bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of loading dose colistin versus carbapenems for treatment of extended spectrum beta lactamase producing Enterobacteriaceae
Authors: Katip Wasan , Yoodee Jukapun , Uitrakul Suriyon , Oberdorfer Peninnah
Published: January 2021

Colistin provides in vitro activity against numerous ESBL-producing and carbapenem-resistant bacteria. However, clinical information with respect to its utilization in infection caused by ESBL producers is limited. The aim of this study was a comparison of mortality rates of loading dose (LD) colistin and carbapenems as definitive therapies in a cohort of patients with infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae. A retrospective cohort study in 396 patients with ESBL-producing E.coli and K.pneumoniae infection at a university-affiliated hospital was conducted between 1 January 2005 and 30 June 2015 to compare outcomes of infected patients who received LD colistin (95 patients) with carbapenems (301 patients). The three primary outcomes were 30-day mortality, clinical response and microbiological response. The most common infection types were urinary tract infection (49.49%), followed by pneumonia (40.66%), bacteremia (13.64%), skin and soft tissue infections (4.80%) and intra-abdominal infection (3.03%). LD colistin group provided higher 30-day mortality when compared with carbapenems group (HR 7.97; 95% CI 3.68 to 17.25; P = 0.001). LD colistin was also independently associated with clinical failure (HR 4.30; 95% CI 1.93 to 9.57; P = 0.001) and bacteriological failure (HR 9.49; 95% CI 3.76 to 23.96; P = 0.001) when compared with those who received carbapenems. LD colistin treatment was associated with poorer outcomes, i.e. mortality rate, clinical response and microbiological response. Moreover, when adjusted confounding factors, LD colistin was still less effective than carbapenems. It should be noted that, however, the use of Vitek-2 to assess colistin susceptibility could provide inaccurate results. Also, the difference in baseline characteristics could still remain in retrospective study although compensation by hazard ratio adjustment was performed. Therefore, clinical utilization of LD colistin should be recommended as an alternative for treatment ESBL-producing Enterobacteriaceae only in the circumstances where carbapenems cannot be utilized, but this recommendation must be considered carefully.
Reconstruction of forest dynamics in the Western Palaearctic based on phylogeographic analysis of the ringlet butterfly Erebia aethiops
Authors: Wendt Martin , Husemann Martin , Kramp Katja , Schmitt Thomas
Published: January 2021

Glacial refugia are centers of high biodiversity. Therefore, knowledge on their locations and reactions of associated populations and landscapes to climatic changes is crucial for conservation management. We here investigated the biogeography of a butterfly species linked to open forest habitats. Using mitochondrial and nuclear markers in combination with Bayesian simulations, we analyzed the location and age of potential glacial refugia of the species. We identified five putative refugia in Europe. Considering the ecological needs of our study species, tree density within these refugial areas, in contrast to earlier assumptions, must have exceeded the level of individually scattered trees. Our results also provide evidence that especially the refuge areas in the Carpathians were previously underestimated regarding their age: the refugia in the Southern Carpathians presented suitable conditions throughout several glacial cycles, probably since the Mindel or Riss cycles. Additionally, our analyses provided support for a forest refugium near the Tatra Mountains persisting the last glacial maximum. Our results underline the usefulness of this and probably other butterfly species as indicators of forest refugia.
Octenidine-based hydrogel shows anti-inflammatory and protease-inhibitory capacities in wounded human skin
Authors: Seiser Saskia , Janker Lukas , Zila Nina , Mildner Michael , Rakita Ana , Matiasek Johannes , Bileck Andrea , Gerner Christopher , Paulitschke Verena , Elbe-Bürger Adelheid
Published: January 2021

Octenidine dihydrochloride (OCT) is a widely used antiseptic molecule, promoting skin wound healing accompanied with improved scar quality after surgical procedures. However, the mechanisms by which OCT is contributing to tissue regeneration are not yet completely clear. In this study, we have used a superficial wound model by tape stripping of ex vivo human skin. Protein profiles of wounded skin biopsies treated with OCT-containing hydrogel and the released secretome were analyzed using liquid chromatography-mass spectrometry (LC–MS) and enzyme-linked immunosorbent assay (ELISA), respectively. Proteomics analysis of OCT-treated skin wounds revealed significant lower levels of key players in tissue remodeling as well as reepithelization after wounding such as pro-inflammatory cytokines (IL-8, IL-6) and matrix-metalloproteinases (MMP1, MMP2, MMP3, MMP9) when compared to controls. In addition, enzymatic activity of several released MMPs into culture supernatants was significantly lower in OCT-treated samples. Our data give insights on the mode of action based on which OCT positively influences wound healing and identified anti-inflammatory and protease-inhibitory activities of OCT.
p-adic numbers encode complex networks
Authors: Hua Hao , Hovestadt Ludger
Published: January 2021

The Erdős-Rényi (ER) random graph G(n, p) analytically characterizes the behaviors in complex networks. However, attempts to fit real-world observations need more sophisticated structures (e.g., multilayer networks), rules (e.g., Achlioptas processes), and projections onto geometric, social, or geographic spaces. The p-adic number system offers a natural representation of hierarchical organization of complex networks. The p-adic random graph interprets n as the cardinality of a set of p-adic numbers. Constructing a vast space of hierarchical structures is equivalent for combining number sequences. Although the giant component is vital in dynamic evolution of networks, the structure of multiple big components is also essential. Fitting the sizes of the few largest components to empirical data was rarely demonstrated. The p-adic ultrametric enables the ER model to simulate multiple big components from the observations of genetic interaction networks, social networks, and epidemics. Community structures lead to multimodal distributions of the big component sizes in networks, which have important implications in intervention of spreading processes.
Hydrogen–methane breath testing results influenced by oral hygiene
Authors: Erdrich Sharon , Tan Edwin C. K. , Hawrelak Jason A. , Myers Stephen P. , Harnett Joanna E.
Published: January 2021

The measurement of hydrogen–methane breath gases is widely used in gastroenterology to evaluate malabsorption syndromes and bacterial overgrowth. Laboratories offering breath testing provide variable guidance regarding oral hygiene practices prior to testing. Given that oral dysbiosis has the potential to cause changes in breath gases, it raises concerns that oral hygiene is not a standard inclusion in current breath testing guidelines. The aim of this study was to determine how a pre-test mouthwash may impact hydrogen–methane breath test results. Participants presenting for breath testing who had elevated baseline gases were given a chlorhexidine mouthwash. If a substantial reduction in expired hydrogen or methane occurred after the mouthwash, breath samples were collected before and after a mouthwash at all breath sample collection points for the duration of testing. Data were evaluated to determine how the mouthwash might influence test results and diagnostic status. In 388 consecutive hydrogen–methane breath tests, modifiable elevations occurred in 24.7%. Administration of a chlorhexidine mouthwash resulted in significantly (p ≤ 0.05) reduced breath hydrogen in 67% and/or methane gas in 93% of those consenting to inclusion. In some cases, this modified the diagnosis. Mean total gas concentrations pre- and post-mouthwash were 221.0 ppm and 152.1 ppm (p < 0.0001) for hydrogen, and 368.9 ppm and 249.8 ppm (p < 0.0001) for methane. Data suggest that a single mouthwash at baseline has a high probability of returning a false positive diagnosis. Variations in gas production due to oral hygiene practices has significant impacts on test interpretation and the subsequent diagnosis. The role of oral dysbiosis in causing gastrointestinal symptoms also demands exploration as it may be an underlying factor in the presenting condition that was the basis for the referral.
Investigation of a connection between abdominal wall defects and severity of the herniation in fetuses with gastroschisis and omphalocele
Authors: Logsdon Natasha T. , Gallo Carla M. , Favorito Luciano Alves , Sampaio Francisco J.
Published: January 2021

Analyze the biometric parameters and the size (area) of abdominal wall defect (AWD) in fetuses with gastroschisis and omphaloceles and correlate them with the herniated internal organs. We studied 22 fetuses (11 with AWDs and 11 without anomalies). In all fetuses we evaluated the xiphopubic distance (XPD) and iliac crest distance (ICD). In fetuses with AWDs we dissected the abdominal wall and measured the width and length of the defect for calculating its area and studying the correlation between the size of the defect with the organs that were herniated. For statistical analysis, the Anova and Tukey post-test were used (p < 0.05). The XPD in the control group had mean of 4.2 mm (2.3–5.9; SD ± 1.11), while in the AWDs it was 4.2 mm (2.9–5.5; SD ± 0.98) (p = 0.4366). The ICD had mean values of 2.5 mm (1.6–3.4; SD ± 0.58) in the control group, and 2.3 mm (1.2–3.0; SD ± 0.56) in AWDs fetuses (p = 0.6963). The number of herniate organs do not have significant correlation with the area of the defect (r2 = 0.2504, p = 0.5068). There is no correlation between the size (area) of abdominal wall defects and the number of the internal organs that herniated. Therefore, the hole size is not a predictor of the severity of the gastroschisis or omphalocele.
Adaptation to mis-pronounced speech: evidence for a prefrontal-cortex repair mechanism
Authors: Blanco-Elorrieta Esti , Gwilliams Laura , Marantz Alec , Pylkkänen Liina
Published: January 2021

Speech is a complex and ambiguous acoustic signal that varies significantly within and across speakers. Despite the processing challenge that such variability poses, humans adapt to systematic variations in pronunciation rapidly. The goal of this study is to uncover the neurobiological bases of the attunement process that enables such fluent comprehension. Twenty-four native English participants listened to words spoken by a “canonical” American speaker and two non-canonical speakers, and performed a word-picture matching task, while magnetoencephalography was recorded. Non-canonical speech was created by including systematic phonological substitutions within the word (e.g. [s] → [sh]). Activity in the auditory cortex (superior temporal gyrus) was greater in response to substituted phonemes, and, critically, this was not attenuated by exposure. By contrast, prefrontal regions showed an interaction between the presence of a substitution and the amount of exposure: activity decreased for canonical speech over time, whereas responses to non-canonical speech remained consistently elevated. Grainger causality analyses further revealed that prefrontal responses serve to modulate activity in auditory regions, suggesting the recruitment of top-down processing to decode non-canonical pronunciations. In sum, our results suggest that the behavioural deficit in processing mispronounced phonemes may be due to a disruption to the typical exchange of information between the prefrontal and auditory cortices as observed for canonical speech.
Restoration of surfactant activity by polymyxin B in lipopolysaccharide-potentiated injury of immature rabbit lungs
Authors: Calkovska Andrea , Haegerstrand-Björkman Marie , Curstedt Tore
Published: January 2021

During postnatal adaptation pulmonary surfactant may be inactivated by lipopolysaccharide (LPS). We evaluated the effect of surfactant therapy in combination with antibiotic polymyxin B (PxB) in double-hit model of neonatal lung injury. Surfactant (poractant alfa, Curosurf) was exposed to smooth (S) LPS without/with PxB and tested in captive bubble surfactometer. Preterm rabbits received intratracheally saline (control) or S-LPS and were ventilated with 100% oxygen. After 30 min, LPS-treated animals received no treatment, or surfactant (200 mg/kg) without/with 3% PxB; controls received the same dose of surfactant. Animals were ventilated for further 2 h. In vitro, addition of 5% S-LPS to surfactant increased minimum surface tension (γmin) and addition of 1–3% PxB to surfactant/S-LPS mixture restored γmin to low values. Animals only given S-LPS had lower lung compliance and lung gas volume (LGV) compared to surfactant groups. Treatment with surfactant/PxB, but not with surfactant only, restored LGV. Addition of PxB to the surfactant increased the alveolar expansion. S-LPS interferes with surface activity of the pulmonary surfactant and PxB improves the resistance of surfactant to LPS-induced inactivation. In our neonatal model of respiratory distress syndrome surfactant gives positive response even in simultaneous exposure to S-LPS, when enriched with PxB.
Time-resolved non-invasive metabolomic monitoring of a single cancer spheroid by microfluidic NMR
Authors: Patra Bishnubrata , Sharma Manvendra , Hale William , Utz Marcel
Published: January 2021

We present a quantitative study of the metabolic activity of a single spheroid culture of human cancer cells. NMR (nuclear magnetic resonance) spectroscopy is an ideal tool for observation of live systems due to its non-invasive nature. However, limited sensitivity has so far hindered its application in microfluidic culture systems. We have used an optimised micro-NMR platform to observe metabolic changes from a single spheroid. NMR spectra were obtained by directly inserting microfluidic devices containing spheroids ranging from 150 $$\upmu$$
μ
m to 300 $$\upmu$$
μ
m in diameter in 2.5 $$\upmu$$
μ
L of culture medium into a dedicated NMR probe. Metabolite concentrations were found to change linearly with time, with rates approximately proportional to the number of cells in the spheroid. The results demonstrate that quantitative monitoring of a single spheroid with $$\le$$
≤
2500 cells is possible. A change in spheroid size by 600 cells leads to a clearly detectable change in the l-Lactic acid production rate ($$p=3.5\times 10^{-3}$$

p
=
3.5
×

10

-
3

). The consumption of d-Glucose and production of l-Lactic acid were approximately 2.5 times slower in spheroids compared to monolayer culture of the same number of cells. Moreover, while cells in monolayer culture were found to produce l-Alanine and l-Glutamine, spheroids showed slight consumption in both cases.
PDGFRα mediated survival of myofibroblasts inhibit satellite cell proliferation during aberrant regeneration of lacerated skeletal muscle
Authors: Thooyamani Abinaya Sundari , Mukhopadhyay Asok
Published: January 2021

Aberrant regeneration or fibrosis in muscle is the denouement of deregulated cellular and molecular events that alter original tissue architecture due to accumulation of excessive extracellular matrix. The severity of the insult to the skeletal muscle determines the nature of regeneration. Numerous attempts at deciphering the mechanism underlying fibrosis and the subsequent strategies of drug therapies have yielded temporary solutions. Our intent is to understand the interaction between the myofibroblasts (MFs) and the satellite cells (SCs), during skeletal muscle regeneration. We hypothesize that MFs contribute to the impairment of SCs function by exhibiting an antagonistic influence on their proliferation. A modified laceration based skeletal muscle injury model in mouse was utilized to evaluate the dynamics between the SCs and MFs during wound healing. We show that the decline in MFs’ number through inhibition of PDGFRα signaling consequently promotes proliferation of the SCs and exhibits improved skeletal muscle remodeling. We further conclude that in situ administration of PDGFRα inhibitor prior to onset of fibrosis may attenuate aberrant regeneration. This opens new possibility for the early treatment of muscle fibrosis by specific targeting of MFs rather than transplantation of SCs.
Fractional anisotropy thresholding for deterministic tractography of the roots of the brachial plexus
Authors: Wade Ryckie G. , Teh Irvin , Andersson Gustav , Yeh Fang-Cheng , Wiberg Mikael , Bourke Grainne
Published: January 2021

Diffusion tensor imaging (DTI) metrics, such as the fractional anisotropy (FA) and estimates of diffusivity are sensitive to the microstructure of peripheral nerves and may be displayed as tractograms. However, the ideal conditions for tractography of the roots of the brachial plexus are unclear, which represents the rationale for this study. Ten healthy adults were scanned using a Siemens Prisma (3T) and single-shot echo-planar imaging (b-value 0/1000 s/mm2, 64 directions, 2.5 mm3 with 4 averages; repeated in opposing phase encoding directions). Susceptibility correction and tractography were performed in DSI Studio by two independent raters. The effect of FA thresholding at increments of 0.01 (from 0.04 to 0.10) were tested. The mean FA varied between subjects by 2% (95% CI 1%, 3%). FA thresholds of 0.04, 0.05 and 0.06 all propagated 96% of tracts representing the roots; thresholding at 0.07 yielded 4% fewer tracts (p = 0.2), 0.08 yielded 11% fewer tracts (p = 0.008), 0.09 yielded 15% fewer tracts (p = 0.001) and 0.1 yielded 20% fewer tracts (p < 0.001). There was < 0.1% inter-rater variability in the measured FA and 99% agreement for tractography (κ = 0.92, p < 0.001). The fractional anisotropy thresholds required to generate tractograms of the roots of the brachial plexus appears to be lower than those used in the brain. We provide estimates of the probability of generating true tracts for each spinal nerve root of the brachial plexus, at different fractional anisotropy thresholds.
Steady streaming as a method for drug delivery to the inner ear
Authors: Sumner Laura , Mestel Jonathan , Reichenbach Tobias
Published: January 2021

The inner ear, or cochlea, is a fluid-filled organ housing the mechanosensitive hair cells. Sound stimulation is relayed to the hair cells through waves that propagate on the elastic basilar membrane. Sensorineural hearing loss occurs from damage to the hair cells and cannot currently be cured. Although drugs have been proposed to prevent damage or restore functionality to hair cells, a difficulty with such treatments is ensuring adequate drug delivery to the cells. Because the cochlea is encased in the temporal bone, it can only be accessed from its basal end. However, the hair cells that are responsible for detecting speech-frequency sounds reside at the opposite, apical end. In this paper we show that steady streaming can be used to transport drugs along the cochlea. Steady streaming is a nonlinear process that accompanies many fluctuating fluid motions, including the sound-evoked waves in the inner ear. We combine an analytical approximation for the waves in the cochlea with computational fluid dynamic simulations to demonstrate that the combined steady streaming effects of several different frequencies can transport drugs from the base of the cochlea further towards the apex. Our results therefore show that multi-frequency sound stimulation can serve as a non-invasive method to transport drugs efficiently along the cochlea.
Analysis of paint traces to determine the ship responsible for a collision
Authors: Lee H. , Lee D. , Seo J. M.
Published: January 2021

Although there have been many instances of ship collision at sea in recent times, not much research has been conducted on the topic. In this study, paint from an actual site of ship collision was collected and analyzed as evidence. The amount of evidence collected from the ships involved in the collision is either small or has inconsistent morphology. In addition, the contaminants and samples are often mixed in this evidence, making its analysis difficult. Paint traces of the damaged ship and the ship suspected to be responsible for the collision were compared through scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM–EDS), attenuated total reflection–Fourier transform infrared spectroscopy (ATR–FTIR), thermogravimetry (TG) and derivative thermogravimetry (DTG), and pyrolysis–gas chromatography/mass spectrometry (Py–GC/MS) analyses. The ship responsible for the collision could be identified by characterization and by performing a comparative analysis of the extracted paint. Among the methods used in this study, Py–GC/MS can sensitively analyze even similar paints, and identified styrene and phthalic anhydride as the most prominent components of the paint used as evidence. The results obtained can be used to investigate the evidence collected from collision sites and to determine the ship responsible for the collision.
A computationally efficient hybrid 2D–3D subwoofer model
Authors: Bokhari Ahmad H. , Berggren Martin , Noreland Daniel , Wadbro Eddie
Published: January 2021

A subwoofer generates the lowest frequency range in loudspeaker systems. Subwoofers are used in audio systems for live concerts, movie theatres, home theatres, gaming consoles, cars, etc. During the last decades, numerical simulations have emerged as a cost- and time-efficient complement to traditional experiments in the design process of different products. The aim of this study is to reduce the computational time of simulating the average response for a given subwoofer design. To this end, we propose a hybrid 2D–3D model that reduces the computational time significantly compared to a full 3D model. The hybrid model describes the interaction between different subwoofer components as interacting modules whose acoustic properties can partly be pre-computed. This allows us to efficiently compute the performance of different subwoofer design layouts. The results of the hybrid model are validated against both a lumped element model and a full 3D model over a frequency band of interest. The hybrid model is found to be both accurate and computationally efficient.
Presence of sarcopenia does not affect the clinical results of balloon kyphoplasty for acute osteoporotic vertebral fracture
Authors: Ohyama Shoichiro , Hoshino Masatoshi , Takahashi Shinji , Hori Yusuke , Yasuda Hiroyuki , Terai Hidetomi , Hayashi Kazunori , Tsujio Tadao , Kono Hiroshi , Suzuki Akinobu , Tamai Koji , Toyoda Hiromitsu , Dohzono Sho , Nakamura Hiroaki
Published: January 2021

Sarcopenia has been associated with poor clinical outcomes in several diseases. Herein, the clinical results of balloon kyphoplasty (BKP) for acute osteoporotic vertebral fracture (OVF) treatment were assessed and compared between sarcopenia and non-sarcopenia patients. Sixty patients who underwent BKP for treatment of acute OVF with poor prognostic factors between April 2016 and September 2017 and were assessed for sarcopenia were enrolled. Clinical results (back pain on visual analogue scale [VAS]; short-form [SF] 36; vertebral deformity; activities of daily living levels; and incidence of adjacent vertebral fractures) were compared between the two groups at 6 months post-BKP. Data analysis revealed that back pain on VAS, SF-36 scores, and vertebral deformity improved from baseline to 6 months after BKP. Thirty-nine patients (65.0%) were diagnosed with sarcopenia and demonstrated a lower body mass index (21.2 vs. 23.3 kg/m2, p = 0.02), skeletal muscle mass index (5.32 vs. 6.55 kg/m2, p < 0.01), hand-grip strength (14.7 vs. 19.2 kg, p = 0.01), and bone mineral density of the femoral neck (0.57 vs. 0.76 g/cm2, p < 0.01) than those of patients without sarcopenia. However, no significant differences were observed in the clinical results between these groups. Therefore, BKP’s clinical results for the treatment of acute OVF are not associated with sarcopenia.
The effect of subcutaneous and intraperitoneal anesthesia on post laparoscopic pain: a randomized controlled trial
Authors: Gluck Ohad , Barber Elad , Feldstein Ohad , Tal Ori , Kerner Ram , Keidar Ran , Wolfson Inna , Ginath Shimon , Bar Jacob , Sagiv Ron
Published: January 2021

A few modes of perioperative local analgesia have been studied in order to reduce postoperative pain after laparoscopy, including preemptive local anesthetics in the trocar sites and intraperitoneal anesthetics administration at the end of the surgery. However, the evidence regarding their efficacy are conflicting. In addition, the combination of both aforementioned methods has been rarely studied. Our aim was to evaluate whether subcutaneous trocar site and/or intraperitoneal analgesia reduce pain after gynecologic operative laparoscopy. This was a single-centered, randomized, controlled, double-blinded trial. The patients were randomly assigned to one of four equally sized groups: group 1—subcutaneous and intraperitoneal analgesia; group 2—subcutaneous analgesia and intraperitoneal placebo; group 3—subcutaneous placebo and intraperitoneal analgesia; Group 4—subcutaneous and intraperitoneal placebo. The patients, the surgeons, and the pain evaluators were all blinded to the patient’s allocation. Included were patients who underwent elective operative laparoscopy. Exclusion criteria were: active infection, pregnancy, known sensitivity to Bupivacaine-Hydrochloride, chronic pelvic pain, surgeries with additional vaginal procedures, conversion to laparotomy, and malignancy. A total of 9 ml of Bupivacaine-Hydrochloride (Marcaine) 0.5%, or Sodium-Chloride 0.9%, as a placebo, were injected subcutaneously to the trocar sites (3 ml to each trocar site), prior to skin incision. In addition, 10 ml of Bupivacaine-Hydrochloride 0.5%, diluted with 40 ml of Sodium-Chloride 0.9% (a total of 50 ml solution), or 50 ml of Sodium-Chloride 0.9%, as a placebo, were injected intraperitoneally at the end of the surgery. By utilizing the 10 cm Visual-analogue-scale (VAS) we assessed post-operative pain at rest at 3, 8, and 24 h, and during ambulation at 8 and 24 h. The study was approved by the local Institutional Review Board and has been registered at clinicaltrials.gov. We conformed to the CONSORT recommendations. Between December 2016 and July 2019, a total of 119 patients were included in the study. Demographic and interventional characteristics were similar among the groups. The level of postoperative pain, either at rest or with change of position, was not significantly different between the groups, at all-time points. Application of subcutaneous and/or intraperitoneal analgesia is not effective in reducing pain after gynecologic operative laparoscopy.

Clinical trial identification number: NCT02976571. Date of trial registration 11/29/2016. URL of the registration site: https://clinicaltrials.gov.
Social distancing and epidemic resurgence in agent-based susceptible-infectious-recovered models
Authors: Mukhamadiarov Ruslan I. , Deng Shengfeng , Serrao Shannon R. , Priyanka  , Nandi Riya , Yao Louie Hong , Täuber Uwe C.
Published: January 2021

Once an epidemic outbreak has been effectively contained through non-pharmaceutical interventions, a safe protocol is required for the subsequent release of social distancing restrictions to prevent a disastrous resurgence of the infection. We report individual-based numerical simulations of stochastic susceptible-infectious-recovered model variants on four distinct spatially organized lattice and network architectures wherein contact and mobility constraints are implemented. We robustly find that the intensity and spatial spread of the epidemic recurrence wave can be limited to a manageable extent provided release of these restrictions is delayed sufficiently (for a duration of at least thrice the time until the peak of the unmitigated outbreak) and long-distance connections are maintained on a low level (limited to less than five percent of the overall connectivity).
Sensitive detection of extremely small iron oxide nanoparticles in living mice using MP2RAGE with advanced image co-registration
Authors: Kim Joong H. , Dodd Stephen , Ye Frank Q. , Knutsen Andrew K. , Nguyen Duong , Wu Haitao , Su Shiran , Mastrogiacomo Simone , Esparza Thomas J. , Swenson Rolf E. , Brody David L.
Published: January 2021

Magnetic resonance imaging (MRI) is a widely used non-invasive methodology for both preclinical and clinical studies. However, MRI lacks molecular specificity. Molecular contrast agents for MRI would be highly beneficial for detecting specific pathological lesions and quantitatively evaluating therapeutic efficacy in vivo. In this study, an optimized Magnetization Prepared—RApid Gradient Echo (MP-RAGE) with 2 inversion times called MP2RAGE combined with advanced image co-registration is presented as an effective non-invasive methodology to quantitatively detect T1 MR contrast agents. The optimized MP2RAGE produced high quality in vivo mouse brain T1 (or R1 = 1/T1) map with high spatial resolution, 160 × 160 × 160 µm3 voxel at 9.4 T. Test–retest signal to noise was > 20 for most voxels. Extremely small iron oxide nanoparticles (ESIONPs) having 3 nm core size and 11 nm hydrodynamic radius after polyethylene glycol (PEG) coating were intracranially injected into mouse brain and detected as a proof-of-concept. Two independent MP2RAGE MR scans were performed pre- and post-injection of ESIONPs followed by advanced image co-registration. The comparison of two T1 (or R1) maps after image co-registration provided precise and quantitative assessment of the effects of the injected ESIONPs at each voxel. The proposed MR protocol has potential for future use in the detection of T1 molecular contrast agents.
The shifted balance of arginine metabolites in acute myocardial infarction patients and its clinical relevance
Authors: Molek Patrycja , Zmudzki Pawel , Wlodarczyk Aleksandra , Nessler Jadwiga , Zalewski Jaroslaw
Published: January 2021

The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% (P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area (R = 0.34, P = 0.004) and infarct size (R = 0.33, P = 0.006). Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67 (95% confidence interval 0.54–0.81) for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.
Comparing efficacy of intraarticular single crosslinked Hyaluronan (HYAJOINT Plus) and platelet-rich plasma (PRP) versus PRP alone for treating knee osteoarthritis
Authors: Sun Shu-Fen , Lin Guan-Chyun , Hsu Chien-Wei , Lin Huey-Shyan , Liou I.-H.siu , Wu Shin-Yi
Published: January 2021

Intraarticular hyaluronan or platelet-rich plasma (PRP) is widely used in the treatment of knee osteoarthritis (OA). The efficacy of combined hyaluronan with PRP remained inconclusive. This study aimed to investigate the efficacy of combined a single crosslinked hyaluronan (HYAJOINT Plus) and a single PRP versus a single PRP in patients with knee OA. In a prospective randomized-controlled trial, 85 patients with knee OA (Kellgren-Lawrence 2) were randomized to receive a single intraarticular injection of HYAJOINT Plus (3 ml, 20 mg/ml) followed by 3 ml PRP (the combined-injection group, N = 43) or a single injection of 3 ml PRP (the one-injection group, N = 42). The primary outcome was the change from baseline in the visual analog scale (VAS) pain (0–00 mm) at 6 months. Secondary outcomes included The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, Likert Scale), Lequesne index, single leg stance test (SLS), use of rescue analgesics and patient satisfaction at 1, 3 and 6 months. Seventy-eight patients were available for the intention-to-treat analysis at 6 months. Both groups improved significantly in VAS pain, WOMAC, Lequesne index and SLS at each follow-up visit (p < 0.001). Patients receiving a single PRP experienced significantly greater improvements in VAS pain than patients receiving combined injections at 1-month follow-up (adjusted mean difference: − 5.6; p = 0.017). There were no significant between-group differences in several of the second outcomes at each follow-up visit, except the WOMAC-pain and WOMAC-stiffness scores favoring the one-injection group at 1 month (p = 0.025 and p = 0.011). However, at 6-month follow-up, the combined-injection group achieved significantly better VAS pain reduction (p = 0.020). No serious adverse events occurred following injections. In conclusion, either combined injections of HYAJOINT Plus and PRP or a single PRP alone was safe and effective for 6 months in patients with Kellgren-Lawrence 2 knee OA. Combined injections of HYAJOINT Plus and PRP achieved better VAS pain reduction than a single PRP at 6 months. The results indicating a long term benefit effect of a combination of HYAJOINT Plus and PRP in a particular subset of patients with moderate knee OA need to be replicated in larger trials.

ClinicalTrials.gov number NCT04315103.
Sulf2a controls Shh-dependent neural fate specification in the developing spinal cord
Authors: Danesin Cathy , Darche-Gabinaud Romain , Escalas Nathalie , Bouguetoch Vanessa , Cochard Philippe , Al Oustah Amir , Ohayon David , Glise Bruno , Soula Cathy
Published: January 2021

Sulf2a belongs to the Sulf family of extracellular sulfatases which selectively remove 6-O-sulfate groups from heparan sulfates, a critical regulation level for their role in modulating the activity of signalling molecules. Data presented here define Sulf2a as a novel player in the control of Sonic Hedgehog (Shh)-mediated cell type specification during spinal cord development. We show that Sulf2a depletion in zebrafish results in overproduction of V3 interneurons at the expense of motor neurons and also impedes generation of oligodendrocyte precursor cells (OPCs), three cell types that depend on Shh for their generation. We provide evidence that Sulf2a, expressed in a spatially restricted progenitor domain, acts by maintaining the correct patterning and specification of ventral progenitors. More specifically, Sulf2a prevents Olig2 progenitors to activate high-threshold Shh response and, thereby, to adopt a V3 interneuron fate, thus ensuring proper production of motor neurons and OPCs. We propose a model in which Sulf2a reduces Shh signalling levels in responding cells by decreasing their sensitivity to the morphogen factor. More generally, our work, revealing that, in contrast to its paralog Sulf1, Sulf2a regulates neural fate specification in Shh target cells, provides direct evidence of non-redundant functions of Sulfs in the developing spinal cord.
Temperature compensation design and experiment for a giant magnetostrictive actuator
Authors: Zhao Zhangrong , Sui Xiaomei
Published: January 2021

Because the performance of giant magnetostrictive materials (GMMs) can vary at different temperatures, the positioning accuracy of a giant magnetostrictive actuator is affected by heat. In this work, a new simplified control strategy under compulsory water cooling is proposed to maintain a constant GMM temperature. Based on this strategy, a coupled turbulent flow field and temperature field finite element model is created for a GMM smart component. The model is simulated using COMSOL Multiphysics software version 5.3. Through simulations, the temperature field distribution of GMM smart components is analysed under different drive input currents and cooling water flow rates. Based on the obtained simulation results, a GMM intelligent component temperature control device is constructed. The experimental results are in good agreement with the simulation results; a thermostatic control effect is achieved in the thermostat of the giant magnetostrictive rod. Thus, the proposed temperature control strategy is proven effective via simulations and experiments.
Preclinical safety and immunogenicity of Streptococcus pyogenes (Strep A) peptide vaccines
Authors: Reynolds Simone , Pandey Manisha , Dooley Jessica , Calcutt Ainslie , Batzloff Michael , Ozberk Victoria , Mills Jamie-Lee , Good Michael
Published: January 2021

We have developed two candidate vaccines to protect against multiple strains of Strep A infections. The candidates are combinatorial synthetic peptide vaccines composed of a M protein epitope (J8 or p*17) and a non-M protein epitope (K4S2). To enhance immunogenicity, each peptide is conjugated to the carrier protein CRM197 (CRM) and formulated with aluminium hydroxide adjuvant Alhydrogel (Alum) to make the final vaccines, J8-CRM + K4S2-CRM/Alum and p*17-CRM + K4S2-CRM/Alum. The safety and toxicity of each vaccine was assessed. Sprague Dawley rats were administered three intramuscular doses, over a six-week study with a 4-week recovery period. A control group received CRM only formulated with Alum (CRM/Alum). There was no evidence of systemic toxicity in the rats administered either vaccine. There was an associated increase in white blood cell, lymphocyte and monocyte counts, increased adrenal gland weights, adrenocortical hypertrophy, and increased severity of granulomatous inflammation at the sites of injection and the associated inguinal lymph nodes. These changes were considered non-adverse. All rats administered vaccine developed a robust and sustained immunological response. The absence of clinical toxicity and the development of an immunological response in the rats suggests that the vaccines are safe for use in a phase 1 clinical trial in healthy humans.
Seasonal variability of the vitamin D effect on physical fitness in adolescents
Authors: Milani Gregorio P. , Simonetti Giacomo D. , Edefonti Valeria , Lava Sebastiano A. G. , Agostoni Carlo , Curti Maurus , Stettbacher Andreas , Bianchetti Mario G. , Muggli Franco
Published: January 2021

Studies investigating the relationship between vitamin D and physical fitness in youth have provided inconsistent findings. Recent evidence indicates that the expression of receptors and vitamin D-modulated genes in young subjects has a seasonal profile. Therefore, we investigated the role of vitamin D on physical fitness across seasons in a total of 977 male adolescents. Anthropometrics, lifestyle, dietary habits, biochemical profiles and physical fitness were studied. Multiple linear regression models, including pairwise interaction terms involving total 25-OH-vitamin D, were fitted. The interacting effect of season and total 25-OH-vitamin D had a significant influence on physical fitness performance (spring and total 25-OH-vitamin D: ß 0.19, SE 0.07, p = 0.007; summer and total 25-OH-vitamin D: ß 0.10, SE 0.06, p = 0.11; autumn and total 25-OH-vitamin D: ß 0.18, SE 0.07, p = 0.01), whereas the main effect of total 25-OH-vitamin D alone was not significant (p = 0.30). Body fat percentage, recreational physical activity level, time spent per day gaming/TV-watching, smoking, and hemoglobin levels were also related to the physical fitness performance score. Future studies should further explore the role of seasonal-dependent effects of vitamin D on health.
Usefulness of selective arterial calcium injection tests for functional pancreatic neuroendocrine tumors
Authors: Nakano Yutaka , Kitago Minoru , Shinoda Masahiro , Nakatsuka Seishi , Kurihara Isao , Yagi Hiroshi , Abe Yuta , Oshima Go , Hori Shutaro , Yokose Takahiro , Kitagawa Yuko
Published: January 2021

The selective arterial calcium injection (SACI) test is useful for patients with functional pancreatic neuroendocrine tumors (F-PNETs). This study evaluated which patients with F-PNETs would benefit from the SACI test. We retrospectively analyzed the preoperative findings of patients on computed tomography (CT), magnetic resonance imaging (MRI), CT angiography (CTA), and the SACI test. Fourteen patients who underwent pancreatectomy between January 1997 and September 2016 for F-PNETs were evaluated. We classified these patients into groups A, B, and C; group A, one tumor detected by either CT or MRI; group B, multiple tumors detected; and group C, the tumor location was accordant on CT, MRI, and CTA, but the SACI test revealed another tumor. In group A, the tumor was also detected by CTA and the SACI test was positive on calcium injection. In group B, the focus tumor among the multiple tumors was detected by the SACI test. In group C, another tumor was identified by the SACI test, whose location was different from that detected using CT and MRI. The SACI test is more useful for multiple F-PNETs on CT or MRI. If CT or MRI detects a single tumor, the SACI test or CTA may be unnecessary.
First reported quantitative microbiota in different livestock manures used as organic fertilizers in the Northeast of Thailand
Authors: Wongsaroj Lampet , Chanabun Ratmanee , Tunsakul Naruemon , Prombutara Pinidphon , Panha Somsak , Somboonna Naraporn
Published: January 2021

Northeastern Thailand relies on agriculture as a major economic activity, and has used high levels of agrochemicals due to low facility, and salty sandy soil. To support soil recovery and sustainable agriculture, local farmers have used organic fertilizers from farmed animal feces. However, knowledge about these animal fecal manures remains minimal restricting their optimal use. Specifically, while bacteria are important for soil and plant growth, an abundance and a diversity of bacterial composition in these animal fecal manures have not been reported to allow selection and adjustment for a more effective organic fertilizer. This study thereby utilized metagenomics combined with 16S rRNA gene quantitative PCR (qPCR) and sequencing to analyze quantitative microbiota profiles in association with nutrients (N, P, K), organic matters, and the other physiochemical properties, of the commonly used earthworm manure and other manures from livestock animals (including breed and feeding diet variations) in the region. Unlike the other manures, the earthworm manure demonstrated more favorable nutrient profiles and physiochemical properties for forming fertile soil. Despite low total microbial biomass, the microbiota were enriched with maximal OTUs and Chao richness, and no plant pathogenic bacteria were found based on the VFDB database. The microbial metabolic potentials supported functions to promote crop growth, such as C, N and P cyclings, xenobiotic degradation, and synthesis of bioactive compounds. Pearson’s correlation analyses indicated that the quantitative microbiota of the earthworm manure were clustered in the same direction as N, and conductivity, salinity, and water content were essential to control the microbiota of animal manures.
Breath biopsy of breast cancer using sensor array signals and machine learning analysis
Authors: Yang Hsiao-Yu , Wang Yi-Chia , Peng Hsin-Yi , Huang Chi-Hsiang
Published: January 2021

Breast cancer causes metabolic alteration, and volatile metabolites in the breath of patients may be used to diagnose breast cancer. The objective of this study was to develop a new breath test for breast cancer by analyzing volatile metabolites in the exhaled breath. We collected alveolar air from breast cancer patients and non-cancer controls and analyzed the volatile metabolites with an electronic nose composed of 32 carbon nanotubes sensors. We used machine learning techniques to build prediction models for breast cancer and its molecular phenotyping. Between July 2016 and June 2018, we enrolled a total of 899 subjects. Using the random forest model, the prediction accuracy of breast cancer in the test set was 91% (95% CI: 0.85–0.95), sensitivity was 86%, specificity was 97%, positive predictive value was 97%, negative predictive value was 97%, the area under the receiver operating curve was 0.99 (95% CI: 0.99–1.00), and the kappa value was 0.83. The leave-one-out cross-validated discrimination accuracy and reliability of molecular phenotyping of breast cancer were 88.5 ± 12.1% and 0.77 ± 0.23, respectively. Breath tests with electronic noses can be applied intraoperatively to discriminate breast cancer and molecular subtype and support the medical staff to choose the best therapeutic decision.
Convolutional autoencoder based model HistoCAE for segmentation of viable tumor regions in liver whole-slide images
Authors: Roy Mousumi , Kong Jun , Kashyap Satyananda , Pastore Vito Paolo , Wang Fusheng , Wong Ken C. L. , Mukherjee Vandana
Published: January 2021

Liver cancer is one of the leading causes of cancer deaths in Asia and Africa. It is caused by the Hepatocellular carcinoma (HCC) in almost 90% of all cases. HCC is a malignant tumor and the most common histological type of the primary liver cancers. The detection and evaluation of viable tumor regions in HCC present an important clinical significance since it is a key step to assess response of chemoradiotherapy and tumor cell proportion in genetic tests. Recent advances in computer vision, digital pathology and microscopy imaging enable automatic histopathology image analysis for cancer diagnosis. In this paper, we present a multi-resolution deep learning model HistoCAE for viable tumor segmentation in whole-slide liver histopathology images. We propose convolutional autoencoder (CAE) based framework with a customized reconstruction loss function for image reconstruction, followed by a classification module to classify each image patch as tumor versus non-tumor. The resulting patch-based prediction results are spatially combined to generate the final segmentation result for each WSI. Additionally, the spatially organized encoded feature map derived from small image patches is used to compress the gigapixel whole-slide images. Our proposed model presents superior performance to other benchmark models with extensive experiments, suggesting its efficacy for viable tumor area segmentation with liver whole-slide images.