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We investigated the time courses of saccade rate following visual stimuli during three conditions of free viewing in macaque monkeys. Under all conditions, saccade rate decreased transiently after the onset of visual stimuli. These results suggest that saccadic inhibition occurs during free viewing.

The exotic internal structure of polar topologies in multi-ferroic materials offers a rich landscape for materials science research. As the spatial scale of these entities are often sub-atomic in nature, aberration corrected transmission electron microscopy (TEM) is the ideal characterisation technique. Software to quantify and visualise the slight shifts in atomic placement within unit cells is of paramount importance due to the now routine acquisition of images at such resolution. In the previous ~decade since the commercialisation of aberration corrected TEM, many research groups have written their own code to visualise these polar entities. More recently, open access Python packages have been developed for the purpose of TEM atomic position quantification. Building on these packages, we introduce the TEMUL Toolkit: a Python package for analysis and visualisation of atomic resolution images. Here, we focus specifically on the TopoTEM module of the toolkit where we show an easy to follow, streamlined version of calculating the atomic displacements relative to the surrounding lattice and thus polarisation plotting. We hope this toolkit will benefit the rapidly expanding field of topology based nano-electronic and quantum materials research, and we invite the electron microscopy community to contribute to this open access project., 22 pages, 9 figures

In recent years, atomic resolution imaging of two-dimensional (2D) materials using scanning transmission electron microscopy (STEM) has become routine. Individual dopant atoms in 2D materials can be located and identified using their contrast in annular dark-field (ADF) STEM. However, in order to understand the effect of these dopant atoms on the host material, there is now the need to locate and quantify them on a larger scale. In this work, we analyze STEM images of MoS2 monolayers that have been ion-implanted with chromium at ultra-low energies. We use functions from the open-source TEMUL Toolkit to create and refine an atomic model of an experimental image based on the positions and intensities of the atomic columns in the image. We then use the refined model to determine the likely composition of each atomic site. Surface contamination stemming from the sample preparation of 2D materials can prevent accurate quantitative identification of individual atoms. We disregard atomic sites from regions of the image with hydrocarbon surface contamination to demonstrate that images acquired using contaminated samples can give significant atom statistics from their clean regions, and can be used to calculate the retention rate of the implanted ions within the host lattice. We find that some of the implanted chromium ions have been successfully integrated into the MoS2 lattice, with 4.1% of molybdenum atoms in the transition metal sublattice replaced with chromium.

The CTLH complex is a multi-subunit ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via the substrate receptor GID4. Recently, focus has turned to this complex as a potential mediator of targeted protein degradation, but the role GID4-mediated substrate ubiquitylation and proteasomal degradation plays in humans has thus far remained unclear. Here, we report PFI-7, a potent, selective, and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation enabled the identification of dozens of endogenous GID4-interacting proteins that bind via the GID4 substrate binding pocket, only a subset of which possess canonical Pro/N-degron sequences. GID4 interactors are enriched for nuclear and nucleolar proteins including RNA helicases. GID4 antagonism by PFI-7 altered protein levels of several proteins including RNA helicases as measured by label-free quantitative proteomics, defining proteins that are regulated by GID4 and the CTLH complex in humans. Interactions with GID4 via Pro/N-degron pathway did not result in proteasomal degradation, demonstrating that CTLH interactors are regulated through a combination of degradative and non-degradative functions. The lack of degradation of GID4 interactors highlights potential challenges in utilizing GID4-recruiting bifunctional molecules for targeted protein degradation. Going forward, PFI-7 will be a valuable research tool for defining CTLH complex biology and honing targeted protein degradation strategies.

Purpose: Functional capacity and cardiac function can decline during breast cancer (BC) therapy. In non-cancer populations, higher physical activity (PA) is associated with better physical function and cardiac health. This study compared baseline PA, functional capacity, and cardiac function between women with and without BC and tested if greater PA participation was related to higher functional capacity and/or better heart function after three months of BC therapy. Methods: Data was collected in 104 women without BC (82% Caucasian, baseline only) and 110 women with stage I-III BC (82% Caucasian) before therapy and after three months of treatment. Participants self-reported PA and underwent six-minute walk distance (6MWD) testing to measure functional capacity and cardiovascular magnetic resonance to assess left ventricular ejection fraction (LVEF). Analyses were adjusted for age, race, body mass index (BMI), and medication use. Results: The BC group was older (56.2 ± 10.7 vs 52.1 ± 14.7 yrs, P=0.02) with a higher average BMI than the non-cancer group (30.3 ± 6.8 vs 27.7 ± 6.2 kg/m2, P

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

We developed a biophysically-detailed model of the macaque auditory thalamocortical circuits, including primary auditory cortex (A1), medial geniculate body (MGB) and thalamic reticular nuclei (TRN), using the NEURON simulator and NetPyNE multiscale modeling tool. We simulated A1 as a cortical column with a depth of 2000 μm and 200 μm diameter, containing over 12k neurons and 30M synapses. Neuron densities, laminar locations, classes, morphology and biophysics, and connectivity at the long-range, local and dendritic scale were derived from published experimental data. The A1 model included 6 cortical layers and multiple populations of neurons consisting of 4 excitatory and 4 inhibitory types, and was reciprocally connected to the thalamus (MGB and TRN), mimicking anatomical connectivity. MGB included core and matrix thalamocortical neurons with layer-specific projection patterns to A1, and thalamic interneurons projecting locally. Auditory stimulus-related inputs to the MGB were simulated using phenomenological models of the cochlear/auditory nerve and the inferior colliculus. The model generated cell type and layer-specific firing rates consistent with experimentally observed ranges, and accurately simulated the corresponding local field potentials (LFPs), current source density (CSD), and electroencephalogram (EEG) signals. Laminar CSD patterns during spontaneous activity, and in response to speech input, were similar to those recorded experimentally. Physiological oscillations emerged spontaneously across frequency bands without external rhythmic inputs and were comparable to those recorded in vivo. We used the model to unravel the contributions from distinct cell type and layer-specific neuronal populations to oscillation events detected in CSD, and explored how these relate to the population firing patterns. Overall, the computational model provides a quantitative theoretical framework to integrate and interpret a wide range of experimental data in auditory circuits. It also constitutes a powerful tool to evaluate hypotheses and make predictions about the cellular and network mechanisms underlying common experimental measurements, including MUA, LFP and EEG signals.

Multiferroic topologies are an emerging solution for future low-power magnetic nanoelectronics due to their combined tuneable functionality and mobility. Here, we show that in addition to being magnetoelectric multiferroic at room temperature, thin-film Aurivillius phase Bi6TixFeyMnzO18 is an ideal material platform for both domain wall and vortex topology-based nanoelectronic devices. Utilizing atomic-resolution electron microscopy, we reveal the presence and structure of 180°-type charged head-to-head and tail-to-tail domain walls passing throughout the thin film. Theoretical calculations confirm the subunit cell cation site preference and charged domain wall energetics for Bi6TixFeyMnzO18. Finally, we show that polar vortex-type topologies also form at out-of-phase boundaries of stacking faults when internal strain and electrostatic energy gradients are altered. This study could pave the way for controlled polar vortex topology formation via strain engineering in other multiferroic thin films. Moreover, these results confirm that the subunit cell topological features play an important role in controlling the charge and spin state of Aurivillius phase films and other multiferroic heterostructures.

npj 2D materials and applications 6(1), 42 (2022). doi:10.1038/s41699-022-00318-4, Published by Nature Publishing Group, London

Dual-fuel engines present an opportunity to increase the electric efficiency and fuel flexibility of combined-heat-and-power (CHP) units. It is becoming increasingly important to find alternative liquid fuels, which can be used as a pilot fuel is such units. While being able to be produced from renewable sources, polyoxymethylenedimethylethers (PODE, OME or POMDME) also provide promising combustion characteristics, such as reducing particle matter emissions (PM). However, little knowledge exists regarding the utilisation of these fuels in full-scale engines, as used in CHP-units. Therefore, we investigated the performance, combustion behaviour and exhaust emissions of a dual-fuel CHP-engine operating with biomethane as main fuel and a 50/50-PODE-blend and neat diesel as pilot fuel. The injection behaviour of the PODE-diesel-blends was investigated on a common-rail-injection test-bench. When replicating small injection quantities, as required for pilot injection, the injection rate was found to be almost identical when comparing diesel and the PODE-diesel-blend. The pilot fuel quantity showed to be decisive for performance and emissions of the engine. When keeping the injected energy equal between the PODE-blend and diesel, the NOX-emissions increased by up to 45% and the PM-emissions decreased by up to 67%, while the efficiency of the engine increased by up to 2.5%.

BackgroundEarly intervention in psychosis (EIP) services target the early manifestation of psychosis and provide multidisciplinary care. They demonstrate effectiveness and cost-effectiveness. Implementation of EIP services is inconsistent and piecemeal. This systematic review and narrative synthesis aims to identify barriers and facilitators to EIP service implementation.MethodsWe conducted an electronic search of databases (EMBASE, Medline, Web of Science, and PsychINFO) to detect papers reporting EIP service implementation findings and associated barriers and facilitators. The search occurred between June to August 2020, and again in January 2021. Articles meeting inclusion criteria were extracted and narratively synthesized. A quality assessment was conducted using the Mixed Methods Appraisal Tool.ResultsTwenty-three studies were selected. The most common study design was descriptive accounts of implementation. Patient age ranged varied from 14 to 35 years. We identified three barrier and facilitator domains: (a) system; (b) services; and (c) staff, and a range of subdomains. The most frequent subdomains were “funding” and “strength of collaboration and communication between EIP and outside groups and services”. Associations between domains and subdomains were evident, particularly between systems and services.ConclusionsA range of barriers and facilitators to EIP implementation exist. Some of these are generic factors germane across health systems and services, while others are specific to EIP services. A thorough prior understanding of these challenges and enablers are necessary before implementation is attempted. Accounting for these issues within local and national contexts may help predict and increase the likelihood of services’ success, stability, and longevity.

[Image: see text] The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.

Electrophysiological oscillations in the brain have been shown to occur as multicycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We developed an open-source wavelet-based tool to detect and characterize such oscillation events (OEvents) and exemplify the use of this tool in both simulations and two invasively-recorded electrophysiology datasets: one from human, and one from nonhuman primate (NHP) auditory system. After removing incidentally occurring event-related potentials (ERPs), we used OEvents to quantify oscillation features. We identified ∼2 million oscillation events, classified within traditional frequency bands: δ, θ, α, β, low γ, γ, and high γ. Oscillation events of 1–44 cycles could be identified in at least one frequency band 90% of the time in human and NHP recordings. Individual oscillation events were characterized by nonconstant frequency and amplitude. This result necessarily contrasts with prior studies which assumed frequency constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clear intraevent rhythmicity, there was also evidence of interevent rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano factor (FF) measures differed significantly from a Poisson distribution assumption. Overall, our study provides an easy-to-use tool to study oscillation events at the single-trial level or in ongoing recordings, and demonstrates that rhythmic, multicycle oscillation events dominate auditory cortical dynamics.

Polyoxymethylene dimethyl ethers (OME) with the chemical structure H3CO[-CH2-O-]nCH3 are a promising alternative fuel for improving emissions characteristics of internal combustion engines and can be produced from renewable sources. Especially the PM-NOx trade-off of diesel engines is known to be effectively mitigated by blending OME with diesel. Recent investigations concentrate on the utilization OME fuels in mobile applications. However, these fuels could also be of interest for stationary engines used in gensets and combined heat and power units (CHP). In the present paper we examine the use of OME2-6/diesel blends up to 50% in a CHP unit in practical operation equipped with a heavy-duty six-cylinder engine, applying different load conditions and engine settings, including Exhaust Gas Recirculation (EGR) and the adjustment of injection timings. No negative effects on the performance and efficiency of the engine were observed with the OME blends. Particulate Matter (PM) and Particle Number (PN) decreased significantly with increasing content of OME in the blend, especially when EGR was applied. The Particle Number Size Distribution (PNSD) showed a trend towards smaller particle sizes. NOx rose slightly in direct comparison, but this was by far overcompensated by the reduction achieved through EGR. The results indicate that OME fuels in combination with EGR could become a feasible option for emission reduction in diesel gensets and CHP units due to the very low particle emissions, which mitigate the risk of EGR cooler fouling.

Background Although culture-based methods remain a staple element of microbiology analysis, advanced molecular methods increasingly supplement the testing repertoire. Since the advent of 16s and 18s ribosomal RNA PCR in the 2000s, there has been interest in its utility for pathogen detection. Nonetheless, studies assessing the impact on antimicrobial prescribing are limited. We report a single-centre experience of the influence of 16s and 18s PCR testing on antimicrobial treatment, including a cost-analysis. Methods Data were collected retrospectively for all samples sent for 16s and 18s PCR testing between January 2014 and December 2020. Results were compared to any culture-based result. Assessment focused on any change of antimicrobial treatment based on PCR result, or use of the result as supportive evidence for microbiological diagnosis. Results 310 samples relevant to 268 patients were referred for 16s/18s rRNA PCR testing during the period. Culture was performed for 234 samples. Enrichment culture was performed for 83 samples. 82 of 300 samples sent for 16s PCR had positive results (20.8%). When culture was performed, enrichment reduced the outcome of 16s PCR only positive results (4/36 [11.1%] versus 14/35 [40.0%], p = 0.030 where a pathogen found). 18s PCR yielded 9 positive results from 67 samples. The 16s PCR result influenced antimicrobial change for 6 patients (2.2%). We estimated the cost for 16s PCR testing to result in one significant change in antimicrobial therapy to be €3,340. 18s PCR did not alter antimicrobial treatment. Conclusion There was limited impact of 16s PCR results on antimicrobial treatments. Relevance to practice was affected by relatively long turn-around-time for results. Utility may be increased in specialised surgical centres, or by reducing turn-around-time. Enrichment culture should be considered on samples where 16s PCR is requested. There remains limited evidence for use of 18s PCR in clinical management, and further studies in this area are likely warranted.

Electrophysiological oscillations in the brain have been shown to occur as multi-cycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We used two invasively-recorded electrophysiology datasets: one from human, and one from non-human primate auditory system. After removing incidentally occuring event related potentials, we used a wavelet transform based method to quantify oscillation features. We identified about 2 million oscillation events, classified within traditional frequency bands: delta, theta, alpha, beta, low gamma, gamma, high gamma. Oscillation events of 1-44 cycles were present in at least one frequency band in 90% of the time in human and non-human primate recordings. Individual oscillation events were characterized by non-constant frequency and amplitude. This result naturally contrasts with prior studies which assumed such constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clear intra-event rhythmicity, there was also evidence of inter-event rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano Factor measures differed significantly from a Poisson distribution assumption. Overall, our study demonstrates that rhythmic, multi-cycle oscillation events dominate auditory cortical dynamics.

Summary Previous studies indicate that motor sampling patterns modulate neuronal excitability in sensory brain regions by entraining brain rhythms, a process termed motor-initiated entrainment. In addition, rhythms of the external environment are also capable of entraining brain rhythms. Our first goal was to investigate the properties of motor-initiated entrainment in the auditory system using a prominent visual motor sampling pattern in primates, saccades. Second, we wanted to determine whether/how motor-initiated entrainment interacts with visual environmental entrainment. We examined laminar profiles of neuronal ensemble activity in primary auditory cortex and found that whereas motor-initiated entrainment has a suppressive effect, visual environmental entrainment has an enhancive effect. We also found that these processes are temporally coupled, and their temporal relationship ensures that their effect on excitability is complementary rather than interfering. Altogether, our results demonstrate that motor and sensory systems continuously interact in orchestrating the brain's context for the optimal sampling of our multisensory environment., Graphical Abstract, Highlights • Our study demonstrates that saccades modulate A1 excitability • Rhythmic visual stimuli entrain A1 neural oscillations to a high excitability phase • Saccades entrain A1 neural oscillations to an opposite, suppressive state • Saccade probability increases between visual stimuli likely to avoid interference, Biological Sciences; Neuroscience; Sensory Neuroscience

The Khayelitsha subdistrict has the highest burden of reported tuberculosis (TB) cases in Cape Town, Western Cape Province, South Africa.To characterise the TB burden, spectrum and treatment outcomes among children managed at a district-level hospital, the Khayelitsha District Hospital.Retrospective medical record review of all children (age13 years) diagnosed with TB in January-July 2014. A lay health care worker completed daily surveillance and supported linkage to TB care. Symptoms and investigations at presentation, TB disease spectrum, referral pathways and outcomes were reported.Most children were aged 2 years (84/99, 85%), 18/96 (19%) were infected with the human immunodeficiency virus, 31/91 (34%) were malnourished and 80/99 (81%) had pulmonary TB only. The majority of the children (63/80, 79%) presented with cough of acute onset (2 weeks). Only 5/36 (14%) eligible child contacts had documentation of receiving isoniazid preventive therapy. Twelve (13%) children had bacteriologically confirmed pulmonary TB. Overall, 93/97 (96%) children successfully continued TB care after hospital discharge. Favourable TB treatment outcomes were recorded in only 77 (78%) children.Children with TB managed at this district-level hospital were young, and frequently had acute symptoms and substantial comorbidities. Missed opportunities for TB prevention were identified. Linkage to care support resulted in excellent continuation of TB care; however, treatment outcomes could be further improved.

Significance Our results indicate that nonhuman primates detect complex repeating acoustic sequences in a continuous auditory stream, which is an important precursor for human speech learning and perception. We demonstrate that oscillatory entrainment, known to support the attentive perception of rhythmic stimulus sequences, can occur for rhythms defined solely by stimulus context rather than physical boundaries. As opposed to acoustically driven entrainment by rhythmic tone sequences demonstrated previously, this form of entrainment relies on the brain’s ability to group auditory inputs based on their statistical regularities. The internally initiated, context-driven modulation of excitability in the medial pulvinar prior to A1 supports the notion of top-down entrainment., Prior studies have shown that repetitive presentation of acoustic stimuli results in an alignment of ongoing neuronal oscillations to the sequence rhythm via oscillatory entrainment by external cues. Our study aimed to explore the neural correlates of the perceptual parsing and grouping of complex repeating auditory patterns that occur based solely on statistical regularities, or context. Human psychophysical studies suggest that the recognition of novel auditory patterns amid a continuous auditory stimulus sequence occurs automatically halfway through the first repetition. We hypothesized that once repeating patterns were detected by the brain, internal rhythms would become entrained, demarcating the temporal structure of these repetitions despite lacking external cues defining pattern on- or offsets. To examine the neural correlates of pattern perception, neuroelectric activity of primary auditory cortex (A1) and thalamic nuclei was recorded while nonhuman primates passively listened to streams of rapidly presented pure tones and bandpass noise bursts. At arbitrary intervals, random acoustic patterns composed of 11 stimuli were repeated five times without any perturbance of the constant stimulus flow. We found significant delta entrainment by these patterns in the A1, medial geniculate body, and medial pulvinar. In A1 and pulvinar, we observed a statistically significant, pattern structure-aligned modulation of neuronal firing that occurred earliest in the pulvinar, supporting the idea that grouping and detecting complex auditory patterns is a top-down, context-driven process. Besides electrophysiological measures, a pattern-related modulation of pupil diameter verified that, like humans, nonhuman primates consciously detect complex repetitive patterns that lack physical boundaries.

Background. Healthcare-associated infections (HAIs) cause substantial morbidity, mortality and healthcare costs. The prevalence of neonatal/paediatric HAI at South African (SA) district and regional hospitals is unknown. Objectives. To document HAI rates, antimicrobial use for HAI, infection prevention staffing, hand hygiene (HH) provisions and HH compliance rates in neonatal and paediatric wards in two district and two regional hospitals in the Western Cape Province, SA. Methods. An HAI point prevalence survey (PPS) was conducted in neonatal and paediatric wards at two district and two regional hospitals in the Western Cape during December 2016, applying National Healthcare Safety Network HAI definitions. HAI events and antimicrobial therapy active at 08h00 on the PPS day and during the preceding 7 days (period prevalence) were documented. Provisions for HH and HH compliance rates were observed on each ward using the World Health Organization’s HH surveillance tool. Results. Pooled point and period HAI prevalence were 9.9% (15/151; 95% confidence interval (CI) 6 - 15.8) and 12.6% (19/151; 95% CI 8 - 18.9), respectively. Hospital-acquired pneumonia (5/15, 33.3%), bloodstream infection (3/15, 20.0%) and urinary tract infection (3/15, 20.0%) were predominant HAI types. Risk factors for HAI were a history of recent hospitalisation (8/19, 42.1% v. 17/132, 12.9%; p

Purpose/Objective(s) Robust auto-segmentation based on daily MRI is highly desirable for MR-guided adaptive radiation therapy (MRgART). However, it is generally challenging particularly if the daily MRI is acquired with multiple sequences or if it is for imaging complex anatomy, e.g., abdomen. To overcome these issues, we developed a deep learning algorithm to segment abdominal organs quickly and automatically on multi-sequence MRI. Materials/Methods The deep learning auto-segmentation model was developed using a modified U-net, ResUnet3D, with end-to-end mapping, and was trained with 85 daily MRI sets acquired during MRgART on a 1.5T MR-Linac for 37 patients with abdominal tumors. The daily MRI sets were motion averaged images derived from 4D MRI acquired with multiple sequences, including Fast Field Echo (FFE), Balanced Turbo Field Echo (BTFE) and TFE. Each daily MRI was paired with a CT. All MRIs were pre-processed using bias field correction and intensity standardization. The ground truth contours were created manually based on existing guidelines. For the training datasets, field-of-view extension via online random 3D elastic transform/deformation was utilized to augment and improve the quality of datasets. During the model training, a patient-based z-score normalization method was employed to standardize the multi-contrast images. Two models were trained, one for 11 organs: aorta, duodenum, kidneys, liver, pancreas, spinal cord, spleen, stomach, large bowel, and small bowel, and another for 10 organs with combined large and small bowel. Performance of the obtained models was evaluated using 11 test datasets in terms of dice similarity coefficient (DSC), mean distance to agreement (MDA) and time efficiency using an Intel Xeon CPU (2.4 GHz, 64GB RAM) hardware. Results For the challenging bowels, the auto-segmentation accuracy for the model trained with the combined bowel was better, with MDA/DSC of 2.1/0.86 versus 6.8/0.76 (large bowel) and 6.1/0.68 (small bowel) for the separate-bowel model. Average DSC for the obtained contours of aorta, left kidney, right kidney, liver, spinal cord, spleen, and stomach was 0.93, 0.93, 0.94, 0.94, 0.83, 0.92 and 0.88, respectively from both models. While no significant difference in model performance was observed with BTFE versus TFE testing datasets, a slightly improved segmentation was seen on the BTFE images for pancreas and duodenum, DSC 0.71 and 0.72. This improvement may be attributed to the enhanced contrast seen in BTFE images when compared to the TFE and FFE images. The time required to generate all organs on an MRI was 20-24 seconds. Conclusion We have developed deep learning auto-segmentation models based on multi-sequence MRI sets for abdominal organs. The models performed reasonably well. With further development using large datasets, the models may be integrated in MRgART for fast, fully automated, and accurate contouring of abdominal organs on daily MRI.

The aim of this study was to investigate the hydraulic stability of micro injections when using polyoxymethylene dimethyl ether (PODE) as pilot fuel for a dual fuel heavy-duty stationary engine. A two-layered 8-hole solenoid injector with an injection angle of 75° was used for the investigation. The challenge with regard to the investigated type of diesel-ignited gas engines is that the injector has to provide a stable injection for both full-diesel mode and dual fuel mode. The stability of the injection was evaluated using the following values: The injection rate, injection gravimetric quantity, injected amount of energy, standard deviation of the injection quantity, coefficient of variation of the injected quantity, the momentum flux, injection duration and injection delay at various pressures and energizing times with neat base diesel fuel, neat PODE and a 50- vol-% PODE-diesel-blend. PODE was found to have a similar gravimetric total injection rates of all holes compared to base diesel fuel with almost the same standard deviation. At higher injection pressures and longer energizing times, the influence of the fuel on the injection quantity becomes more relevant. The influence of the fuel on the injection delay and injection duration was found to be small. An empiric correlation between the discharge coefficient and the Reynolds number was determined which can be used to calculate the discharge coefficient. In summary, we can conclude that with regard to the hydraulic injection characteristics, PODE could be used as a suitable replacement for diesel as pilot fuel in dual fuel engines.

SummaryBackground The diagnosis of colorectal cancer (CRC) can be difficult as symptoms are variable with poor specificity. Thus, there is a quest for simple, non-invasive testing that can help streamline those with significant colonic pathology. Aim To assess using faecal immunochemical test for haemoglobin (FIT) or faecal calprotectin (FCP) to detect CRC and adenoma in symptomatic patients referred from primary care. Methods A total of 799 referred for urgent lower gastrointestinal investigations were prospectively recruited. Of these, 430 completed colonic investigations and returned stool samples, and were included in the final statistical analysis. Faecal immunochemical test for haemoglobin was performed on HM-JACKarc analyser (Kyowa Medex, Tokyo, Japan), and FCP by the EliA Calprotectin immunoassay (Thermo Fisher Scientific, Waltham, United States). Results The negative predictive value (NPV) using FIT alone or both markers (FIT and FCP) in combination was similar at 99% for CRC, with a sensitivity and specificity of 84% and 93%, respectively. FIT measurements were significantly higher in left-sided colonic lesions compared with the right side; 713 vs. 94; P = 0.0203). For adenoma, the NPV using FIT alone, or both markers (FIT and FCP) in combination, was similar at 94% with a sensitivity and specificity of 69% and 56%, respectively. Conclusions Undetectable faecal immunochemical test for haemoglobin is sufficiently sensitive to exclude colorectal cancer, with higher values in left-sided lesions. FCP in combination does not appear to provide additional diagnostic information. Further studies to determine the health economic benefits of implementing faecal immunochemical test for haemoglobin in primary care are required.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but not E. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.

Background Mismatch negativity (MMN) is an extensively validated biomarker of cognitive function across both normative and clinical populations and has previously been localized to supratemporal auditory cortex. MMN is thought to represent a comparison of the features of the present stimulus versus a mnemonic template formed by the prior stimuli. Methods We used concurrent thalamic and primary auditory cortical (A1) laminar recordings in 7 macaques to evaluate the relative contributions of core (lemniscal) and matrix (nonlemniscal) thalamic afferents to MMN generation. Results We demonstrated that deviance-related activity is observed mainly in matrix regions of auditory thalamus, MMN generators are most prominent in layer 1 of cortex as opposed to sensory responses that activate layer 4 first and sequentially all cortical layers, and MMN is elicited independent of the frequency tuning of A1 neuronal ensembles. Consistent with prior reports, MMN-related thalamocortical activity was strongly inhibited by ketamine. Conclusions Taken together, our results demonstrate distinct matrix versus core thalamocortical circuitry underlying the generation of a higher-order brain response (MMN) versus sensory responses.

SUMMARYBackground Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. Objective To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. Methods We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. Results Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39–520) and 30 min (range 5–100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). Conclusion The RAPID protocol reduces unwarranted delays without compromising efficacy.

Previous research demonstrated that while selectively attending to relevant aspects of the external world, the brain extracts pertinent information by aligning its neuronal oscillations to key time points of stimuli or their sampling by sensory organs. This alignment mechanism is termed oscillatory entrainment. We investigated the global, long-timescale dynamics of this mechanism in the primary auditory cortex of nonhuman primates, and hypothesized that lapses of entrainment would correspond to lapses of attention. By examining electrophysiological and behavioral measures we observed that besides the lack of entrainment by external stimuli, attentional lapses were characterized by high amplitude alpha oscillations, with alpha frequency structuring of neuronal ensemble and single unit operations. Strikingly, entrainment and alpha oscillation dominated periods were strongly anti-correlated and fluctuated rhythmically at an ultra-slow rate. Our results indicate that these two distinct brain states represent externally versus internally oriented computational resources engaged by large-scale task-positive and task-negative functional networks.

[Image: see text] Potent covalent inhibitors of Bruton’s tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

Summary Background Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are Gram-negative, multi-drug-resistant organisms that are of major clinical significance among immunocompromised patients in high-risk areas in hospital settings. In Ireland, the number of ESBL-E bloodstream infections is increasing. Aims To conduct a prevalence study of ESBL-E among immunocompromised patients in high-risk areas [intensive care unit (ICU), liver transplantation and haematology/oncology wards], characterize any ESBL genes detected by polymerase chain reaction (PCR), and perform epidemiological typing using pulsed-field gel electrophoresis (PFGE). Methods In total, 317 non-duplicate rectal swabs from patients in high-risk wards were screened anonymously for ESBL-E carriage. Positive isolates were characterized using PCR to detect bla CTX-M , bla TEM , bla OXA-1 and bla SHV ESBL-E genes. Clonal relationships of these isolates were investigated using PFGE. Findings Fifty (15.8%) high-risk patients were found to harbour ESBL-E. Prevalence rates of 21.9% ( N = 28), 14.3% ( N = 15) and 8.3% ( N = 7) of ESBL-E were isolated from patients on the liver transplantation, ICU and haematology/oncology wards, respectively. Seventy percent of ESBL-E isolates carried more than one resistance gene. Of the 25 ESBL-producing Escherichia coli isolates typed by PFGE, two pairs of two isolates demonstrated >80% homology, and four of the five ESBL-producing Enterobacter cloacae isolates typed by PFGE demonstrated >80% homology, suggesting clonal relatedness and potential cross-transmission from individual patients. Conclusion A significant proportion of the patients screened were found to be colonized with ESBL-E. Typing revealed three incidents of potential cross-infection. Therefore, timely detection of ESBL-E among patients in high-risk wards is critical for treatment and infection control.