular MAP control components, as measured by the distribution of net present value of a representative U.S. dairy operation. In particular, although testing and culling for MAP resulted in a reduction in MAP incidence, that control led to lower net present value (NPV) per cow. When testing was used, ELISA was more economically beneficial than alternative testing regimes, especially if mastitis was explicitly modeled as more likely in MAP-infected animals, but ELISA testing was only significantly associated with higher NPV if mastitis was not included in the model at all. Additional hygiene was associated with a lower NPV per cow, although it lowered MAP prevalence. Overall, the addition of an increased risk of mastitis in MAP-infected animals did not change model recommendations as much as failing to consider. [ABSTRACT FROM AUTHOR]

Objectives: Bloodstream infections in critically ill require a speeded-up microbiological diagnosis to improve clinical outcomes. In this pre-post intervention study, we evaluated how a molecular identification test directly performed on positive blood cultures of critically ill improves patient’s therapeutic management. Methods: All adult patients staying at the intensive care unit (ICU) at the time of positive blood culture detection were study-eligible. In the 8-month pre-intervention period (P0), standard positive blood culture management was performed. In the 10-month intervention period (P1), a BioFire® FilmArray® blood culture identification (FA-BCID) test (bioMérieux) was additionally performed 24/7 at detection. The evaluated clinical outcome was time to optimal antimicrobial treatment of the bloodstream infection. FA-BCID microbiological test performances were also analysed. Results: 163 positive blood culture episodes were allocated to P0 and 166 to P1. After the withdrawal of episodes in accordance with defined exclusion criteria, outcome analysis was performed on 110 bloodstream infections both in P0 and P1. Time to optimal antimicrobial treatment in P0 was 14h41 compared to 4h39 in P1. FA-BCID test results led to a treatment adjustment in 35/110 (31.8%) P1 episodes including 26 where the adjustment was the optimal antimicrobial treatment. FA-BCID testing identified 96.2% of the on-panel microorganisms thereby covering 85.2% of our ICU-strain epidemiology. Time to identification with FA-BCID testing was calculated at 1h35. Resistance detection was in complete concordance with routine results. Considering 150 FA-BCID tests were initially performed in P1, 4,3 tests were required to have 1 test leading to an improved therapeutic outcome. Conclusions: FA-BCID testing drastically reduced time to optimal antimicrobial treatment in critically ill with bloodstream infections. [ABSTRACT FROM AUTHOR]

Background: Sand is an easy-to-access, cost-free resource that can be used to treat pronated feet (PF). Therefore, the aims of this study were to contrast the effects of walking on stable ground versus walking on sand on ground reaction forces (GRFs) and electromyographic (EMG) activity of selected lower limb muscles in PF individuals compared with healthy controls. Methods: Twenty-nine controls aged 22.2±2.5 years and 30 PF individuals aged 22.2±1.9 years were enrolled in this study. Participants walked at preferred speed and in randomized order over level ground and sand. A force plate was included in the walkway to collect GRFs. Muscle activities were recorded using EMG system. Results: No statistically significant between-group differences were found in preferred walking speed when walking on stable ground (PF: 1.33±0.12 m/s; controls: 1.35±0.14 m/s; p = 0.575; d = 0.15) and sand (PF: 1.19±0.11 m/s; controls: 1.23±0.18 m/s; p = 0.416; d = 0.27). Irrespective of the group, walking on sand (1.21±0.15 m/s) resulted in significantly lower gait speed compared with stable ground walking (1.34±0.13 m/s) (p<0.001; d = 0.93). Significant main effects of “surface” were found for peak posterior GRFs at heel contact, time to peak for peak lateral GRFs at heel contact, and peak anterior GRFs during push-off (p<0.044; d = 0.27–0.94). Pair-wise comparisons revealed significantly smaller peak posterior GRFs at heel contact (p = 0.005; d = 1.17), smaller peak anterior GRFs during push-off (p = 0.001; d = 1.14), and time to peak for peak lateral GRFs (p = 0.044; d = 0.28) when walking on sand. No significant main effects of “group” were observed for peak GRFs and their time to peak (p>0.05; d = 0.06–1.60). We could not find any significant group by surface interactions for peak GRFs and their time to peak. Significant main effects of “surface” were detected for anterior-posterior impulse and peak positive free moment amplitude (p<0.048; d = 0.54–0.71). Pair-wise comparisons revealed a significantly larger peak positive free moment amplitude (p = 0.010; d = 0.71) and a lower anterior-posterior impulse (p = 0.048; d = 0.38) when walking on sand. We observed significant main effects of “group” for the variable loading rate (p<0.030; d = 0.59). Pair-wise comparisons revealed significantly lower loading rates in PF compared with controls (p = 0.030; d = 0.61). Significant group by surface interactions were observed for the parameter peak positive free moment amplitude (p<0.030; d = 0.59). PF individuals exhibited a significantly lower peak positive free moment amplitude (p = 0.030, d = 0.41) when walking on sand. With regards to EMG, no significant main effects of “surface”, main effects of “group”, and group by surface interactions were observed for the recorded muscles during the loading and push-off phases (p>0.05; d = 0.00–0.53). Conclusions: The observed lower velocities during walking on sand compared with stable ground were accompanied by lower peak positive free moments during the push-off phase and loading rates during the loading phase. Our findings of similar lower limb muscle activities during walking on sand compared with stable ground in PF together with lower free moment amplitudes, vertical loading rates, and lower walking velocities on sand may indicate more relative muscle activity on sand compared with stable ground. This needs to be verified in future studies. [ABSTRACT FROM AUTHOR]

Alpha event-related desynchronization (ERD) has been widely applied to understand the psychophysiological role of this band in cognition. In particular, a considerable number of publications have described spectral alterations in several pathologies using this time-frequency approach. However, ERD is not capable of specifically showing nonphase (induced) activity related to the presentation of stimuli. Recent studies have described an evoked and induced activity in the early phases (first 200 ms) of stimulus processing. However, scarce studies have analyzed induced and evoked modulations in longer latencies (>200 ms) and their potential roles in cognitive processing. The main goal of the present study was to analyze diverse evoked and induced modulations in response to visual stimuli. Thus, 58-channel electroencephalogram (EEG) was recorded in 21 healthy subjects during the performance of a visual attention task, and analyses were performed for both target and standard stimuli. The initial result showed that phase-locked and nonphase locked activities coexist in the early processing of target and standard stimuli as has been reported by previous studies. However, more modulations were evident in longer latencies in both evoked and induced activities. Correlation analyses suggest that similar maps were present for evoked and induced activities at different timepoints. In the discussion section, diverse proposals will be stated to define the potential roles of these modulations in the information processing for this cognitive task. As a general conclusion, induced activity enables the observation of cognitive mechanisms that are not visible by ERD or ERP modulations. [ABSTRACT FROM AUTHOR]

Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in this context is unknown. We hypothesised that the osteocyte, being the principal cell type in the sub-chondral bone, was capable of expressing the pain mediator Nerve Growth Factor (NGF), and that this may be altered in the presence of PPS. We tested the expression of NGF and the response to PPS in the presence or absence of the proinflammatory cytokine tumour necrosis factor-alpha (TNFα), in human osteocytes. For this we differentiated human primary osteoblasts grown from subchondral bone obtained at primary knee arthroplasty for KOA to an osteocyte-like stage over 28d. We also tested NGF expression in fresh osteocytes obtained by sequential digestion from KOA bone and by immunofluorescence in KOA bone sections. We demonstrate for the first time the production and secretion of NGF/proNGF by this cell type derived from patients with KOA, implicating osteocytes in the pain response in this pathological condition and possibly others. PPS inhibited TNFα-induced levels of proNGF secretion and TNFα induced NGF mRNA expression. Together, this provides evidence that PPS may act to suppress the release of NGF in the subchondral bone to ameliorate pain associated with knee osteoarthritis. [ABSTRACT FROM AUTHOR]

The blood flow through the major vessels holds great diagnostic potential for the identification of cardiovascular complications and is therefore routinely assessed with current diagnostic modalities. Heart valves are subject to high hydrodynamic loads which render them prone to premature degradation. Failing native aortic valves are routinely replaced with bioprosthetic heart valves. This type of prosthesis is limited by a durability that is often less than the patient’s life expectancy. Frequent assessment of valvular function can therefore help to ensure good long-term outcomes and to plan reinterventions. In this article, we describe how unsupervised novelty detection algorithms can be used to automate the interpretation of blood flow data to improve outcomes through early detection of adverse cardiovascular events without requiring repeated check-ups in a clinical environment. The proposed method was tested in an in-vitro flow loop which allowed simulating a failing aortic valve in a laboratory setting. Aortic regurgitation of increasing severity was deliberately introduced with tube-shaped inserts, preventing complete valve closure during diastole. Blood flow recordings from a flow meter at the location of the ascending aorta were analyzed with the algorithms introduced in this article and a diagnostic index was defined that reflects the severity of valvular degradation. The results indicate that the proposed methodology offers a high sensitivity towards pathological changes of valvular function and that it is capable of automatically identifying valvular degradation. Such methods may be a step towards computer-assisted diagnostics and telemedicine that provide the clinician with novel tools to improve patient care. [ABSTRACT FROM AUTHOR]

The understanding of mammalian spermatogenesis niche factors active during sexual development may be leveraged to impact reproduction in farm animals. The aim of this study was to evaluate the effects of r-met-hu/G-CSF (filgrastim) on prepubertal sexual development of guinea pigs (Cavia porcellus) and ram lambs (Ovis aries). Individuals of both species were administered r-met-hu/G-CSF daily for 4 days. During and after administration protocols, testicular function and development were assessed through hematological responses, hormonal profiles (gonadotropins, testosterone and cortisol) testicular morphometry and germ cell kinetics. As expected, r-met-hu/G-CSF acutely mobilized white-lineage blood cells in both species. LH was increased by r-met-hu/G-CSF in guinea pigs (P<0.01) but T remained unchanged. In ram lambs gonadotropins and T increased in dose-response fashion (P<0.01) while cortisol values were stable and similar in treated and control animals (P>0.05). In guinea pigs there were no differences in testicular weights and volumes 2-mo after r-met-hu/G-CSF application (P>0.05). However, ram lambs showed a dose-response effect regarding testis weight (P<0.05). 66.66% of ram lambs had initial testes not yet in meiosis or starting the first spermatogenic wave. After 60-days only 25% of control animals were pubertal while all treated animals (1140-μg) had reached puberty. We propose an integrated hypothesis that G-CSF can stimulate spermatogenesis through two possible ways. 1) r-met-hu/G-CSF may go through the brain blood barrier and once there it can stimulate GnRH-neurons to release GnRH with the subsequent release of gonadotrophins. 2) a local testicular effect through stimulation of steroidogenesis that enhances spermiogenesis via testosterone production and a direct stimulation over spermatogonial stem cells self-renewal. In conclusion, this study shows that r-met-hu/G-CSF differentially affects prepubertal sexual development in hystricomorpha and ovine species, a relevant fact to consider when designing methods to hasten sexual developmental in mammalian species. [ABSTRACT FROM AUTHOR]

Ookinetes, one of the motile and invasive forms of the malaria parasite, rely on gliding motility in order to establish an infection in the mosquito host. Here we characterize the protein PBANKA_0407300 which is conserved in the Plasmodium genus but lacks significant similarity to proteins of other eukaryotes. It is expressed in gametocytes and throughout the invasive mosquito stages of P. berghei, but is absent from asexual blood stages. Mutants lacking the protein developed morphologically normal ookinetes that were devoid of productive motility although some stretching movement could be detected. We therefore named the protein Ookinete Motility Deficient (OMD). Several key factors known to be involved in motility however were normally expressed and localized in the mutant. Importantly, the mutant failed to establish an infection in the mosquito which resulted in a total malaria transmission blockade. [ABSTRACT FROM AUTHOR]

Sleep quality is an important health indicator, and the current measurements of sleep rely on questionnaires, polysomnography, etc., which are intrusive, expensive or time consuming. Therefore, a more nonintrusive, inexpensive and convenient method needs to be developed. Use of the Kinect sensor to capture one’s gait pattern can reveal whether his/her sleep quality meets the requirements. Fifty-nine healthy students without disabilities were recruited as participants. The Pittsburgh Sleep Quality Index (PSQI) and Kinect sensors were used to acquire the sleep quality scores and gait data. After data preprocessing, gait features were extracted for training machine learning models that predicted sleep quality scores based on the data. The t-test indicated that the following joints had stronger weightings in the prediction: the Head, Spine Shoulder, Wrist Left, Hand Right, Thumb Left, Thumb Right, Hand Tip Left, Hip Left, and Foot Left. For sleep quality prediction, the best result was achieved by Gaussian processes, with a correlation of 0.78 (p < 0.001). For the subscales, the best result was 0.51 for daytime dysfunction (p < 0.001) by linear regression. Gait can reveal sleep quality quite well. This method is a good supplement to the existing methods in identifying sleep quality more ecologically and less intrusively. [ABSTRACT FROM AUTHOR]

Swine influenza virus (SIVs) infections cause a significant economic impact to the pork industry. Moreover, pigs may act as mixing vessel favoring genome reassortment of diverse influenza viruses. Such an example is the pandemic H1N1 (pH1N1) virus that appeared in 2009, harboring a combination of gene segments from avian, pig and human lineages, which rapidly reached pandemic proportions. In order to confront and prevent these possible emergences as well as antigenic drift phenomena, vaccination remains of vital importance. The present work aimed to evaluate a new DNA influenza vaccine based on distinct conserved HA-peptides fused with flagellin and applied together with Diluvac Forte as adjuvant using a needle-free device (IntraDermal Application of Liquids, IDAL®). Two experimental pig studies were performed to test DNA-vaccine efficacy against SIVs in pigs. In the first experiment, SIV-seronegative pigs were vaccinated with VC4-flagellin DNA and intranasally challenged with a pH1N1. In the second study, VC4-flagellin DNA vaccine was employed in SIV-seropositive animals and challenged intranasally with an H3N2 SIV-isolate. Both experiments demonstrated a reduction in the viral shedding after challenge, suggesting vaccine efficacy against both the H1 and H3 influenza virus subtypes. In addition, the results proved that maternally derived antibodies (MDA) did not constitute an obstacle to the vaccine approach used. Moreover, elevated titers in antibodies both against H1 and H3 proteins in serum and in bronchoalveolar lavage fluids (BALFs) was detected in the vaccinated animals along with a markedly increased mucosal IgA response. Additionally, vaccinated animals developed stronger neutralizing antibodies in BALFs and higher inhibiting hemagglutination titers in sera against both the pH1N1 and H3N2 influenza viruses compared to unvaccinated, challenged-pigs. It is proposed that the described DNA-vaccine formulation could potentially be used as a multivalent vaccine against SIV infections. [ABSTRACT FROM AUTHOR]

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high fat diets. HLB444 shares similar phenotypic traits with engineered full- and adipose-specific Klf15 knockout strains; however, some phenotypic differences between this mutant and the other models suggest that the Klf15 mutation in HLB444 is a hypomorphic variant. The HLB444 model will inform further annotation of transcriptional functions of KLF15, especially with respect to the role of the first zinc-finger domain. [ABSTRACT FROM AUTHOR]

Acute appendicitis is one of the major causes for emergency surgery in childhood and adolescence. Appendectomy is still the therapy of choice, but conservative strategies are increasingly being studied for uncomplicated inflammation. Diagnosis of acute appendicitis remains challenging, especially due to the frequently unspecific clinical picture. Inflammatory blood markers and imaging methods like ultrasound are limited as they have to be interpreted by experts and still do not offer sufficient diagnostic certainty. This study presents a method for automatic diagnosis of appendicitis as well as the differentiation between complicated and uncomplicated inflammation using values/parameters which are routinely and unbiasedly obtained for each patient with suspected appendicitis. We analyzed full blood counts, c-reactive protein (CRP) and appendiceal diameters in ultrasound investigations corresponding to children and adolescents aged 0–17 years from a hospital based population in Berlin, Germany. A total of 590 patients (473 patients with appendicitis in histopathology and 117 with negative histopathological findings) were analyzed retrospectively with modern algorithms from machine learning (ML) and artificial intelligence (AI). The discovery of informative parameters (biomarker signatures) and training of the classification model were done with a maximum of 35% of the patients. The remaining minimum 65% of patients were used for validation. At clinical relevant cut-off points the accuracy of the biomarker signature for diagnosis of appendicitis was 90% (93% sensitivity, 67% specificity), while the accuracy to correctly identify complicated inflammation was 51% (95% sensitivity, 33% specificity) on validation data. Such a test would be capable to prevent two out of three patients without appendicitis from useless surgery as well as one out of three patients with uncomplicated appendicitis. The presented method has the potential to change today’s therapeutic approach for appendicitis and demonstrates the capability of algorithms from AI and ML to significantly improve diagnostics even based on routine diagnostic parameters. [ABSTRACT FROM AUTHOR]

Recently, high-resolution magnetometry surveys have led to the discovery of a special category of buildings–so-called ‘mega-structures’–situated in highly visible positions in the public space of Tripolye giant-settlements of the late 5th and first half of the 4th millennium BCE. In this paper we explore what these buildings actually are and how they can contribute to the understanding of the development of social space in Tripolye giant-settlements. For this investigation, we linked newly obtained excavation data from the giant-settlement Maidanetske, Ukraine, with a much larger sample of such buildings from magnetic plans obtained in the region between the Carpathian foothills and the Dnieper River. Accordingly, Tripolye mega-structures represent a particular kind of integrative building documented in many non-ranked ethnographic contexts. Based on our results we are interpreting that these buildings were used for various ritual and non-ritual activities, joint decision-making, and the storage and consumption of surplus. In Tripolye giant-settlements at least three different categories of mega-structures could be identified which most likely represent different levels of socio-political integration and decision-making. The emergence of this hierarchical system of high-level integrative buildings for the whole community and different low-level integrative architectures for certain segments of local communities was related to the rise of Tripolye mega-sites. The presence of different integrative levels most likely reflects the fusion of different previously independent communities in the giant-settlements. Later in the mega-site development, we observe how low-level integrative buildings increasingly lose their importance indicated by shrinking size and, finally, their disappearance. This observation might indicate that the power which was previously distributed across the community was transferred to a central institution. It is argued that the non-acceptance of this concentration of power and the decline of lower decision-making levels might be a crucial factor for the disintegration of Tripolye giant-settlements around 3600 BCE. [ABSTRACT FROM AUTHOR]

Background and objectives: There have been limited studies regarding the association between glomerular hyperfiltration (GHF) and restrictive spirometry pattern (RSP) in Korean adults. Methods: We used data of 23,189 adults from the Korea National Health and Nutritional Examination Survey 2009–2015 with a complete data set including spirometry, serum creatinine, and anthropometric measurements. Spirometry data included the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). We defined GHF as the >90th percentile of age & sex adjusted estimated glomerular filtration rate (eGFR), and RSP was defined as an FVC <80%-predicted value and an FEV1/FVC ratio ≥0.7. Results: Participants with RSP showed higher blood pressure, fasting glucose, and triglyceride, reduced high density lipoprotein cholesterol, and central obesity, which resulted in a higher prevalence of metabolic syndrome (MetS) compared to those without RSP. Multivariate logistic regression revealed that the odds for RSP were significantly increased with an increased number of MetS components. In addition, increased eGFR was associated with decreased FVC, showing an inverted J-shaped relationship in a multivariate generalized additive model analysis. In the multivariate logistic regression analysis, the adjusted odds ratio and 95% confidence interval of GHF for RSP was 1.184 (1.026–1.368, P = 0.021), which was evident in groups without metabolic disorders. Conclusions: We concluded that GHF was associated with increased odds for RSP, particularly in groups without metabolic disorders. Further prospective studies are needed to confirm our study results. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics. Objective: A clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthritis in RA patients. Methods: RA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of [18F]DPA-714, [11C]DPA-713 and/or (R)-[11C]PK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison. Results: Clinically active arthritis was present in 110 hand joints (2–17 pp). Arthritic joints were visualized with both [11C]DPA-713 and [18F]DPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for [11C]DPA-713 than for [18F]DPA-714, the latter being not significantly different from (R)-[11C]PK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-[11C]PK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for [11C]DPA-713. Conclusions: [11C]DPA-713 and [18F]DPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for [11C]DPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA. [ABSTRACT FROM AUTHOR]

Podoplanin, a transmembrane glycoprotein, is overexpressed in certain types of tumors and induces platelet aggregation by binding to C-type lectin-like receptor 2 (CLEC-2) on the platelet membrane. Activated platelets release granule components, which in turn, trigger epithelial-mesenchymal transition and confer invasive capacity to the tumor cells. Therefore, blocking the podoplanin-CLEC-2 interaction by a small-molecule compound is a potential therapeutic strategy to prevent cancer metastasis and invasion. To effectively identify such inhibitory compounds, we have developed a pull-down-based inhibitory compound screening system. An immunoglobulin Fc domain-CLEC-2 fusion protein was used as a bait to capture podoplanin derived from podoplanin-overexpressing HeLa cells in the presence and absence of the test compound. The protein complex was then pulled down using protein A beads. To shorten the turnaround time, increase throughput, and decrease the workload for the operators, centrifugal filter units were employed to separate free and bound podoplanin, instead of using customary aspiration-centrifugation washing cycles. Slot blotting was also utilized in lieu of gel electrophoresis and electrical transfer. Thus, the use of our pull down screening system could facilitate the effective selection of potential inhibitor compounds of the podoplanin-CLEC-2 interaction for cancer therapy. Importantly, our methodology is also applicable to targeting other protein-protein interactions. [ABSTRACT FROM AUTHOR]

Inverse dynamics problems are usually solved in the analysis of human gait to obtain reaction forces and moments at the joints. However, these actions are not the actual forces and moments supported by the joint structure, because they do not consider the forces of the muscles acting across the joint. Therefore, to analyse bone-on bone forces it is necessary to estimate those muscle forces. Usually, this problem is addressed by means of optimization algorithms. One of the parameters required to solve this problem is the musculotendon geometry. These data are usually taken from cadavers or MRI data from several subjects, different from the analysed subject. Then, the model is scaled to the subject morphology. This procedure constitutes a source of error. The goals of this work were two. First, to perform a sensitivity analysis of the influence of muscle insertion locations on the muscle forces acting on the hip joint and on the hip joint bone-on-bone forces. Second, to compare the hip joint bone-on-bone forces during gait cycle obtained through muscle insertion locations taken from a musculoskeletal model template and a scaling procedure to those obtained from a subject-specific model using an MRI of the subject. The problem was solved using OpenSim. Results showed that anatomical variability should be analysed from two perspectives. One the one hand, throughout the gait cycle, in a global way. On the other hand, at a characteristic instant of the gait cycle. Variations of ±1 cm in the position of the attachment points of certain muscles caused variations of up to 14.21% in averaged deviation of the muscle forces and 58.96% in the peak force in the modified muscle and variations up to 57.23% in the averaged deviation of the muscle force and up to 117.23% in the peak force in the rest of muscles. Then, the influence of that variability on muscle activity patterns and hip bone-on-bone forces could be described more precisely. A biomechanical analysis of a subject-specific musculoskeletal model was carried out. Using MRI data, variations up to 5 cm in the location of the insertion points were introduced. These modifications showed significant differences between the baseline model and the customized model: within the range [-12%, 10%] for muscle forces and around 35% of body weight for hip bone-on-bone forces. [ABSTRACT FROM AUTHOR]

Background and aims: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. Material and methods: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. Results: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision. Conclusions: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials. [ABSTRACT FROM AUTHOR]

Urine is an acceptable, non-invasive sample for investigating the human urogenital microbiota and for the diagnosis of sexually transmitted infections. However, low quantities of bacterial DNA and PCR inhibitors in urine may prevent efficient PCR amplification for molecular detection of bacteria. Furthermore, cold temperatures used to preserve DNA and bacteria in urine can promote precipitation of crystals that interfere with DNA extraction. Saline, Dulbecco’s Phosphate Buffered Saline, or Tris-EDTA buffer were added to urine from adult men to determine if crystal precipitation could be reversed without heating samples beyond ambient temperature. Total bacterial DNA concentrations and PCR inhibition were measured using quantitative PCR assays to compare DNA yields with and without buffer addition. Dissolution of crystals with Tris-EDTA prior to urine centrifugation was most effective in increasing bacterial DNA recovery and reducing PCR inhibition. DNA recovery using Tris-EDTA was further tested by spiking urine with DNA from bacterial isolates and median concentrations of Lactobacillus jensenii and Escherichia coli 16S rRNA gene copies were found to be higher in urine processed with Tris-EDTA. Maximizing bacterial DNA yield from urine may facilitate more accurate assessment of bacterial populations and increase detection of specific bacteria in the genital tract. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the concurrent validity of two different inertial measurement units for measuring spatiotemporal parameters during running on a treadmill, by comparing data with a high-speed video analysis (VA) at 1,000 Hz. Forty-nine endurance runners performed a running protocol on a treadmill at comfortable velocity (i.e., 3.25 ± 0.36 m.s-1). Those wearable devices (i.e., Stryd™ and RunScribe™ systems) were compared to a high-speed VA, as a reference system for measuring spatiotemporal parameters (i.e. contact time [CT], flight time [FT], step frequency [SF] and step length [SL]) during running at comfortable velocity. The pairwise comparison revealed that the Stryd™ system underestimated CT (5.2%, p < 0.001) and overestimated FT (15.1%, p < 0.001) compared to the VA; whereas the RunScribe™ system underestimated CT (2.3%, p = 0.009). No significant differences were observed in SF and SL between the wearable devices and VA. The intra class correlation coefficient (ICC) revealed an almost perfect association between both systems and high-speed VA (ICC > 0.81). The Bland-Altman plots revealed heteroscedasticity of error (r2 = 0.166) for the CT from the Stryd™ system, whereas no heteroscedasticity of error (r2 < 0.1) was revealed in the rest of parameters. In conclusion, the results obtained suggest that both foot pods are valid tools for measuring spatiotemporal parameters during running on a treadmill at comfortable velocity. If the limits of agreement of both systems are considered in respect to high-speed VA, the RunScribe™ seems to be a more accurate system for measuring temporal parameters and SL than the Stryd™ system. [ABSTRACT FROM AUTHOR]

The equine hoof inner epithelium is folded into primary and secondary epidermal lamellae which increase the dermo-epidermal junction surface area of the hoof and can be affected by laminitis, a common disease of equids. Two keratin proteins (K), K42 and K124, are the most abundant keratins in the hoof lamellar tissue of Equus caballus. We hypothesize that these keratins are lamellar tissue-specific and could serve as differentiation- and disease-specific markers. Our objective was to characterize the expression of K42 and K124 in equine stratified epithelia and to generate monoclonal antibodies against K42 and K124. By RT-PCR analysis, keratin gene (KRT) KRT42 and KRT124 expression was present in lamellar tissue, but not cornea, haired skin, or hoof coronet. In situ hybridization studies showed that KRT124 localized to the suprabasal and, to a lesser extent, basal cells of the lamellae, was absent from haired skin and hoof coronet, and abruptly transitions from KRT124-negative coronet to KRT124-positive proximal lamellae. A monoclonal antibody generated against full-length recombinant equine K42 detected a lamellar keratin of the appropriate size, but also cross-reacted with other epidermal keratins. Three monoclonal antibodies generated against N- and C-terminal K124 peptides detected a band of the appropriate size in lamellar tissue and did not cross-react with proteins from haired skin, corneal limbus, hoof coronet, tongue, glabrous skin, oral mucosa, or chestnut on immunoblots. K124 localized to lamellar cells by indirect immunofluorescence. This is the first study to demonstrate the localization and expression of a hoof lamellar-specific keratin, K124, and to validate anti-K124 monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) disease reactivates from distant latent infection or recent (re)infection. Progression risks increase with age. Across the World Health Organisation Western Pacific region, many populations are ageing and have the highest per capita TB incidence rates in older age groups. However, methods for analysing age-specific TB incidence and forecasting epidemic trends while accounting for demographic change remain limited. Methods: We applied the Lee-Carter models, which were originally developed for mortality modelling, to model the temporal trends in age-specific TB incidence data from 2005 to 2018 in Taiwan. Females and males were modelled separately. We combined our demographic forecasts, and age-specific TB incidence forecasts to project TB incidence until 2035. We compared TB incidence projections with demography fixed in 2018 to projections accounting for demographic change. Results: Our models quantified increasing incidence rates with age and declining temporal trends. By 2035, the forecast suggests that the TB incidence rate in Taiwan will decrease by 54% (95% Prediction Interval (PI): 45%-59%) compared to 2015, while most age-specific incidence rates will reduce by more than 60%. In 2035, adults aged 65 and above will make up 78% of incident TB cases. Forecast TB incidence in 2035 accounting for demographic change will be 39% (95% PI: 36%-42%) higher than without population ageing. Conclusions: Age-specific incidence forecasts coupled with demographic forecasts can inform the impact of population ageing on TB epidemics. The TB control programme in Taiwan should develop plans specific to older age groups and their care needs. [ABSTRACT FROM AUTHOR]

The dementia epidemic is likely to expand worldwide as the aging population continues to grow. A better understanding of the molecular mechanisms that lead to dementia is expected to reveal potentially modifiable risk factors that could contribute to the development of prevention strategies. Alzheimer’s disease is the most prevalent form of dementia. Currently we only partially understand some of the pathophysiological mechanisms that lead to development of the disease in aging individuals. In this study, Switch Miner software was used to identify key switch genes in the brain whose expression may lead to the development of Alzheimer’s disease. The results indicate that switch genes are enriched in pathways involved in the proteasome, oxidative phosphorylation, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and metabolism in the hippocampus and posterior cingulate cortex. Network analysis identified the krupel like factor 9 (KLF9), potassium channel tetramerization domain 2 (KCTD2), Sp1 transcription factor (SP1) and chromodomain helicase DNA binding protein 1 (CHD1) as key transcriptional regulators of switch genes in the brain of AD patients. These transcriptions factors have been implicated in conditions associated with Alzheimer’s disease, including diabetes, glucocorticoid signaling, stroke, and sleep disorders. The specific pathways affected reveal potential modifiable risk factors by lifestyle changes. [ABSTRACT FROM AUTHOR]

Perfusion-related information is reportedly embedded in the low-frequency component of a blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. The blood-propagation pattern through the cerebral vascular tree is detected as an interregional lag variation of spontaneous low-frequency oscillations (sLFOs). Mapping of this lag, or phase, has been implicitly treated as a projection of the vascular tree structure onto real space. While accumulating evidence supports the biological significance of this signal component, the physiological basis of the “perfusion lag structure,” a requirement for an integrative resting-state fMRI-signal model, is lacking. In this study, we conducted analyses furthering the hypothesis that the sLFO is not only largely of systemic origin, but also essentially intrinsic to blood, and hence behaves as a virtual tracer. By summing the small fluctuations of instantaneous phase differences between adjacent vascular regions, a velocity response to respiratory challenges was detected. Regarding the relationship to neurovascular coupling, the removal of the whole lag structure, which can be considered as an optimized global-signal regression, resulted in a reduction of inter-individual variance while preserving the fMRI response. Examination of the T2* and S0, or non-BOLD, components of the fMRI signal revealed that the lag structure is deoxyhemoglobin dependent, while paradoxically presenting a signal-magnitude reduction in the venous side of the cerebral vasculature. These findings provide insight into the origin of BOLD sLFOs, suggesting that they are highly intrinsic to the circulating blood. [ABSTRACT FROM AUTHOR]

Goat fat is one of the best sources of conjugated linoleic acid (CLA), a fatty acid which has health benefits. However, though CLA is generated in ruminants, CLA consumption is limited to meats and milk products. This study aimed to replace vegetable fat with goat milk fat enriched with CLA. From differing fat sources, four cookie recipes were developed: CVF–vegetable fat cookies; CB–butter cookies; CG–goat milk fat cookies without CLA; CGCLA–goat milk fat cookies with CLA. The cookies were evaluated using physical (color and texture), physical-chemical parameters (lipids, proteins, total sugars, fiber, ash, moisture and Aw), consumer testing (n = 123), and lipid profiles. The CGCLA presented higher values in the color parameters. The highest and the lowest scores obtained for hardness were respectively 5.54 (CB) and 2.21 (CVF). Lipids and total sugars varied inversely; the highest percentages of lipids were in the CVF and CG samples which obtained lower total sugar content. There were no differences in acceptance or preference for the four formulations. The goat cream formulations (CG and CGCLA) were as well accepted as the CFV formulation. For lipid profiles, CFV presented the highest percentage of trans-fatty acids (TFA) at 16.76%. CGCLA presented 70% more CLA than either CB or CG, certifying that CGCLA presents CLA in relevant quantities, even after cooking. The CGCLA presented higher levels of CLA, and in this study it was verified that goat milk cream enriched with CLA can be used in producing cookies, adding functional and nutritional properties, and offering another alternative(s) to produce food from goat milk fat. [ABSTRACT FROM AUTHOR]

Previous studies suggest theory of mind (ToM) ability declines with age. However, prior tasks not only required ToM competence but also imposed high executive function (EF) demands, so decline in ToM ability could be caused by deterioration in ToM competence, EF, or both. It was predicted that if the elderly have intact ToM competence but compromised EF, then they should perform similarly to younger adults when using ToM tasks that lower executive demands, such as spontaneous-response tasks. Results showed that on tasks with reduced demands, older adults tracked belief to the same extent as younger adults, despite their declining EF. The findings support a model in which age-related decline in ToM ability is primarily caused by compromised EF, not ToM competence, suggesting that underlying ToM mechanisms are still intact in the elderly. We discuss implications of this work for competence-performance issues in ToM processing and the underlying sources of age-related deterioration of ToM. [ABSTRACT FROM AUTHOR]

Objective: Previous research associated the left inferior frontal cortex with implicit structure learning. The present study tested patients with lesions encompassing the left inferior frontal gyrus (LIFG; including Brodmann areas 44 and 45) to further investigate this cognitive function, notably by using non-verbal material, implicit investigation methods, and by enhancing potential remaining function via dynamic attending. Patients and healthy matched controls were exposed to an artificial pitch grammar in an implicit learning paradigm to circumvent the potential influence of impaired language processing. Methods: Patients and healthy controls listened to pitch sequences generated within a finite-state grammar (exposure phase) and then performed a categorization task on new pitch sequences (test phase). Participants were not informed about the underlying grammar in either the exposure phase or the test phase. Furthermore, the pitch structures were presented in a highly regular temporal context as the beneficial impact of temporal regularity (e.g. meter) in learning and perception has been previously reported. Based on the Dynamic Attending Theory (DAT), we hypothesized that a temporally regular context helps developing temporal expectations that, in turn, facilitate event perception, and thus benefit artificial grammar learning. Results: Electroencephalography results suggest preserved artificial grammar learning of pitch structures in patients and healthy controls. For both groups, analyses of event-related potentials revealed a larger early negativity (100–200 msec post-stimulus onset) in response to ungrammatical than grammatical pitch sequence events. Conclusions: These findings suggest that (i) the LIFG does not play an exclusive role in the implicit learning of artificial pitch grammars, and (ii) the use of non-verbal material and an implicit task reveals cognitive capacities that remain intact despite lesions to the LIFG. These results provide grounds for training and rehabilitation, that is, learning of non-verbal grammars that may impact the relearning of verbal grammars. [ABSTRACT FROM AUTHOR]

Recent studies have begun to elucidate a role for E3 ubiquitin ligases as important mediators of the innate immune response. Our previous work defined a role for the ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) in mouse and human innate immunity. Here, we present novel data describing a role for NKLAM in regulating the immune response to Sendai virus (SeV), a murine model of paramyxoviral pneumonia. NKLAM expression was significantly upregulated by SeV infection. SeV-infected mice that are deficient in NKLAM demonstrated significantly less weight loss than wild type mice. In vivo, Sendai virus replication was attenuated in NKLAM-/- mice. Autophagic flux and the expression of autophagy markers LC3 and p62/SQSTM1 were also less in NKLAM-/- mice. Using flow cytometry, we observed less neutrophils and macrophages in the lungs of NKLAM-/- mice during SeV infection. Additionally, phosphorylation of STAT1 and NFκB p65 was lower in NKLAM-/- than wild type mice. The dysregulated phosphorylation profile of STAT1 and NFκB in NKLAM-/- mice correlated with decreased expression of numerous proinflammatory cytokines that are regulated by STAT1 and/or NFκB. The lack of NKLAM and the resulting attenuated immune response is favorable to NKLAM-/- mice receiving a low dose of SeV; however, at a high dose of virus, NKLAM-/- mice succumbed to the infection faster than wild type mice. In conclusion, our novel results indicate that NKLAM plays a role in regulating the production of pro-inflammatory cytokines during viral infection. [ABSTRACT FROM AUTHOR]

Importance: Despite its efficacy, low tidal volume ventilation (LTVV) remains severely underutilized for patients with acute respiratory distress syndrome (ARDS). Physician under-recognition of ARDS is a significant barrier to LTVV use. We propose a computational method that addresses some of the limitations of the current approaches to automated measurement of whether ARDS is recognized by physicians. Objective: To quantify patient and physician factors affecting physicians’ tidal volume selection and to build a computational model of physician recognition of ARDS that accounts for these factors. Design, setting, and participants: In this cross-sectional study, electronic health record data were collected for 361 ARDS patients and 388 non-ARDS hypoxemic (control) patients in nine adult intensive care units at four hospitals between June 24 and December 31, 2013. Methods: Standardized tidal volumes (mL/kg predicted body weight) were chosen as a proxy for physician decision-making behavior. Using data-science approaches, we quantified the effect of eight factors (six severity of illness, two physician behaviors) on selected standardized tidal volumes in ARDS and control patients. Significant factors were incorporated in computational behavioral models of physician recognition of ARDS. Results: Hypoxemia severity and ARDS documentation in physicians’ notes were associated with lower standardized tidal volumes in the ARDS cohort. Greater patient height was associated with lower standardized tidal volumes (which is already normalized for height) in both ARDS and control patients. The recognition model yielded a mean (99% confidence interval) physician recognition of ARDS of 22% (9%-42%) for mild, 34% (19%-49%) for moderate, and 67% (41%-100%) for severe ARDS. Conclusions and relevance: In this study, patient characteristics and physician behaviors were demonstrated to be associated with differences in ventilator management in both ARDS and control patients. Our model of physician ARDS recognition measurement accounts for these clinical variables, providing an electronic approach that moves beyond relying on chart documentation or resource intensive approaches. [ABSTRACT FROM AUTHOR]

Objectives: The association of obstructive sleep apnea (OSA) with hypothalamic pituitary adrenal (HPA) axis activation has not been fully understood from results of previous studies using hormonal assessments. We aimed to investigate the relationship between adrenal size, a potential marker reflecting HPA axis activity, and sleep parameters related to OSA. Methods: We retrospectively reviewed data on 284 consecutive adult patients aged 20 to 80 y who had undergone polysomnography and abdominal computed tomography (CT). OSA was defined as none/mild (apnea-hypopnea index [AHI] <15, n = 75), moderate (AHI 15 to 30, n = 80), and severe OSA (AHI ≥30, n = 129). Widths of adrenal body and limbs were measured by abdominal CT. Results: Adrenal size was greater in participants with severe OSA than in those with none/mild or moderate OSA (adrenal body width: 6.03 mm, none/mild OSA; 6.09 mm, moderate OSA; 6.78 mm, severe OSA; p <0.001; adrenal limb width: 3.75 mm, none/mild OSA; 3.95 mm, moderate OSA; 4.26 mm, severe OSA, p <0.001). Multivariate regression analysis showed that not the 3% oxygen desaturation index and time of SpO2 <90% but a higher arousal index was the only determinant factor for increased adrenal limb width (β = 0.27, p <0.001) after adjusting for other variables that could affect adrenal size. Neither the arousal index nor hypoxic parameters were associated with adrenal body width. Conclusions: Results indicated that adrenal glands may enlarge in response to longstanding sleep fragmentation, suggesting the involvement of OSA in HPA axis augmentation. [ABSTRACT FROM AUTHOR]

Background and aim: Prevalence and motives for nipple shield use are not well studied in preterm infants and recommendations of nipple shield use in preterm infants are inconsistent. The aim of this study was to determine the prevalence of nipple shield use, explore the motives for nipple shield use and elucidate the association with exclusive breastfeeding in preterm infants. Methods: The study was part of a prospective survey of a Danish national cohort of preterm infants based on questionnaires answered by the 1221 mothers of 1488 preterm infants with gestational age of 24–36 weeks. Data on nipple shield use was available for 1407 infants. Results: Nipple shields were used by 54% of the mother-infant dyads for many different motives and was more often related to breastfeeding problems associated with the infant than with the mother. The most common motive for nipple shield use was “infant slipped the nipple” (52%). The lower the gestational age, the more frequently nipple shields were used for motives related to the infant. For those using a nipple shield, only the motive “infant fell asleep at the breast” was associated with a higher risk of not breastfeeding exclusively at discharge (OR 1.90 (95% CI 1.15; 3.13), p = 0.012), and “breast too engorged” with a lower risk of not breastfeeding exclusively (OR 0.32 (0.16; 0.63), p = 0.001), but overall nipple shield use was associated with failure of exclusive breastfeeding. Conclusion: The present study does not give justifiable motives for nipple shield use, except for “breast too engorged”. Nipple shields should not be recommended for infants falling asleep at the breast, instead, staff and mothers should be patient, allowing the dyad time skin-to-skin. The results indicate that the use of a nipple shield does not promote exclusive breastfeeding in preterm infants. [ABSTRACT FROM AUTHOR]

The survey described in this research paper aimed to investigate the economic and health impacts of birds on dairies. Birds are common pests on dairies, consuming and contaminating feed intended for cattle. As a result, dairy operators experience increased feed costs and increased pathogen and disease risk. We surveyed dairy operators attending the 2017 Washington Dairy Conference to examine the impact of birds on dairies in Washington State. Dairy operators reported feed losses valued at $55 per cow resulting in annual losses totaling $5.5 million in the Western region of the state and $9.2 million in the Eastern region of the state. Shooting was the most commonly used bird management method and European starlings (Sternus vulgaris) were the most frequently implicated species statewide. Bird abundance greater than 10,000 birds per day was associated with larger herd size and with self-reported presence of Johne’s disease and Salmonella. [ABSTRACT FROM AUTHOR]

A high work of breathing can compromise limb oxygen delivery during sustained high-intensity exercise. However, it is unclear if the same is true for intermittent sprint exercise. This project examined the effect of adding an inspiratory load on locomotor muscle tissue reoxygenation during repeated-sprint exercise. Ten healthy males completed three experiment sessions of ten 10-s sprints, separated by 30-s of passive rest on a cycle ergometer. The first two sessions were “all-out’ efforts performed without (CTRL) or with inspiratory loading (INSP) in a randomised and counterbalanced order. The third experiment session (MATCH) consisted of ten 10-s work-matched intervals. Tissue saturation index (TSI) and deoxy-haemoglobin (HHb) of the vastus lateralis and sixth intercostal space was monitored with near-infrared spectroscopy. Vastus lateralis reoxygenation (ΔReoxy) was calculated as the difference from peak HHb (sprint) to nadir HHb (recovery). Total mechanical work completed was similar between INSP and CTRL (effect size: -0.18, 90% confidence limit ±0.43), and differences in vastus lateralis TSI during the sprint (-0.01 ±0.33) and recovery (-0.08 ±0.50) phases were unclear. There was also no meaningful difference in ΔReoxy (0.21 ±0.37). Intercostal HHb was higher in the INSP session compared to CTRL (0.42 ±0.34), whilst the difference was unclear for TSI (-0.01 ±0.33). During MATCH exercise, differences in vastus lateralis TSI were unclear compared to INSP for both sprint (0.10 ±0.30) and recovery (-0.09 ±0.48) phases, and there was no meaningful difference in ΔReoxy (-0.25 ±0.55). Intercostal TSI was higher during MATCH compared to INSP (0.95 ±0.53), whereas HHb was lower (-1.09 ±0.33). The lack of difference in ΔReoxy between INSP and CTRL suggests that for intermittent sprint exercise, the metabolic O2 demands of both the respiratory and locomotor muscles can be met. Additionally, the similarity of the MATCH suggests that ΔReoxy was maximal in all exercise conditions. [ABSTRACT FROM AUTHOR]

Albeit differences in climbing-specific strength of the forearms have been demonstrated between lead and boulder climbers, little is known about the potential differences in force and power output of the upper body pulling-apparatus between disciplines. The aim of this study was to compare the climbing-specific upper-body strength and finger flexor endurance between lead and boulder climbers, as well as to examine the relative utilization of force when testing on a ledge hold compared to a jug hold. Sixteen boulder climbers (red-point climbing grade 17.9 ± 3.3) and fifteen lead climbers (red-point climbing grade 20.5 ± 3.5) performing on an advanced level volunteered for the study. Peak force, average force and rate of force development (RFD) were measured during an isometric pull-up, average velocity in dynamic pull-up, and finger flexor endurance in an intermittent test to fatigue. The isometric pull-up was performed on a ledge hold (high finger strength requirements) and on a jug hold (very low finger strength requirements). Boulder climbers demonstrated a higher maximal and explosive strength in all strength and power measurements (26.2–52.9%, ES = 0.90–1.12, p = 0.006–0.023), whereas the finger flexor endurance test showed no significant difference between the groups (p = 0.088). Both groups were able to utilize 57–69% of peak force, average force and RFD in the ledge condition compared to the jug condition, but the relative utilization was not different between the groups (p = 0.290–0.996). In conclusion, boulder climbers were stronger and more explosive compared to lead climbers, whereas no differences in finger flexor endurance were observed. Performing climbing-specific tests on a smaller hold appears to limit the force and power output equally between the two groups. [ABSTRACT FROM AUTHOR]

Purpose: Associations between brain region volume and weight status have been observed in children cross-sectionally. However, it is unclear if differences in brain region volume precede weight gain. Methods: Two high-quality structural brain images were obtained approximately one year apart in 53 children aged 9–12 years old. Children’s height and weight were also measured at each scan. Structural images were processed using the FreeSurfer software-package providing volume measures for regions of interest including the entorhinal cortex, nucleus accumbens, and hippocampus. Age- and sex-adjusted BMI z-scores (BMIz) were calculated at both timepoints. The association between brain region volume and BMIz was examined cross-sectionally using linear regression and longitudinally using structural equation modeling. All models were adjusted by estimated cranial volume to account for individual variation in head size and were corrected for multiple comparisons (pFDR<0.05). Results: The sample of children was primarily healthy weight at baseline (79.78%). Cross-sectionally at the one-year follow-up, a positive relationship was observed between right hippocampal volume and BMIz (β = 0.43, 95% CI = (0.10, 0.77)). Longitudinally a negative relationship was observed between right entorhinal volume at baseline and BMIz at the one-year follow-up (β = −0.25, 95% CI = (−0.44, −0.07)). Conclusion: These results suggest that measured volumes from certain regions of the brain that have been associated with BMI in adults are associated with both concurrent BMIz and BMIz change over one-year in a primarily healthy weight sample of children. As the entorhinal cortex integrates signals from both reward and control regions, this region may be particularly important to weight management during child development. [ABSTRACT FROM AUTHOR]

We previously reported that allogeneic, intraperitoneally administered “Neo-Islets,” composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided pilot study (INAD 012–776) in insulin-dependent, spontaneously diabetic pet dogs by ultrasound-guided, intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) and sedated animals. We report here interim observations on the first 4 canine Neo-Islet-treated, insulin-dependent pet dogs that are now in the early to intermediate-term follow-up phase of the planned 3 year study (> 6 months post treatment). Current results from this translational study indicate that in dogs, Neo-Islets appear to engraft, redifferentiate and physiologically produce insulin, and are rejected by neither auto- nor allo-immune responses, as evidenced by (a) an absent IgG response to the allogeneic cells contained in the administered Neo-Islets, and (b) progressively improved glycemic control that achieves up to a 50% reduction in daily insulin needs paralleled by a statistically significant decrease in serum glucose concentrations. This is accomplished without the use of anti-rejection drugs or encapsulation devices. No adverse or serious adverse events related to the Neo-Islet administration have been observed to date. We conclude that this minimally invasive therapy has significant translational relevance to veterinary and clinical Type 1 diabetes mellitus by achieving complete and at this point partial glycemic control in two species, i.e., diabetic mice and dogs, respectively. [ABSTRACT FROM AUTHOR]