Notes

Cardiovascular calculated tomography radiomics: an emerging tool for the non-invasive review of coronary coronary artery disease.
Achromatopsia is an inherited retinal disease characterized by loss of cone photoreceptor function. Day blind CNGA3 mutant Improved Awassi sheep provide a large animal model for achromatopsia. This study measured refractive error and axial length parameters of the eye in this model and evaluated chromatic pupillary light reflex (cPLR) testing as a potential screening test for loss of cone function. Twenty-one CNGA3 mutant, Improved Awassi, 12 control Afec-Assaf and 12 control breed-matched wild-type (WT) Awassi sheep were examined using streak retinoscopy and B-mode ocular ultrasonography. Four CNGA3 mutant and four Afec-Assaf control sheep underwent cPLR testing. Statistical tests showed that day-blind sheep are significantly more myopic than both Afec-Assaf and WT Awassi controls. Day-blind sheep had significantly longer vitreous axial length compared to WT Awassi (1.43 ± 0.13 and 1.23 ± 0.06 cm, respectively, p  less then  0.0002) and no response to bright red light compared to both controls. Lack of response to bright red light is consistent with cone dysfunction, demonstrating that cPLR can be used to diagnose day blindness in sheep. Day-blind sheep were found to exhibit myopia and increased vitreous chamber depth, providing a naturally occurring large animal model of myopia.The negative regulator of RNA polymerase (pol) III mafr-1 has been shown to affect RNA pol III transcript abundance, lipid biosynthesis and storage, progeny output, and lifespan. We deleted mafr-1 from the Caenorhabditis elegans genome and found that animals lacking mafr-1 replicated many phenotypes from previous RNAi-based studies and discovered a new sperm-specific role. Utilizing a yeast two-hybrid assay, we discovered several novel interactors of MAFR-1 that are expressed in a sperm- and germline-enriched manner. In support of a role for MAFR-1 in the male germline, we found mafr-1 null males have smaller spermatids that are less capable in competition for fertilization; a phenotype that was dependent on RNA pol III activity. Restoration of MAFR-1 expression specifically in the germline rescued the spermatid-related phenotypes, suggesting a cell autonomous role for MAFR-1 in nematode male fertility. Based on the high degree of conservation of Maf1 activity across species, our study may inform similar roles for Maf1 and RNA pol III in mammalian male fertility.An amendment to this paper has been published and can be accessed via a link at the top of the paper.We hypothesized that, in discrimination between benign and malignant parotid gland tumors, high diagnostic accuracy could be obtained with a small amount of imbalanced data when anomaly detection (AD) was combined with deep leaning (DL) model and the L2-constrained softmax loss. The purpose of this study was to evaluate whether the proposed method was more accurate than other commonly used DL or AD methods. Magnetic resonance (MR) images of 245 parotid tumors (22.5% malignant) were retrospectively collected. We evaluated the diagnostic accuracy of the proposed method (VGG16-based DL and AD) and that of classification models using conventional DL and AD methods. A radiologist also evaluated the MR images. ROC and precision-recall (PR) analyses were performed, and the area under the curve (AUC) was calculated. In terms of diagnostic performance, the VGG16-based model with the L2-constrained softmax loss and AD (local outlier factor) outperformed conventional DL and AD methods and a radiologist (ROC-AUC = 0.86 and PR-ROC = 0.77). The proposed method could discriminate between benign and malignant parotid tumors in MR images even when only a small amount of data with imbalanced distribution is available.Matter under different equilibrium conditions of pressure and temperature exhibits different states such as solid, liquid, gas, and plasma. Exotic states of matter, such as Bose-Einstein condensates, superfluidity, chiral magnets, superconductivity, and liquid crystalline blue phases are observed in thermodynamic equilibrium. Rather than being a result of an aggregation of matter, their emergence is due to a change of a topological state of the system. These topological states can persist out of thermodynamics equilibrium. Here we investigate topological states of matter in a system with injection and dissipation of energy by means of oscillatory forcing. In an experiment involving a liquid crystal cell under the influence of a low-frequency oscillatory electric field, we observe a transition from a non-vortex state to a state in which vortices persist, topological transition. Depending on the period and the type of the forcing, the vortices self-organise, forming square lattices, glassy states, and disordered vortex structures. The bifurcation diagram is characterised experimentally. A continuous topological transition is observed for the sawtooth and square forcings. The scenario changes dramatically for sinusoidal forcing where the topological transition is discontinuous, which is accompanied by serial transitions between square and glassy vortex lattices. Based on a stochastic amplitude equation, we recognise the origin of the transition as the balance between stochastic creation and deterministic annihilation of vortices. Numerical simulations show topological transitions and the emergence of square vortex lattice. Our results show that the matter maintained out of equilibrium by means of the temporal modulation of parameters can exhibit exotic states.Compartmental transmission models have become an invaluable tool to study the dynamics of infectious diseases. The Susceptible-Infectious-Recovered (SIR) model is known to have an exact semi-analytical solution. In the current study, the approach of Harko et al. (Appl. Math. Comput. 236184-194, 2014) is generalised to obtain an approximate semi-analytical solution of the Susceptible-Exposed-Infectious-Recovered (SEIR) model. The SEIR model curves have nearly the same shapes as the SIR ones, but with a stretch factor applied to them across time that is related to the ratio of the incubation to infectious periods. This finding implies an approximate characteristic timescale, scaled by this stretch factor, that is universal to all SEIR models, which only depends on the basic reproduction number and initial fraction of the population that is infectious.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an "exhaustion-resistant" phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value  less then  6e-08 and 22.9% increase, p value  less then  5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.Recently, flood risk assessments have been extended to national and continental scales. Most of these assessments assume homogeneous scenarios, i.e. the regional risk estimate is obtained by summing up the local estimates, whereas each local damage value has the same probability of exceedance. This homogeneity assumption ignores the spatial variability in the flood generation processes. Here, we develop a multi-site, extreme value statistical model for 379 catchments across Europe, generate synthetic flood time series which consider the spatial correlation between flood peaks in all catchments, and compute corresponding economic damages. We find that the homogeneity assumption overestimates the 200-year flood damage, a benchmark indicator for the insurance industry, by 139%, 188% and 246% for the United Kingdom (UK), Germany and Europe, respectively. Our study demonstrates the importance of considering the spatial dependence patterns, particularly of extremes, in large-scale risk assessments.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Automatic remote reflectance spectral imaging of large painted areas in high resolution, from distances of tens of meters, has made the imaging of entire architectural interior feasible. However, it has significantly increased the volume of data. Here we present a machine learning based method to automatically detect 'hidden' writings and map material variations. Clustering of reflectance spectra allowed materials at inaccessible heights to be properly identified by performing non-invasive analysis on regions in the same cluster at accessible heights using a range of complementary spectroscopic techniques. The world heritage site of the Mogao caves, along the ancient Silk Road, consists of 492 richly painted Buddhist cave temples dating from the fourth to fourteenth century. Cave 465 at the northern end of the site is unique in its Indo-Tibetan tantric Buddhist style, and like many other caves, the date of its construction is still under debate. This study demonstrates the powers of an interdisciplinary approach that combines material identification, palaeographic analysis of the revealed Sanskrit writings and archaeological evidence for the dating of the cave temple paintings, narrowing it down to the late twelfth century to thirteenth century.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The evidence supporting an initial mycophenolate mofetil (MMF) dose of 2 g daily in tacrolimus-treated renal transplant recipients is limited. In a non-contemporaneous single-centre cohort study we compared the incidence of leukopaenia, rejection and graft dysfunction in patients initiated on MMF 1.5 g and 2 g daily. Baseline characteristics and tacrolimus trough levels were similar by MMF group. MMF doses became equivalent between groups by 12-months post-transplant, driven by dose reductions in the 2 g group. Leukopaenia occurred in 42.4% of patients by 12-months post-transplant. MMF 2 g was associated with a 1.80-fold increased risk of leukopaenia compared to 1.5 g. Rejection occurred in 44.8% of patients by 12-months post-transplantation. MMF 2 g was associated with half the risk of rejection relative to MMF 1.5 g. Over the first 7-years post-transplantation there was no difference in renal function between groups. Additionally, the development of leukopaenia or rejection did not result in reduced renal function at 7-years post-transplant. Leukopaenia was not associated with an increased incidence of serious infections or rejection. This study demonstrates the initial MMF dose has implications for the incidence of leukopaenia and rejection. Since neither dose produced superior long-term graft function, clinical equipoise remains regarding the optimal initial mycophenolate dose in tacrolimus-treated renal transplant recipients.Patients with mono-lateral pneumonia and severe respiratory failure can be positioned in lateral decubitus, with the healthy lung dependent, to improve ventilation-perfusion coupling. Oxygenation response to this manoeuvre is heterogeneous and derecruitment of dependent lung has not been elucidated. Nine pigs (32.2 ± 1.2 kg) were sedated and mechanically ventilated. Mono-lateral right-sided pneumonia was induced with intrabronchial challenge of Pseudomonas aeruginosa. After 24 h, lungs were recruited and the animals were randomly positioned on right or left side. After 3 h of lateral positioning, the animals were placed supine; another recruitment manoeuvre was performed, and the effects of contralateral decubitus were assessed. Primary outcome was lung ultrasound score (LUS) of the dependent lung after 3-h lateral positioning. LUS of the left non-infected lung worsened while positioned in left-lateral position (from 1.33 ± 1.73 at baseline to 6.78 ± 4.49; p = 0.005). LUS of the right-infected lung improved when placed upward (9.22 ± 2.73 to 6.67 ± 3.24; p = 0.09), but worsened in right-lateral position (7.78 ± 2.86 to 13.33 ± 3.08; p  less then  0.001). PaO2/FiO2 improved in the left-lateral position (p = 0.005). In an animal model of right-lung pneumonia, left-lateral decubitus improved oxygenation, but collapsed the healthy lung. Right-lateral orientation further collapsed the diseased lung. Our data raise potential clinical concerns for the use of lateral position in mono-lateral pneumonia.A longstanding focus of perceptual learning research is learning specificity, the difficulty for learning to transfer to tasks and situations beyond the training setting. Previous studies have focused on promoting transfer across stimuli, such as from one sound frequency to another. Here we examined whether learning could transfer across tasks, particularly from fine discrimination of sound features to speech perception in noise, one of the most frequently encountered perceptual challenges in real life. Separate groups of normal-hearing listeners were trained on auditory interaural level difference (ILD) discrimination, interaural time difference (ITD) discrimination, and fundamental frequency (F0) discrimination with non-speech stimuli delivered through headphones. While ITD training led to no improvement, both ILD and F0 training produced learning as well as transfer to speech-in-noise perception when noise differed from speech in the trained feature. These training benefits did not require similarity of task or stimuli between training and application settings, construing far and wide transfer. Thus, notwithstanding task specificity among basic perceptual skills such as discrimination of different sound features, auditory learning appears readily transferable between these skills and their "upstream" tasks utilizing them, providing an effective approach to improving performance in challenging situations or challenged populations.Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells.Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Baloch population possesses low activity genotypes. The frequencies found in various ethnic groups in Pakistan were comparable with ethnicities in the South Asian region except for the Baloch population. These results suggest that pharmacogenetics screening for low activity genotypes may be a helpful tool for clinicians while prescribing medications metabolized by CYP2C9.Metabolic rate is intricately linked to the ecology of organisms and can provide a framework to study the behaviour, life history, population dynamics, and trophic impact of a species. Acquiring measures of metabolic rate, however, has proven difficult for large water-breathing animals such as sharks, greatly limiting our understanding of the energetic lives of these highly threatened and ecologically important fish. Here, we provide the first estimates of resting and active routine metabolic rate for the longest lived vertebrate, the Greenland shark (Somniosus microcephalus). Estimates were acquired through field respirometry conducted on relatively large-bodied sharks (33-126 kg), including the largest individual shark studied via respirometry. We show that despite recording very low whole-animal resting metabolic rates for this species, estimates are within the confidence intervals predicted by derived interspecies allometric and temperature scaling relationships, suggesting this species may not be unique among sharks in this respect. Additionally, our results do not support the theory of metabolic cold adaptation which assumes that polar species maintain elevated metabolic rates to cope with the challenges of life at extreme cold temperatures.Previous meta-analyses of intervention studies have come to different conclusions about effects of consumption of low-calorie sweeteners (LCS) on body weight. The present review included 60 articles reporting 88 parallel-groups and cross-over studies ≥1 week in duration that reported either body weight (BW), BMI and/or energy intake (EI) outcomes. Studies were analysed according to whether they compared (1) LCS with sugar, (2) LCS with water or nothing, or (3) LCS capsules with placebo capsules. Results showed an effect in favour of LCS vs sugar for BW (29 parallel-groups studies, 2267 participants BW change, -1.06 kg, 95% CI -1.50 to -0.62, I2 = 51%), BMI and EI. Effect on BW change increased with 'dose' of sugar replaced by LCS, whereas there were no differences in study outcome as a function of duration of the intervention or participant blinding. Overall, results showed no difference in effects of LCS vs water/nothing for BW (11 parallel-groups studies, 1068 participants BW change, 0.10 kg, 95% CI -0.87 to 1.07, I2 = 82%), BMI and EI; and inconsistent effects for LCS consumed in capsules (BW change -0.28 kg, 95% CI -0.80 to 0.25, I2 = 0%; BMI change 0.20 kg/m2, 95% CI 0.04 to 0.36, I2 = 0%). Occurrence of adverse events was not affected by the consumption of LCS. The studies available did not permit robust analysis of effects by LCS type. In summary, outcomes were not clearly affected when the treatments differed in sweetness, nor when LCS were consumed in capsules without tasting; however, when treatments differed in energy value (LCS vs sugar), there were consistent effects in favour of LCS. The evidence from human intervention studies supports the use of LCS in weight management, constrained primarily by the amount of added sugar that LCS can displace in the diet.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The aim of the research has been to determine the role of phenolic compounds in the processes of transformations of organic matter in meadow soils, leading to the formation of humic substances. The research has been performed based on the plant material and soil sampled from Europe's unique complex of permanent grasslands irrigated continuously for 150 years applying the slope-and-flooding system, the Czerskie Meadows. Phenolic compounds were isolated from the plant material samples (hay, sward and roots) and soils (horizon A, AE and Bsv) and from the fraction of humic and fulvic acids. It was found that the contents of phenolic compounds decrease in the following order hay > sward > roots > A horizon soil > AE horizon soil > Bsv horizon soil > A horizon fulvic acids > AE horizon fulvic acids > Bsv horizon fulvic acids > A horizon fulvic acids > AE horizon fulvic acids > Bsv horizon fulvic acids. A significantly higher share of cinnamyl than vanillyl and syringyl compounds in the extracts of fulvic acids and slightly higher in the hydrolysates of humic acids confirms the effect of the chemical composition of the plant material undergoing decomposition on the properties of the emerging humic substances.While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.It is argued that elite athletes often demonstrate superior body balance. Despite the apparent significance of perfect balance ability in volleyball, little is known about the specific nature of postural control adjustments among first-rate volleyball competitors. This study compared postural performance and strategies in quiet stance between world vice-champions and young, healthy, physically active male subjects. The center-of-pressure (COP) signals recorded on a force plate were used to compute several measures of sway. In both axes of movement, athletes had lower COP range, but not its standard deviation and higher COP speed and frequency than controls. These findings indicate that postural regulation in athletes was more precise and less vulnerable to external disturbances which support optimal timing and precision of actions. Postural strategies in athletes standing quietly were similar to those exhibited by non-athletes performing dual tasks. It demonstrates a significant effect of sport practice on changes in postural control. In anterior-posterior axis, athletes displayed a much higher COP fractal dimension and surprisingly lower COP-COG frequency than controls. This accounts for their high capacity to use diversified postural strategies to maintain postural stability and significantly reduced the contribution of proprioception to save this function for carrying out more challenging posture-motor tasks.In many resonant structures the damping of parasitic or higher order modes is indispensable to guarantee a correct and stable performance. This is particularly true in the microwave region in case of cavities or other resonant systems operating in accelerating structures, where the mitigation of spurious resonance effects is mandatory to achieve high quality particle beams. We present the results on the mode suppression in a real pillbox cavity by inserting a properly designed pyramidal metamaterial that acts as light, small volume damper for specific resonances in the range 3-4 GHz, only slightly perturbing other intrinsic modes. Measurements of the cavity response without and with the metamaterial absorber are presented and compared with full wave simulations. Field distribution for the pillbox intrinsic modes under scrutiny is also presented, showing that damping induced by the metamaterial critically depends on its relative position inside the cavity.As an energy-sensitive post-translational modification, O-GlcNAcylation plays a major role in endothelial nitric oxide synthase (eNOS) activity regulation. However, effects of glucose deprivation on eNOS O-GlcNAcylation and the presence of novel O-GlcNAcylation sites of eNOS under glucose deprivation remain unknown. Hence, we aim to determine the effects of glucose deprivation on O-GlcNAcylation and novel O-GlcNAcylation sites of eNOS. Bovine aortic endothelial cells (BAECs) and Sprague-Dawley rats were induced by glucose deprivation and their eNOS O-GlcNAcylation was subjected to immunoblotting. eNOS and transfected eNOS were purified by pull-down assay and immunoprecipitation respectively. Novel O-GlcNAcylation sites of eNOS were predicted by HPLC-MS and MS/MS Ion and determined by immunoblotting. eNOS activity was detected by Elisa and isotope labeling method. In BAECs and rat thoracic aorta, low glucose-associated activation of eNOS was accompanied by elevated O-GlcNAcylation, which did not affect O-linken and activity of eNOS, potentially by the AMPK-OGT pathway, suggesting that Thr866 is a novel O-GlcNAcylation site involved in glucose-deprivation mediated eNOS activation.New treatments for oropharyngeal gonorrhoea are required to address rising antimicrobial resistance. We aimed to examine the efficacy of a 14-day course of mouthwash twice daily compared to standard treatment (antibiotic) for the treatment of oropharyngeal gonorrhoea. The OMEGA2 trial was a parallel-group and open-labelled randomised controlled trial among men with untreated oropharyngeal gonorrhoea that was conducted between September 2018 and February 2020 at Melbourne Sexual Health Centre in Australia. Men were randomised to the intervention (rinsing, gargling and spraying mouthwash twice daily for 14 days) or control (standard treatment) arm and followed for 28 days. Participants in both arms were advised to abstain from sex and kissing with anyone for 14 days after enrolment. Oropharyngeal swabs were collected at baseline, Day 14 and Day 28 and tested for Neisseria gonorrhoeae by nucleic acid amplification test (NAAT) and culture. The primary outcome was the detection of oropharyngeal N. gonorrhoeae by NAAT at Day 14 after treatment. This trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12618001380280). This trial stopped early due to a high failure rate in the mouthwash arm. Twelve men were randomly assigned to either mouthwash (n = 6) or standard treatment (n = 6). Of the 11 men who returned at Day 14, the cure rate for oropharyngeal gonorrhoea in the mouthwash arm was 20% (95% CI 1-72%; 1/5) and in the standard treatment arm was 100% (95% CI 54-100%; 6/6). A 14-day course of mouthwash failed to cure a high proportion of oropharyngeal gonorrhoea cases.Superimposition of 3D maxillary digital dental models of different time points based on palatal vault region has been used to evaluate tooth movement during orthodontic treatment. This study evaluated the accuracy and reliability of 3D maxillary digital model (MDM) superimposition in adults by comparing it with CBCT maxillary superimposition. In CBCT maxillary superimposition, voxel-based superimposition was firstly conducted, and MDMs were matched with corresponding CBCT models (CBCT-MDM superimposition). MDM superimposition (palatal vault regional superimposition) were performed on another pair of pre- and posttreatment MDMs. The position and orientation of upper first molars (U6s) and upper central incisors (U1s) on the posttreatment MDMs were compared to assess the accuracy of the MDM superimposition methods. The reliability was validated in both MDM superimposition and CBCT maxillary superimposition. In terms of accuracy, the average linear deviations in U6 and U1 positions were less than ± 0.3 mm, the average angular deviations of U6s and U1s were less than ± 0.2°, both have no significant difference from zero. The ICCs for MDM superimposition ranged from 0.85 to 0.99. The ICCs for CBCT-MDM superimposition were larger than 0.99 in all items. MDM superimposition was an efficient, accurate and reliable method for evaluating teeth movement in adults, although its reliability is slightly lower than CBCT maxillary superimposition.A vaccine for smallpox is no longer administered to the general public, and there is no proven, safe treatment specific to poxvirus infections, leaving people susceptible to infections by smallpox and other zoonotic Orthopoxviruses such as monkeypox. Using vaccinia virus (VACV) as a model organism for other Orthopoxviruses, CRISPR-Cas9 technology was used to target three essential genes that are conserved across the genus, including A17L, E3L, and I2L. Three individual single guide RNAs (sgRNAs) were designed per gene to facilitate redundancy in rendering the genes inactive, thereby reducing the reproduction of the virus. The efficacy of the CRISPR targets was tested by transfecting human embryonic kidney (HEK293) cells with plasmids encoding both SaCas9 and an individual sgRNA. This resulted in a reduction of VACV titer by up to 93.19% per target. Following the verification of CRISPR targets, safe and targeted delivery of the VACV CRISPR antivirals was tested using adeno-associated virus (AAV) as a packaging vector for both SaCas9 and sgRNA. Similarly, AAV delivery of the CRISPR antivirals resulted in a reduction of viral titer by up to 92.97% for an individual target. Overall, we have identified highly specific CRISPR targets that significantly reduce VACV titer as well as an appropriate vector for delivering these CRISPR antiviral components to host cells in vitro.Urinary tract infection (UTI) is one of the most common bacterial infections in children. The symptoms of UTI in young children are nonspecific, therefore urine should be examined whenever UTI cannot be ruled out. In clinical settings, however, collecting urine from children who are not toilet trained is sometimes difficult, presenting a challenge in UTI management. Here, we developed a "diaper UTI test", which enables the quick detection of pyuria in ordinary diapers, and investigated its sensitivity and specificity in a clinical study. The diaper UTI test is based on a leukocyte esterase reaction. Reagent was prepared in liquid form so that it can be absorbed by disposable diapers, where it will produce a violet color in the presence of pyuria. For the clinical study, we enrolled children younger than 3 years with potential UTI who underwent bladder catheterization for urine culture and urinalysis. Of the 65 children included, 21 were diagnosed with UTI. The sensitivity and specificity of the diaper UTI test were 90.5% (95% CI 69.6-98.8) and 93.2% (95% CI 81.3-98.6), respectively. Because of its convenience and good sensitivity, the diaper UTI test may be useful in the screening of pediatric UTI.This paper aims to calculate a relevance model of visual limitation (V.L.) in keratoconus patients based on refractive and topographic parameters. A cross-sectional study was carried out in Torrecárdenas Hospital, Almería, Spain, between February 2018 and July 2019. It included 250 keratoconus patients. Two groups were created according to a grading system of V.L. based on RETICS (Red Temática de Investigación Cooperativa en Salud) classification keratoconus patients with no V.L. (best spectacle-corrected visual acuity (BSCVA) ≤ 0.05 logMAR) and keratoconus patients with V.L. (BSCVA > 0.05 logMAR). Correlations and a binary logistic regression were established. V.L. was correlated with maximum curvature (r = 0.649, p  less then  0.001) and root mean square higher-order aberrations (HOARMS) (r = 0.625, p  less then  0.001). Binary logistic regression included V.L. as the dependent variable and spherical equivalent, HOARMS, spherical aberration and interaction between the anterior and posterior vertical coma as independent variables. The model was a good fit. Area under the curve (A.U.C.) of receiver operating characteristic (R.O.C.) curve was 0.924, sensitivity 91.90%, specificity 83.60%, accuracy 88.94%; and precision 91.17%. Binary logistic regression model of V.L. is a good fit model to predict the early loss of visual acuity in keratoconus patients.Longitudinal inhomogeneity of tracks inscribed in a YAG crystal and the statistics of nonlinear transmittance of the writing beam is studied under conditions of direct femtosecond laser writing in non-thermal mode. Nonlinear transmittance fluctuations inherent in the laser writing were discovered, and their correlation with track inhomogeneity is established. A model of femtosecond laser writing in crystals is built that includes three modes of plastic deformation in the laser impact zone. The modification threshold of the femtosecond direct laser writing is identified with reaching yield stress.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Mass spectrometry enhanced by nanotechnology can achieve previously unattainable sensitivity for characterizing urinary pathogen-derived peptides. We utilized mass spectrometry enhanced by affinity hydrogel particles (analytical sensitivity = 2.5 pg/mL) to study tick pathogen-specific proteins shed in the urine of patients with (1) erythema migrans rash and acute symptoms, (2) post treatment Lyme disease syndrome (PTLDS), and (3) clinical suspicion of tick-borne illnesses (TBI). Targeted pathogens were Borrelia, Babesia, Anaplasma, Rickettsia, Ehrlichia, Bartonella, Francisella, Powassan virus, tick-borne encephalitis virus, and Colorado tick fever virus. Specificity was defined by 100% amino acid sequence identity with tick-borne pathogen proteins, evolutionary taxonomic verification for related pathogens, and no identity with human or other organisms. Using a cut off of two pathogen peptides, 9/10 acute Lyme Borreliosis patients resulted positive, while we identified zero false positive in 250 controls. Two or more pathogen peptides were identified in 40% of samples from PTLDS and TBI patients (categories 2 and 3 above, n = 59/148). Collectively, 279 distinct unique tick-borne pathogen derived peptides were identified. The number of pathogen specific peptides was directly correlated with presence or absence of symptoms reported by patients (ordinal regression pseudo-R2 = 0.392, p = 0.010). Enhanced mass spectrometry is a new tool for studying tick-borne pathogen infections.Common or European hedgehogs can be found throughout Western Europe. They are known carriers of a variety of parasitic and bacterial pathogens, and have also been shown to carry several viruses, including morbilli-like paramyxoviruses, although the pathogenic and zoonotic potential of some of these viruses has yet to be determined. We report here the discovery of a novel paramyxovirus in Belgian hedgehogs, named Belerina virus. The virus was detected by nanopore sequencing of RNA isolated from hedgehog tissue. Out of 147 animals screened in this study, 57 tested positive for Belerina virus (39%), indicating a high prevalence of this virus in the Belgian hedgehog population. Based on its divergence from other known paramyxovirus species, Belerina virus is thought to represent a new species in the family Paramyxoviridae. Phylogenetic analysis groups Belerina virus together with the bat-borne Shaan virus within the genus Jeilongvirus, although expanding the tree with partial genomes shows Belerina virus forming a separate subclade within this genus, alongside a yet-unnamed paramyxovirus isolated from a greater tube-nosed bat. In summary, we discuss the complete genome sequence of Belerina virus, a putative new paramyxovirus species commonly found in Belgian hedgehogs.This study investigated herpes simplex virus type 2 (HSV-2) seroprevalence utility as a predictor of HIV epidemic potential among female sex workers (FSWs) globally. We updated and analyzed a systematically-assembled database for paired HSV-2 and HIV seroprevalence measures among FSWs. The study identified 231 paired HSV-2/HIV prevalence measures from 40 countries. The pooled mean HIV prevalence using meta-analysis increased from 3.7% (95% CI 0.3-9.9%) among populations of FSWs with HSV-2 prevalence  65% of HIV prevalence variation, and identified a strong positive HSV-2/HIV association. Compared to populations of FSWs with HSV-2 prevalence  less then  25%, adjusted odds ratios (AORs) of HIV infection increased from 2.8 (95% CI 1.2-6.3) in those with HSV-2 prevalence 25-49%, to 13.4 (95% CI 6.1-29.9) in those with HSV-2 prevalence 75-100%. HSV-2 is a strong predictor of HIV epidemic potential among FSWs. HSV-2 prevalence of 25-49% indicates potential for intermediate-intensity HIV epidemics, with higher levels indicative of large epidemics. HSV-2 surveillance could inform HIV preparedness in countries where HIV prevalence among FSWs is still limited or at zero-level.Previous research has shown that exposure to volatile anesthetics can induce acute neuroinflammation and neuroapoptopsis in neonatal rodents and that these events can lead to cognitive dysfunction at later stages. Isoflurane and sevoflurane are two of the most popular anesthetics used in the field of pediatrics. However, the relative impact of these two anesthetics on the developing brain at distinct time points after the induction of anesthesia has not been compared. In the present study, we exposed 7-day-old mice to clinically equivalent doses of isoflurane (1.5%) and sevoflurane (2.5%) for 4 h and then investigated consequential changes in the brains of these mice at six different time points. We analyzed the levels of proteins that are directly related to neuroapoptosis, neuroinflammation, synaptic function, and memory, in the brains of neonatal mice. Exposure of neonatal mice to isoflurane and sevoflurane resulted in acute neuronal apoptosis. Our analysis observed significant levels of neuroinflammation and changes in the expression levels of proteins associated with both synaptic transmission and memory in mice from the isoflurane group but not the sevoflurane group. Our results therefore indicate that isoflurane and sevoflurane induce differential effects in the brains of neonatal mice.To prevent the electromagnetic (EM) wakefields excitation, protect detectors from damage at a range of installations and facilities including particle accelerators the EM field control is required. Conductive foils or wires providing EM protection and required thermal and mechanical properties are normally used. We suggest novel composite materials with uniquely designed frequency selective conductivity enabling them to overcome the properties of the conventional materials, protect from EM fields and supress undesirable phenomena. Theoretical and experimental investigations are carried out and the conductivity of designed and composite (dual-layer) aluminium/graphene metamaterials as well as graphene and aluminium foils is studied. The EM properties of these materials are compared, and conditions of full and partial electromagnetic transparency are discussed. Results observed allow engineering materials capable of EM field control, instability suppression including those observed in high-intensity particle accelerators and enabling control of an EM field generating media including relativistic charge particle beams.Dust repelling from transparent polyvinyl chloride film surface via sonic excitation is examined and dynamics of repelled (inflight) dust particles are analyzed. An experimental rig is designed and built to assess the vibrational characteristics of the polyvinyl chloride film at different frequencies of sonic excitation. A high speed recording system and tracking program are utilized monitoring and evaluating the dynamics of the inflight particles. The dynamics of inflight particles are also simulated numerically and the predictions are compared with those of the experimental data. In order to examine the influence of dust particle adhesion on the dynamics of the inflight particles, the polyvinyl chloride film surface is hydrophobized through dip coating by functionalized nano-silica particles. Improvement of the optical transmittance of the dust mitigated film is determined via outdoor tests. The findings demonstrate that sonic excitation repels the particles from the film surface and it is more pronounced at 64 Hz excitation frequency while demonstrating that sonic excitation can be used for dust removal from transparent surfaces. The mitigation via sonic excitation improves the optical transmittance of the dusty surface by 77%, which becomes more apparent for hydrophobic surfaces.Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.The association between habitual intake of the "dietary approaches to stop hypertension" (DASH) eating plan and sarcopenia has received limited attention. The present study aimed to investigate the association between adherence to DASH dietary pattern and sarcopenia and its components including muscle mass, muscle strength, and muscle performance among community-dwelling older adults population. This population-based cross-sectional study was performed in 2011 among 300 older people (150 men and 150 women) aged ≥ 55 years, who were selected using cluster random sampling method. Dietary intake of study participants were examined by the use of a Block-format 117-item food frequency questionnaire (FFQ). The DASH score was constructed based on eight main foods and nutrients emphasized or minimized in the DASH diet. All components of sarcopenia was measured using standard protocols and sarcopenia was defined based on both former and new European Working Group on Sarcopenia in Older People (EWGSOP) guidelines. Mean age and BMI of study participants were 66.7 ± 7.7 years and 27.3 ± 4.2 kg/m2, respectively. Totally, 31 individuals meet the criteria of EWGSOP2-sarcopenia. We found no significant association between adherence to the DASH diet and EWGSOP2-sarcopenia either before (OR 1.08; 95% CI 0.45-2.54) or after adjustment for potential confounders (OR 1.04; 95% CI 0.39-2.75). The same findings were obtained in the gender-stratified analyses (men OR 2.29; 95% CI 0.39-13.29 and women 0.75; 95% CI 0.23-2.45). In conclusion, we found that adherence to the DASH-style diet was not significantly associated with odds of sarcopenia. Future prospective studies are required to confirm these findings.This project aimed to develop and evaluate a fast and fully-automated deep-learning method applying convolutional neural networks with deep supervision (CNN-DS) for accurate hematoma segmentation and volume quantification in computed tomography (CT) scans. Non-contrast whole-head CT scans of 55 patients with hemorrhagic stroke were used. Individual scans were standardized to 64 axial slices of 128 × 128 voxels. Each voxel was annotated independently by experienced raters, generating a binary label of hematoma versus normal brain tissue based on majority voting. The dataset was split randomly into training (n = 45) and testing (n = 10) subsets. A CNN-DS model was built applying the training data and examined using the testing data. Performance of the CNN-DS solution was compared with three previously established methods. The CNN-DS achieved a Dice coefficient score of 0.84 ± 0.06 and recall of 0.83 ± 0.07, higher than patch-wise U-Net ( 0.82). The fully automated CNN-DS approach demonstrated expert-level accuracy in fast segmentation and quantification of hematoma, substantially improving over previous methods. Further research is warranted to test the CNN-DS solution as a software tool in clinical settings for effective stroke management.Globally, fish populations are in decline from overfishing, habitat destruction and poor water quality. Recent mass fish deaths in Australia's Murray-Darling Basin highlight the need for improved conservation methods for endangered fish species. Cryopreservation of testicular tissue allows storage of early sperm precursor cells for use in generating new individuals via surrogacy. We describe successful isolation and cryopreservation of spermatogonia in an Australian rainbowfish. Testis histology showed rainbowfish spermatogonia are large (> 10 μm) and stain positive for Vasa, an early germ line-specific protein. Using size-based flow cytometry, testis cell suspensions were sorted through "A" (> 9 μm) and "B" gates (2-5 μm); the A gate produced significantly more Vasa-positive cells (45.0% ± 15.2%) than the "B" gate (0.0% ± 0.0%) and an unsorted control (22.9% ± 9.5%, p  9 μm) viability (72.6% ± 10.5%) comprised 1.3 M DMSO, 0.1 M trehalose and 1.5% BSA; cell viability was similar to fresh controls (78.8% ± 10.5%) and significantly better than other cryoprotectants (p  less then  0.0006). We have developed a protocol to cryopreserve rainbowfish testicular tissue and recover an enriched population of viable spermatogonia. This is the first step in developing a biobank of reproductive tissues for this family, and other Australian fish species, in the Australian Frozen Zoo.
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