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.

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.

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.

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.

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.

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.

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.

Chronic hepatitis C infection blocks the ability of dendritic cells to secrete IFN-α and stimulate T-cell proliferation.

Dendritic cells (DCs) are likely to play a key role in the compromised T-cell function associated with hepatitis C Virus (HCV) infection. However, studies of DC function in HCV-infected patients to date have yielded conflicting findings possibly because of patient and virus heterogeneity. Here, we report the characterization of monocyte-derived DCs obtained from a homogenous cohort of women who were infected with HCV genotype 1b following exposure to contaminated anti-D immunoglobulin from a single donor source. Patients included in the study had not received anti-viral therapy and all had mild liver disease. We show that phenotypically normal monocyte-derived dendritic cells (MDDCs) (CD11c(+) HLA(-) DR(+) CD1a(+) CD14(lo) ) can be obtained from these patients. These cells respond to both Poly(I:C) and LPS, by up-regulating expression of CD86. They secrete high levels of IL-8 and CCL5 in response to LPS, an indication that the MyD88-dependent and MyD88-independent signalling pathways downstream of TLR4 ligation are functioning normally. However, these cells are poor stimulators of T-cell proliferation in allogeneic mixed lymphocyte reactions. Furthermore, patient MDDCs fail to secrete IFN-α in response to poly(I:C) or IFN-ß stimulation. Altered DC function may contribute to impaired cellular immune responses and chronicity of disease following HCV infection in this cohort. An effective therapeutic vaccine for chronic HCV infection will most likely need to target DCs to elicit an appropriate cellular response; therefore, it is important to resolve how the DCs of different patient cohorts respond to stimulation via TLRs.

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.

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.

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.

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.

Effect of changes in feeding schedule on the diurnal rhythms and daily activity levels of intestinal brush border enzymes and transport systems.

The activities of rat intestinal enzymes, sucrase, lactase, maltase, trehalase, gamma-glutamyltransferase, leucylnaphthylamide-hydrolyzing activity, and the transport system for glucose follow diurnal rhythms on ad libitum and restricted feeding regimes. In response to 6 days of restricted feeding, food available between 1400 and 1800 Eastern Standard Time, all rhythms shifted in time and the daily levels of activities were changed. Alkaline phosphatase activity followed a diurnal rhythm only in restricted fed animals. In restricted fed rats several activity patterns were observed, some with short periods of maximum activity, 3 h or less, and some with plateaus of maximum activity, 5-9 h long. In respect to the time of day of the synchronizer, sucrase peaked before feeding, glucose transport peaked during feeding, alkaline phosphatase peaked after feeding, and the other enzymes had higher levels of activity before, during and after feeding. The effect of restricted feeding on the daily activity levels were: a decrease in leucylnaphthylamide-hydrolyzing activity, no change in alkaline phosphatase, and increases in the others. These enzyme and transport systems exhibit a large amount of individual regulation or control as reflected by the lack of a uniform activity pattern and response to the synchronizer, and the variation in direction and magnitude of the adaptations to restricted feeding.

The effects of polyoxyethylated cholesterol feeding on hepatic cholesterol synthesis and intestinal cholesterol absorption in rats.

Adduction of ethylene glycol moieties to the 3-hydroxy position of cholesterol produces polyoxyethylated cholesterol (POEC), a water-soluble compound that suppresses cholesterol synthesis and esterification in cultured human fibroblasts. Feeding Sprague-Dawley rats a diet containing 2% (wt/wt) POEC with 10 ethoxy groups resulted in a 3-fold increase in hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity compared to activity in rats pair-fed a diet of standard rat chow. POEC with an average of 20 ethoxy groups (POEC-20) caused comparable changes in hepatic [2-14C]acetate incorporation into non-saponifiable lipids under ad libitum feeding conditions, significantly reduced cholesterol absorption (18% vs 57%), and increased fecal excretion of neutral steroids (5.1 vs 2.0 mg/g food intake). POEC-20 also reduced cholesterol absorption in rats fed a diet enriched with 2% cholesterol (11% vs 31%). Histologic studies of intestinal mucosa and hepatic tissues from rats fed POEC showed no pathologic changes. These experiments indicate that POEC reduces cholesterol absorption and causes compensatory increases in hepatic cholesterol synthesis.

Antiretroviral activities of hypericin and rose bengal: photodynamic effects on Friend leukemia virus infection of mice.

The ability of hypericin to protect mice from splenomegaly resulting from infection with Friend leukemia virus (FLV) was re-examined in light of recent evidence showing that light is absolutely required for this drug's antiviral activity. FLV-induced splenomegaly was not prevented or ameliorated in mice injected with 100 micrograms hypericin, either mixed with the FLV inoculum or administered 1 day p.i., either under normal laboratory light or in the dark. These results contradict previous findings. Both hypericin and rose bengal, however, inactivated the FLV inoculum at low doses (< 11 micrograms), provided that the mixture was illuminated for 1 h under a normal fluorescent desk lamp. This procedure protected mice completely from FLV-induced splenomegaly, and provided a possible explanation for the discrepancy between our results and those reported previously. We conclude that for FLV, as for other enveloped viruses studied previously, illumination of hypericin with the virus is absolutely required for hypericin's antiviral (virucidal) effects, thus limiting its potential usefulness as an antiretroviral agent.

Changes in circadian rhythmicity of liver and serum parameters in rats fed a total parenteral nutrition solution by continuous and discontinuous intravenous or intragastric infusion.

Circadian rhythms were assessed in rats (224-246 grams) receiving either an intragastric (IG) or intravenous (IV) infusion continuously (C), or IG or IV infusions discontinuously (D) from 0000 to 1400 hours daily. A control group was maintained on a stock diet ad libitum. IV- and IG-fed rats were infused with 50 milliliters per day of a solution containing 25% dextrose and 4.25% amino acids plus vitamins and minerals. After 10 to 11 days, groups of rats were killed from each treatment every 6 hours over a 24-hour period. Results showed that IG feeding promoted better growth and nitrogen retention than IV feeding. Rhythm patterns for liver weight, glycogen, and protein content were similar between D-IG and D-IV infused rats. All groups except the D-IV fed rats exhibited fluctuations of serum insulin. A rhythm was not present for serum glucose in C-IV fed rats and a rhythm was also absent for serum albumin in both C-IV and D-IV fed rats. C-IV feeding increased serum glucose and insulin levels and decreased serum albumin levels in comparison to IG feeding. In comparison to the ad libitum-fed, control rats, C-IV or D-IV or IG infusions led to alterations in liver and serum parameters.