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We present a novel fully Bayesian analysis to constrain short gamma-ray burst (sGRB) jet structures associated with cocoon, wide-angle, and simple top-hat jet models, as well as the binary neutron star (BNS) merger rate. These constraints are made given the distance and inclination information from GW170817, observed flux of GRB 170817A, observed rate of sGRBs detected by Swift, and the neutron star merger rate inferred from LIGO’s first and second observing runs. A separate analysis is conducted where a fitted sGRB luminosity function is included to provide further constraints. The jet structure models are further constrained using the observation of GW190425, and we find that the assumption that it produced a GRB 170817–like sGRB which went undetected due to the jet geometry is consistent with previous observations. We find and quantify evidence for low-luminosity and wide-angle jet structuring in the sGRB population, independently from afterglow observations, with log Bayes factors of 0.45–0.55 for such models when compared to a classical top-hat jet. Slight evidence is found for a Gaussian jet structure model over all others when the fitted luminosity function is provided, producing log Bayes factors of 0.25–0.9 ± 0.05 when compared to the other models. However, without considering GW190425 or the fitted luminosity function, the evidence favors a cocoon-like model with log Bayes factors of 0.14 ± 0.05 over the Gaussian jet structure. We provide new constraints to the BNS merger rates of 1–1300 Gpc ^−3 yr ^−1 or 2–680 Gpc ^−3 yr ^−1 when a fitted luminosity function is assumed.

Following the faint gamma-ray burst, GRB 170817A, coincident with a gravitational wave-detected binary neutron star merger at d ∼ 40 Mpc, we consider the constraints on a local population of faint short duration GRBs (defined here broadly as T 90 < 4 s). We review proposed low-redshift short-GRBs and consider statistical limits on a d ≲ 200 Mpc population using Swift/Burst Alert Telescope (BAT), Fermi/Gamma-ray Burst Monitor (GBM), and Compton Gamma-Ray Observatory (CGRO) Burst and Transient Source Experiment (BATSE) GRBs. Swift/BAT short-GRBs give an upper limit for the all-sky rate of < 4 y − 1 at d < 200 Mpc, corresponding to < 5% of SGRBs. Cross-correlation of selected CGRO/BATSE and Fermi/GBM GRBs with d < 100 Mpc galaxy positions returns a weaker constraint of ≲ 12 y − 1 . A separate search for correlations due to SGR giant flares in nearby ( d < 11 Mpc) galaxies finds an upper limit of < 3 y − 1 . Our analysis suggests that GRB 170817A-like events are likely to be rare in existing SGRB catalogues. The best candidate for an analogue remains GRB 050906, where the Swift/BAT location was consistent with the galaxy IC 0327 at d ≈ 132 Mpc. If binary neutron star merger rates are at the high end of current estimates, then our results imply that at most a few percent will be accompanied by detectable gamma-ray flashes in the forthcoming LIGO/Virgo science runs.

We present polarimetric and photometric observations from a sample of 15 γ-ray bright blazars with data from the Tuorla blazar monitoring program (KVA DIPOL) and Liverpool Telescope (LT) Ringo2 polarimeters (supplemented with γ-ray data from Fermi-LAT). We find that (1) The optical magnitude and γ-ray flux are positively correlated; (2) electric vector position angle rotations can occur in any blazar subclass; (3) there is no difference in the γ-ray flaring rates in the sample between subclasses; flares can occur during and outside of rotations with no preference for this behaviour; (4) the average degree of polarisation (P), optical magnitude and γ-ray flux are lower during a rotation compared with during non-rotation; (5) the number of observed flaring events and optical polarisation rotations are correlated and (6) the maximum observed P increases from ∼10% to ∼30% to ∼40% for subclasses with synchrotron peaks at high, intermediate and low frequencies respectively.

BackgroundExtractive methods for machine reading comprehension (MRC) tasks have achieved comparable or better accuracy than human performance on benchmark data sets. However, such models are not as successful when adapted to complex domains such as health care. One of the main reasons is that the context that the MRC model needs to process when operating in a complex domain can be much larger compared with an average open-domain context. This causes the MRC model to make less accurate and slower predictions. A potential solution to this problem is to reduce the input context of the MRC model by extracting only the necessary parts from the original context. ObjectiveThis study aims to develop a method for extracting useful contexts from long articles as an additional component to the question answering task, enabling the MRC model to work more efficiently and accurately. MethodsExisting approaches to context extraction in MRC are based on sentence selection strategies, in which the models are trained to find the sentences containing the answer. We found that using only the sentences containing the answer was insufficient for the MRC model to predict correctly. We conducted a series of empirical studies and observed a strong relationship between the usefulness of the context and the confidence score output of the MRC model. Our investigation showed that a precise input context can boost the prediction correctness of the MRC and greatly reduce inference time. We proposed a method to estimate the utility of each sentence in a context in answering the question and then extract a new, shorter context according to these estimations. We generated a data set to train 2 models for estimating sentence utility, based on which we selected more precise contexts that improved the MRC model’s performance. ResultsWe demonstrated our approach on the Question Answering Data Set for COVID-19 and Biomedical Semantic Indexing and Question Answering data sets and showed that the approach benefits the downstream MRC model. First, the method substantially reduced the inference time of the entire question answering system by 6 to 7 times. Second, our approach helped the MRC model predict the answer more correctly compared with using the original context (F1-score increased from 0.724 to 0.744 for the Question Answering Data Set for COVID-19 and from 0.651 to 0.704 for the Biomedical Semantic Indexing and Question Answering). We also found a potential problem where extractive transformer MRC models predict poorly despite being given a more precise context in some cases. ConclusionsThe proposed context extraction method allows the MRC model to achieve improved prediction correctness and a significantly reduced MRC inference time. This approach works technically with any MRC model and has potential in tasks involving processing long texts.

The burden of hypertension has been growing over recent decades. In addition to risk of stroke and cardiovascular disease development, data indicates that hypertension may also pose a hazard to the quality of life (QoL) of individuals. Patient reported outcomes such as QoL are often overlooked, with physicians and healthcare professionals not routinely evaluating or customizing treatments according to QoL. In this study we aimed to assess the QoL of hypertensive men (n = 500) undergoing treatment who visited a charitable hospital in Pune, India. Clinic blood pressure was determined and the Mini Cuestionario de Calidad de Vida en Hipertensión Arterial (MINICHAL) scale was used to assess the health-related (HR)-QoL of patients. More than half of the participants (62%) had uncontrolled hypertension, with a mean systolic blood pressure (BP) of 151 ± 12 mmHg and diastolic blood pressure of 87 ± 6 mmHg as compared to those with controlled blood pressure (mean systolic blood pressure 123 ± 6 mmHg and diastolic blood pressure 84 ± 5 mmHg; P

In research spanning three decades we have estimated brain monoamine turnover (approximately equating with synthesis rate) with sampling from the internal jugular veins and measurement of trans-cerebral plasma monoamine metabolite concentration gradients. Here we report indices of brain noradrenaline and serotonin turnover in patients with major depressive illness (MDD) and panic disorder (PD). Brain noradrenaline turnover was assessed from the combined flux into the internal jugular veins of the metabolites dihydroxyphenylglycol (DHPG) and 3-hydroxy-4-methoxyphenylglycol (MHPG), and brain serotonin turnover from the overflow of the primary metabolite, 5-hydroxyindole acetic acid (5HIAA). Comparison was made with matched healthy research participants. In both MD and PD the estimate of brain noradrenaline turnover provided by metabolite overflow was unremarkable. In contrast, in both patient groups the estimate of brain serotonin turnover provided by 5HIAA overflow was increased 3–4-fold (P < 0.01). This neurotransmitter abnormality was normalized in MDD and PD in clinical remission, during selective serotonin reuptake blocker (SSRI) dosing. We cannot be sure if the brain serotonergic abnormality we find in MDD and PD is causal or a correlate. Measurements in PD were not made during a panic attack. The increased estimated serotonin turnover here may possibly be a substrate for panic attacks; serotonergic raphe nuclei participate in anxiety responses in experimental animals. It is puzzling that the findings were identical in MDD and PD, although it may be pertinent that these psychiatric diagnoses are commonly comorbid. It is unlikely that activation of brain serotonergic neurons is driving the sympathetic nervous activation present, which contributes to cardiovascular risk, persistent sympathetic activation in MDD and episodic activation in PD during panic attacks. We have previously demonstrated that the mechanism of activation of human central sympathetic outflow in other contexts (hypertension, heart failure) is activation of noradrenergic brainstem neurons projecting to the hypothalamus and amygdala.

Abstract Background Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. Methods A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment – Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. Results There was no difference in mean change in musculoskeletal symptoms (− 0.6 ± 1.7 vs − 0.4 ± 1.8, p = 0.69) or VISA-A (moxonidine − 0.2 ± 8.8 vs placebo + 4.2 ± 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. Conclusions This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. Trial registration ClinicalTrials.gov, NCT01504321 . Registered 5 January 2012.

ObjectiveExcess adiposity increases the risk of type-2 diabetes and cardiovascular disease development. Beyond the simple level of adiposity, the pattern of fat distribution may influence these risks. We sought to examine if higher android fat distribution was associated with different hemodynamic, metabolic or vascular profile compared to a lower accumulation of android fat deposits in young overweight males.MethodsForty-six participants underwent dual-energy X-ray absorptiometry and were stratified into two groups. Group 1: low level of android fat (9.5%). Assessments comprised measures of plasma lipid and glucose profile, blood pressure, endothelial function [reactive hyperemia index (RHI)] and muscle sympathetic nerve activity (MSNA).ResultsThere were no differences in weight, BMI, total body fat and lean mass between the two groups. Glucose tolerance and insulin resistance (fasting plasma insulin) were impaired in group 2 (p < 0.05). Levels of plasma triglycerides and 5 lipid species were higher in group 2 (p < 0.05). Endothelial function was less in group 2 (RHI: 1.64 vs. 2.26, p = 0.003) and heart rate was higher (76 vs. 67 bpm, p = 0.004). No difference occurred in MSNA nor blood pressure between the 2 groups.ConclusionPreferential fat accumulation in the android compartment is associated with increased cardiovascular and metabolic risk via alteration of endothelial function.

Objective: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. Research Design and Methods: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

BackgroundThe exact pathophysiology of Tako-Tsubo cardiomyopathy (TTC) remains unknown but a role for sympathetic hyperactivity has been suggested. Up to now, no direct evidence of sympathetic nerve hyperactivity has been established nor involvement of sympathetic baroreflex identified. The aim of our study was to determine, by direct sympathetic nerve activity (SNS) recording if sympathetic nervous system activity is increased and spontaneous baroreflex control of sympathetic activity reduced in patients with TTC.MethodsWe included 13 patients who presented with TTC and compared their SNS activity and spontaneous baroreflex control of sympathetic activity with that of 13 control patients with acutely decompensated chronic heart failure. SNS activity was evaluated by microneurography, a technique assessing muscle sympathetic nerve activity (MSNA). Spontaneous baroreflex control of sympathetic activity was evaluated as the absolute value of the slope of the regression line representing the relationship between spontaneous diastolic blood pressure values and concomitant SNS activity. Control patients were matched for age, sex, left ventricular ejection fraction and creatinine clearance.ResultsThe mean age of the patients with TTC was 80 years, all patients were women. There were no significant differences between the two groups of patients for blood pressure, heart rate or oxygen saturation level. TTC patients presented a significant increase in sympathetic nerve activity (MSNA median 63.3 bursts/min [interquartile range 61.3 to 66.0] vs median 55.7 bursts/min [interquartile range 51.0 to 61.7]; p = 0.0089) and a decrease in spontaneous baroreflex control of sympathetic activity compared to matched control patients (spontaneous baroreflex control of sympathetic activity median 0.7%burst/mmHg [interquartile range 0.4 to 1.9] vs median 2.4%burst/mmHg [interquartile range 1.8 to 2.9]; p = 0.005).ConclusionsWe report for the first time, through direct measurement of sympathetic nerve activity, that patients with TTC exhibit elevated SNS activity associated with a decrease in spontaneous baroreflex control of sympathetic activity. These data may explain the pathophysiology and clinical presentation of patient with TTC.

Reduced function of the noradrenaline transporter (NET) has been demonstrated in patients with major depressive disorder (MDD) and panic disorder. Attempts to explain NET dysfunction in MDD and panic disorder by genetic variation in the NET gene SLC6a2 have been inconclusive. Transcriptional silencing of the SLC6a2 gene may be an alternative mechanism which can lead to NET dysfunction independent of DNA sequence. The objective of this study was to characterise the DNA methylation state of the SLC6a2 gene promoter in patients with MDD and panic disorder. SLC6a2 promoter methylation was also analysed before and after antidepressant treatment. This study was performed with DNA from blood, using bisulphite sequencing and EpiTYPER methylation analyses. Patients with MDD or panic disorder were not found to differ significantly from healthy controls in the pattern of methylation of the SLC6a2 gene promotor. While significant correlations between methylation levels at some CpG sites and physiological measures were identified, overall the variation in DNA methylation between patients was small, and the significance of this variation remains equivocal. No significant changes in SLC6a2 promoter methylation were observed in response to antidepressant treatment. Further in-depth analysis of alternative mechanisms of transcriptional regulation of the SLC6a2 gene in human health and disease would be of value.