Investigating Intra-Individual Networks of Response Inhibition and Interference Resolution using 7T MRI.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Long term detection and quantification of SARS-CoV-2 RNA in wastewater in Bahrain.

Wastewater-based epidemiology is a corroborated environmental surveillance tool in the global fight against SARS-CoV-2. The analysis of wastewater for detection of SARS-CoV-2 RNA may assist policymakers to survey a specific infectious community. Herein, we report on a long-term quantification study in Bahrain to investigate the incidence of the SARS-CoV-2 RNA in wastewater during the COVID-19 pandemic. The ∼260,000 population of Muharraq Island in Bahrain is served by a discrete sewerage catchment, and all wastewater flows to a single large Sewage Treatment Plant (STP) with a capacity of 100,000 m3/day. The catchment is predominately domestic, but also serves several hospitals and Bahrain's international airport. Flow-weighted 24-h composite wastewater samples for the period February 2020 to October 2021 were analyzed for the presence of SARS-CoV-2 N1, N2 and E genes. A Spearman rank correlation demonstrated a moderate correlation between the concentration of SARS-CoV-2 N1, N2 and E genes in the wastewater samples and the number of COVID-19 cases reported on the same day of the sampling. SARS-CoV-2 viral genes were detected in wastewater samples shortly after the first cases of COVID-19 were reported by the health authorities in Bahrain by reverse transcription-polymerase chain reaction (RT-qPCR). The viral genes were detected in 55 of 65 samples (84.62%) during the whole study period and the concentration range was found to be between 0 and 11,508 RNA copies/mL across the viral genes tested (in average N1: 518.4, N2: 366.8 and E: 649.3 copies/mL). Furthermore, wastewater samples from two COVID-19-dedicated quarantine facilities were analysed and detected higher SARS-CoV-2 gene concentrations (range 27-19,105 copies/mL; in average N1: 5044, N2: 4833 and E: 8663 copies/mL). Our results highlight the potential use of RT-qPCR for SARS-CoV-2 detection and quantification in wastewater and present the moderate correlation between concentration of SARS-CoV-2 genes with reported COVID-19 cases for a specified population. Indeed, this study identifies this technique as a mechanism for long term monitoring of SARS-CoV-2 infection levels and hence provides public health and policymakers with a useful environmental surveillance tool during and after the current pandemic.

The interplay between the immune system and viruses.

The human immune response can be divided into two arms: innate and adaptive immunity. The innate immune system consists of "hard-wired" responses encoded by host germline genes. In contrast, the adaptive response consists of gene elements that are somatically rearranged to assemble antigen-binding molecules with specificity for individual foreign structures. In contrast to the adaptive immune system, which depends upon T and B lymphocytes, innate immune protection is a task performed by cells of both hematopoietic and non-hematopoietic origin. Hematopoietic cells involved in innate immune responses include macrophages, dendritic cells, mast cell, neutrophils, eosinophils, natural killer (NK) cells and natural killer T cells. The induction of an adaptive immune response begins when a pathogen is ingested by an Antigen Presenting Cell (APC), such as the Dendritic cell (DC), in the infected tissue. DCs bridge the gap between first line innate responses and powerful adaptive immune responses, by internalizing, processing and presenting antigens on Major Histocompatibility Complex (MHC) and MHC-like molecules to the adaptive immune cells In addition to DCs, macrophages and B cells are deemed antigen presenting cells (Llewelyn & Cohen, 2002).

Axion Dark Matter Experiment: Detailed design and operations.

Axion dark matter experiment ultra-low noise haloscope technology has enabled the successful completion of two science runs (1A and 1B) that looked for dark matter axions in the 2.66-3.1 µeV mass range with Dine-Fischler-Srednicki-Zhitnisky sensitivity [Du et al., Phys. Rev. Lett. 120, 151301 (2018) and Braine et al., Phys. Rev. Lett. 124, 101303 (2020)]. Therefore, it is the most sensitive axion search experiment to date in this mass range. We discuss the technological advances made in the last several years to achieve this sensitivity, which includes the implementation of components, such as the state-of-the-art quantum-noise-limited amplifiers and a dilution refrigerator. Furthermore, we demonstrate the use of a frequency tunable microstrip superconducting quantum interference device amplifier in run 1A, and a Josephson parametric amplifier in run 1B, along with novel analysis tools that characterize the system noise temperature.

Abdominoperineal resection in the prone position: early outcomes at a tertiary institution in the Western Cape, South Africa.

BACKGROUND: Extra-levator abdominoperineal resection (ELAPE) performed in the prone jack-knife position is a new technique in the developing world. Literature on the outcomes of ELAPE in a developing country context is scarce. The objective was to assess early outcomes after ELAPE in the prone jack-knife position, and to compare outcomes of patients who underwent the abdominal part of the procedure performed laparoscopically with an open group, at a tertiary institution in Cape Town. METHODS: Records of patients who underwent ELAPE for rectal adenocarcinoma from February 2011 to February 2017 at Tygerberg Hospital were retrospectively reviewed. Variables of interest included staging, rate of circumferential resection margin involvement (CRMI), intraoperative tumour perforation (IOP), perineal wound complications, early postoperative morbidity, length of intensive care unit (ICU) stay, duration of postoperative hospital stay and 30-day mortality rate. RESULTS: 52 patients (median age: 59 years) were included in the analysis. CRMI was evident in 16% (8/49) of patients and IOP in 6% (3/52). Perineal wound complications occurred in 32% (16/50) of patients. Median length of ICU and postoperative hospital stay was 3 days and 7 days, respectively. Overall morbidity was 47% (24/51) and the 30-day mortality rate was 3% (2/52). A significant difference in length of hospital stay was evident between the open and laparoscopic groups (11.5 days vs 6 days). CONCLUSION: Prone abdominoperineal resection (APR), ELAPE, and laparoscopic ELAPE are acceptable and feasible procedures for patients with rectal cancer in the developing world, with outcomes being comparable to those determined in the developed world.

Revisiting respiratory syncytial virus's interaction with host immunity, towards novel therapeutics.

Every year there are > 33 million cases of Respiratory Syncytial Virus (RSV)-related respiratory infection in children under the age of five, making RSV the leading cause of lower respiratory tract infection (LRTI) in infants. RSV is a global infection, but 99% of related mortality is in low/middle-income countries. Unbelievably, 62 years after its identification, there remains no effective treatment nor vaccine for this deadly virus, leaving infants, elderly and immunocompromised patients at high risk. The success of all pathogens depends on their ability to evade and modulate the host immune response. RSV has a complex and intricate relationship with our immune systems, but a clearer understanding of these interactions is essential in the development of effective medicines. Therefore, in a bid to update and focus our research community's understanding of RSV's interaction with immune defences, this review aims to discuss how our current knowledgebase could be used to combat this global viral threat.

Extended Search for the Invisible Axion with the Axion Dark Matter Experiment.

This Letter reports on a cavity haloscope search for dark matter axions in the Galactic halo in the mass range 2.81-3.31 µeV. This search utilizes the combination of a low-noise Josephson parametric amplifier and a large-cavity haloscope to achieve unprecedented sensitivity across this mass range. This search excludes the full range of axion-photon coupling values predicted in benchmark models of the invisible axion that solve the strong CP problem of quantum chromodynamics.

Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine initiative: patient-centred outcomes.

BACKGROUND: Patient-centred outcomes are increasingly used in perioperative clinical trials. The Standardised Endpoints in Perioperative Medicine (StEP) initiative aims to define which measures should be used in future research to facilitate comparison between studies and to enable robust evidence synthesis. METHODS: A systematic review was conducted to create a longlist of patient satisfaction, health-related quality of life, functional status, patient well-being, and life-impact measures for consideration. A three-stage Delphi consensus process involving 89 international experts was then conducted in order to refine this list into a set of recommendations. RESULTS: The literature review yielded six patient-satisfaction measures, seven generic health-related quality-of-life measures, eight patient well-being measures, five functional-status measures, and five life-impact measures for consideration. The Delphi response rates were 92%, 87%, and 100% for Rounds 1, 2, and 3, respectively. Three additional measures were added during the Delphi process as a result of contributions from the StEP group members. Firm recommendations have been made about one health-related quality-of-life measure (EuroQol 5 Dimension, five-level version with visual analogue scale), one functional-status measure (WHO Disability Assessment Schedule version 2.0, 12-question version), and one life-impact measure (days alive and out of hospital at 30 days after surgery). Recommendations with caveats have been made about the Bauer patient-satisfaction measure and two life-impact measures (days alive and out of hospital at 1 yr after surgery, and discharge destination). CONCLUSIONS: Several patient-centred outcome measures have been recommended for use in future perioperative studies. We suggest that every clinical study should consider using at least one patient-centred outcome within a suite of endpoints.

Broadly tunable femtosecond pulses around 2.06 µm from a diode-pumped Tm3+-doped solid-state laser source.

We report on a broadly tunable diode-pumped femtosecond Tm:LuScO3 laser source around 2.06 µm. Tuning was obtained through the use of a steeply diving birefringent filter, maintaining sub-600 fs pulses over a tuning range of 2019-2110 nm. The minimum pulse duration of 240 fs was recorded at a central wavelength of 2080 nm with an average output power of 93 mW. Higher output coupling of 2% resulted in a narrower tuning range of 2070-2102 nm with generated pulses as short as 435 fs and an average output power of 119 mW at 2090 nm.

A dataset of neonatal EEG recordings with seizure annotations.

Neonatal seizures are a common emergency in the neonatal intensive care unit (NICU). There are many questions yet to be answered regarding the temporal/spatial characteristics of seizures from different pathologies, response to medication, effects on neurodevelopment and optimal detection. The dataset presented in this descriptor contains EEG recordings from human neonates, the visual interpretation of the EEG by the human experts, supporting clinical data and codes to assist access. Multi-channel EEG was recorded from 79 term neonates admitted to the NICU at the Helsinki University Hospital. The median recording duration was 74 min (IQR: 64 to 96 min). The presence of seizures in the EEGs was annotated independently by three experts. An average of 460 seizures were annotated per expert in the dataset; 39 neonates had seizures and 22 were seizure free, by consensus. The dataset can be used as a reference set of neonatal seizures, in studies of inter-observer agreement and for the development of automated methods of seizure detection and other EEG analyses.

Diode-pumped femtosecond Tm3+-doped LuScO3 laser near 2.1 µm.

We report on the first demonstration, to the best of our knowledge, of a diode-pumped Tm:LuScO3 laser. Efficient and broadly tunable continuous wave operation in the 1973-2141 nm region and femtosecond mode-locking through the use of an ion-implanted InGaAsSb quantum-well-based semiconductor saturable absorber mirror are realized. When mode-locked, near-transform-limited pulses as short as 170 fs were generated at 2093 nm with an average output power of 113 mW and a pulse repetition frequency of 115.2 MHz. Tunable picosecond pulse generation was demonstrated in the 2074-2104 nm spectral range.

Functional maturation in preterm infants measured by serial recording of cortical activity.

Minimally invasive, automated cot-side tools for monitoring early neurological development can be used to guide individual treatment and benchmark novel interventional studies. We develop an automated estimate of the EEG maturational age (EMA) for application to serial recordings in preterm infants. The EMA estimate was based on a combination of 23 computational features estimated from both the full EEG recording and a period of low EEG activity (46 features in total). The combination function (support vector regression) was trained using 101 serial EEG recordings from 39 preterm infants with a gestational age less than 28 weeks and normal neurodevelopmental outcome at 12 months of age. EEG recordings were performed from 24 to 38 weeks post-menstrual age (PMA). The correlation between the EMA and the clinically determined PMA at the time of EEG recording was 0.936 (95%CI: 0.932-0.976; n = 39). All infants had an increase in EMA between the first and last EEG recording and 57/62 (92%) of repeated measures within an infant had an increasing EMA with PMA of EEG recording. The EMA is a surrogate measure of age that can accurately determine brain maturation in preterm infants.

1.9 µm waveguide laser fabricated by ultrafast laser inscription in Tm:Lu2O3 ceramic.

The ultrafast laser inscription technique has been used to fabricate channel waveguides in Tm3+-doped Lu2O3 ceramic gain medium for the first time to our knowledge. Laser operation has been demonstrated using a monolithic microchip cavity with a continuous-wave Ti:sapphire pump source at 796 nm. The maximum output power achieved from the Tm:Lu2O3 waveguide laser was 81 mW at 1942 nm. A maximum slope efficiency of 9.5% was measured with the laser thresholds observed to be in the range of 50-200 mW of absorbed pump power. Propagation losses for this waveguide structure are calculated to be 0.7 dB⋅cm-1 ± 0.3 dB⋅cm-1 at the lasing wavelength.

SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use?

Since their discovery, SOCS have been characterised as regulatory cornerstones of intracellular signalling. While classically controlling the JAK/STAT pathway, their inhibitory effects are documented across several cascades, underpinning their essential role in homeostatic maintenance and disease. After 20 years of extensive research, SOCS3 has emerged as arguably the most important family member, through its regulation of both cytokine- and pathogen-induced cascades. In fact, low expression of SOCS3 is associated with autoimmunity and oncogenesis, while high expression is linked to diabetes and pathogenic immune evasion. The induction of SOCS3 by both viruses and bacteria and its impact upon inflammatory disorders, underscores this protein's increasing clinical potential. Therefore, with the aim of highlighting SOCS3 as a therapeutic target for future development, this review revisits its multi-faceted immune regulatory functions and summarises its role in a broad ranges of diseases.

Estimating functional brain maturity in very and extremely preterm neonates using automated analysis of the electroencephalogram.

OBJECTIVE: To develop an automated estimate of EEG maturational age (EMA) for preterm neonates. METHODS: The EMA estimator was based on the analysis of hourly epochs of EEG from 49 neonates with gestational age (GA) ranging from 23 to 32weeks. Neonates had appropriate EEG for GA based on visual interpretation of the EEG. The EMA estimator used a linear combination (support vector regression) of a subset of 41 features based on amplitude, temporal and spatial characteristics of EEG segments. Estimator performance was measured with the mean square error (MSE), standard deviation of the estimate (SD) and the percentage error (SE) between the known GA and estimated EMA. RESULTS: The EMA estimator provided an unbiased estimate of EMA with a MSE of 82days (SD=9.1days; SE=4.8%) which was significantly lower than a nominal reading (the mean GA in the dataset; MSE of 267days, SD of 16.3days, SE=8.4%: p<0.001). The EMA estimator with the lowest MSE used amplitude, spatial and temporal EEG characteristics. CONCLUSIONS: The proposed automated EMA estimator provides an accurate estimate of EMA in early preterm neonates. SIGNIFICANCE: Automated analysis of the EEG provides a widely accessible, noninvasive and continuous assessment of functional brain maturity.

G protein-coupled receptor kinase 2 moderates recruitment of THP-1 cells to the endothelium by limiting histamine-invoked Weibel-Palade body exocytosis.

BACKGROUND: G protein-coupled receptors (GPCRs) are a major family of signaling molecules, central to the regulation of inflammatory responses. Their activation upon agonist binding is attenuated by GPCR kinases (GRKs), which desensitize the receptors through phosphorylation. G protein-coupled receptor kinase 2(GRK2) down-regulation in leukocytes has been closely linked to the progression of chronic inflammatory disorders such as rheumatoid arthritis and multiple sclerosis. Because leukocytes must interact with the endothelium to infiltrate inflamed tissues, we hypothesized that GRK2 down-regulation in endothelial cells would also be pro-inflammatory. OBJECTIVES: To determine whether GRK2 down-regulation in endothelial cells is pro-inflammatory. METHODS: siRNA-mediated ablation of GRK2 in human umbilical vein endothelial cells (HUVECs) was used in analyses of the role of this kinase. Microscopic and biochemical analyses of Weibel-Palade body (WPB) formation and functioning, live cell imaging of calcium concentrations and video analyses of adhesion of monocyte-like THP-1 cells provide clear evidence of GRK2 function in histamine activation of endothelial cells. RESULTS: G protein-coupled receptor kinase 2 depletion in HUVECs increases WPB exocytosis and P-selectin-dependent adhesion of THP-1 cells to the endothelial surface upon histamine stimulation, relative to controls. Further, live imaging of intracellular calcium concentrations reveals amplified histamine receptor signaling in GRK2-depleted cells, suggesting GRK2 moderates WPB exocytosis through receptor desensitization. CONCLUSIONS: G protein-coupled receptor kinase 2 deficiency in endothelial cells results in increased pro-inflammatory signaling and enhanced leukocyte recruitment to activated endothelial cells. The ability of GRK2 to modulate initiation of inflammatory responses in endothelial cells as well as leukocytes now places GRK2 at the apex of control of this finely balanced process.

G protein-coupled receptor kinase 2 moderates recruitment of THP-1 cells to the endothelium by limiting histamine-invoked Weibel-Palade body exocytosis.

BACKGROUND: G protein-coupled receptors (GP-CRs) are a major family of signaling molecules, central to the regulation of inflammatory responses. Their activation upon agonist binding is attenuated by GPCR kinases (GRKs), which desensitize the receptors through phosphorylation. G protein-coupled receptor kinase 2(GRK2) down-regulation in leukocytes has been closely linked to the progression of chronic inflammatory disorders such as rheumatoid arthritis and multiple sclerosis. Because leukocytes must interact with the endothelium to infiltrate inflamed tissues, we hypothesized that GRK2 down-regulation in endothelial cells would also be pro-inflammatory. OBJECTIVES: To determine whether GRK2 down-regulation in endothelial cells is pro-inflammatory. METHODS: siRNA-mediated ablation of GRK2 in human umbilical vein endothelial cells (HUVECs) was used in analyses of the role of this kinase. Microscopic and biochemical analyses of Weibel-Palade body (WPB) formation and functioning, live cell imaging of calcium concentrations and video analyses of adhesion of monocyte-like THP-1 cells provide clear evidence of GRK2 function in histamine activation of endothelial cells. RESULTS: G protein-coupled receptor kinase 2 depletion in HUVECs increases WPB exocytosis and P-selectin-dependent adhesion of THP-1 cells to the endothelial surface upon histamine stimulation, relative to controls. Further, live imaging of intracellular calcium concentrations reveals amplified histamine receptor signaling in GRK2-depleted cells, suggesting GRK2 moderates WPB exocytosis through receptor desensitization. CONCLUSIONS: G protein-coupled receptor kinase 2 deficiency in endothelial cells results in increased pro-inflammatory signaling and enhanced leukocyte recruitment to activated endothelial cells. The ability of GRK2 to modulate initiation of inflammatory responses in endothelial cells as well as leukocytes now places GRK2 at the apex of control of this finely balanced process.

Artefact detection in neonatal EEG.

Artefact detection is an important component of any automated EEG analysis. It is of particular importance in analyses such as sleep state detection and EEG grading where there is no null state. We propose a general artefact detection system (GADS) based on the analysis of the neonatal EEG. This system aims to detect both major and minor artefacts (a distinction based primarily on amplitude). As a result, a two-stage system was constructed based on 14 features extracted from EEG epochs at multiple time scales: [2, 4, 16, 32]s. These features were combined in a support vector machine (SVM) in order to determine the presence of absence of artefact. The performance of the GADS was estimated using a leave-one-out cross-validation applied to a database of hour long recordings from 51 neonates. The median AUC was 1.00 (IQR: 0.95-1.00) for the detection of major artefacts and 0.89 (IQR: 0.83-0.95) for the detection of minor artefacts.

Robustness of time frequency distribution based features for automated neonatal EEG seizure detection.

In this paper we examined the robustness of a feature-set based on time-frequency distributions (TFDs) for neonatal EEG seizure detection. This feature-set was originally proposed in literature for neonatal seizure detection using a support vector machine (SVM). We tested the performance of this feature-set with a smoothed Wigner-Ville distribution and modified B distribution as the underlying TFDs. The seizure detection system using time-frequency signal and image processing features from the TFD of the EEG signal using modified B distribution was able to achieve a median receiver operator characteristic area of 0.96 (IQR 0.91-0.98) tested on a large clinical dataset of 826 h of EEG data from 18 full-term newborns with 1389 seizures. The mean AUC was 0.93.

An automated system for grading EEG abnormality in term neonates with hypoxic-ischaemic encephalopathy.

Automated analysis of the neonatal EEG has the potential to assist clinical decision making for neonates with hypoxic-ischaemic encephalopathy. This paper proposes a method of automatically grading the degree of abnormality in an hour long epoch of neonatal EEG. The automated grading system (AGS) was based on a multi-class linear classifier grading of short-term epochs of EEG which were converted into a long-term grading of EEG using a majority vote operation. The features used in the AGS were summary measurements of two sub-signals extracted from a quadratic time-frequency distribution: the amplitude modulation and instantaneous frequency. These sub-signals were based on a model of EEG as a multiplication of a coloured random process with a slowly varying pseudo-periodic waveform and may be related to macroscopic neurophysiological function. The 4 grade AGS had a classification accuracy of 83% compared to human annotation of the EEG (level of agreement, κ = 0.76). Features estimated on the developed sub-signals proved more effective at grading the EEG than measures based solely on the EEG and the incorporation of additional sub-grades based on EEG states into the AGS also improved performance.