The US Program in Ground-Based Gravitational Wave Science: Contribution from the LIGO Laboratory

Recent gravitational-wave observations from the LIGO and Virgo observatories have brought a sense of great excitement to scientists and citizens the world over. Since September 2015,10 binary black hole coalescences and one binary neutron star coalescence have been observed. They have provided remarkable, revolutionary insight into the "gravitational Universe" and have greatly extended the field of multi-messenger astronomy. At present, Advanced LIGO can see binary black hole coalescences out to redshift 0.6 and binary neutron star coalescences to redshift 0.05. This probes only a very small fraction of the volume of the observable Universe. However, current technologies can be extended to construct "3rd Generation" (3G) gravitational-wave observatories that would extend our reach to the very edge of the observable Universe. The event rates over such a large volume would be in the hundreds of thousands per year (i.e. tens per hour). Such 3G detectors would have a 10-fold improvement in strain sensitivity over the current generation of instruments, yielding signal-to-noise ratios of 1000 for events like those already seen. Several concepts are being studied for which engineering studies and reliable cost estimates will be developed in the next 5 years

Récepteurs A2A de l'adénosine et hypotension artérielle per-dialytique

L'adénosine est un nucléoside ubiquitaire provenant de la déphosphorylation de l'ATP et libérée par les cellules endothéliales et les myocytes. L'adénosine extracellulaire active des récepteurs purinergiques, qui font partie de la superfamille des récepteurs couplés à une protéine G. Ces récepteurs sont impliqués dans le contrôle du système nerveux autonome et régulent le tonus vasculaire et la fréquence cardiaque. Partant de la constatation que l'adénosine est augmentée en concentration dans le plasma des patients traités par hémodialyse, le but de ce travail était d'étudier l'expression des récepteurs A2A de l'adénosine chez ces patients. En effet, les effets de l'adénosine sur le système cardiovasculaire dépendent à la fois de sa concentration extra cellulaire mais également du nombre de récepteurs exprimés à la membrane. A ce titre, nous avons évalué le Bmax, le KD et la quantité d'ARNm des récepteurs A2A de l'adénosine sur des cellules mononuclées périphériques. Le récepteur A2A a été choisi car il est tout particulièrement impliqué dans le contrôle de la pression artérielle systolique et la fréquence cardiaque. Nous montrons que chez les patients faisant des épisodes d'hypotension perdialytique à répétition, complication fréquente de l'hémodialyse, le nombre de récepteurs exprimés à la membrane cellulaire était plus important que chez ceux ne faisant pas d'hypotension. L'hypotension perdialytique à répétition étant néfaste pour le patient, ces résultats ouvrent des perspectives thérapeutiques par l'utilisation de bloqueurs des récepteurs purinergiques.Background :Intradialytic hypotension (IDH) is a common complication of hemodialysis session (HDS). Among different factors, adenosine (ADO) may participate in the drop of blood pressure since ADO via A2A adenosine receptors activation has strong hypotensive effects. Because A2A receptor expression is crucial for blood pressure control, and because changes in peripheral A2A receptors mirror changes of these receptors in the cardiovascular system, we evaluated the expression (i.e Bmax , KD and mRNA amount) of peripheral blood mononuclear cells A2A receptors in IDH patients. We also evaluated ADO plasma level (APL). Methods : Ten hemodialyzed patients (5 men and 5 women, mean age 62+-12 years) with a story of at least 3 episodes of IDH per month were included. The criteria for IDH were a decrease in systolic blood pressure of at least 30mmHg of basal and a systolic blood pressure <100mmHg, accompanied by nausea and or vomiting. Eleven hemodialyzed patients (6 men and 5 women, mean age 65+-13 years), without story of IDH event were also included. Ten healthy subjects (4 men and 6 women, mean age 47+-21 years) without medication served as controls. Results :Before HDS, APL was higher in hemodialyzed patients than in controls (mean+125%). During HDS, APL increased significantly (mean +26%, p<0.05). Non IDH patients have lower Bmax values than controls (mean 72%) ; IDH patients have higher Bmax values than non IDH (mean: before HDS ; +86% ; after HDS +112 % ; p<0.05). However Bmax values of IDH patients remain in the range of controls. KD values were not significantly different in patients and controls and were not influenced by HDS. mRNA amount was increased weakly but significantly during HDS, but this increase was not followed by an increased expression at the cell membrane. Conclusion : we found that A2A receptors are more expressed in IDH patients. The vasodilatory properties of these receptors in a context of high APL may favoured IDH events. The use of A2A blokers may be useful in preventing IDH events.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Influence of the dialysis membrane on markers of tissue ischemia.

BACKGROUND: Hemodialysis (HD) is often accompanied by adverse effects, such as tissue ischemia. We have already observed an increase in plasma adenosine (ADO) levels during HD sessions, which may be the result of tissue ischemia. Here we evaluate the influence of the dialysis membrane on two sensitive and early markers of ischemia: ADO and ischemia-modified albumin (IMA). METHODS: We included in the study 50 patients with end-stage renal failure, 39 hemodialyzed (mean age 61+/-24 years; 24 male; membranes: 23 synthetic and 16 cellulose based) and 11 undialyzed (mean age 55+/-12 years; 6 male), and 10 healthy subjects (mean age 47+/-11 years; 4 male). We compensated for hemoconcentration during HD by measuring either the IMA to albumin (Alb) or the ADO to Alb ratio. RESULTs: Under basal conditions, the IMA to Alb ratio was not significantly different in patients and controls and HD did not significantly modify this ratio. Conversely, the ADO to Alb ratio (mean+/-SD in micromol/g) was higher in patients before HD compared with either undialyzed patients or controls (before HD: 0.077+/-0.02; undialyzed patients: 0.026+/-0.11; controls: 0.022+/-0.01). During HD, there was a significant increase in the ADO to Alb ratio (before HD: 0.077+/-0.02; after HD: 0.09+/-0.029; p<.01). We found no significant difference in the IMA to Alb or ADO to Alb ratio using either synthetic or cellulose-based membranes. CONCLUSIONS: We concluded that ADO is a more sensitive marker of ischemia than IMA and that, under our HD conditions, the ischemia caused by HD was very weak, independent of the dialysis membrane

Influence of the dialysis membrane on markers of tissue ischemia.

BACKGROUND: Hemodialysis (HD) is often accompanied by adverse effects, such as tissue ischemia. We have already observed an increase in plasma adenosine (ADO) levels during HD sessions, which may be the result of tissue ischemia. Here we evaluate the influence of the dialysis membrane on two sensitive and early markers of ischemia: ADO and ischemia-modified albumin (IMA). METHODS: We included in the study 50 patients with end-stage renal failure, 39 hemodialyzed (mean age 61+/-24 years; 24 male; membranes: 23 synthetic and 16 cellulose based) and 11 undialyzed (mean age 55+/-12 years; 6 male), and 10 healthy subjects (mean age 47+/-11 years; 4 male). We compensated for hemoconcentration during HD by measuring either the IMA to albumin (Alb) or the ADO to Alb ratio. RESULTs: Under basal conditions, the IMA to Alb ratio was not significantly different in patients and controls and HD did not significantly modify this ratio. Conversely, the ADO to Alb ratio (mean+/-SD in micromol/g) was higher in patients before HD compared with either undialyzed patients or controls (before HD: 0.077+/-0.02; undialyzed patients: 0.026+/-0.11; controls: 0.022+/-0.01). During HD, there was a significant increase in the ADO to Alb ratio (before HD: 0.077+/-0.02; after HD: 0.09+/-0.029; p<.01). We found no significant difference in the IMA to Alb or ADO to Alb ratio using either synthetic or cellulose-based membranes. CONCLUSIONS: We concluded that ADO is a more sensitive marker of ischemia than IMA and that, under our HD conditions, the ischemia caused by HD was very weak, independent of the dialysis membrane

Relationship between A2A adenosine receptor expression and intradialytic hypotension during hemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is a common complication of hemodialysis sessions (HDSs). Adenosine may contribute to the drop in blood pressure during IDH events because it has hypotensive effects. As A(2A) adenosine receptor expression is essential for blood pressure control, we compared the expression of A(2A) receptors (Bmax, K(D), and messenger ribonucleic acid [mRNA] levels) in peripheral blood mononuclear cells from IDH and non-IDH patients and from controls. We also evaluated adenosine plasma levels (APLs). METHODS: We included 10 hemodialyzed patients with at least three IDH events per month. We also included 11 hemodialyzed patients with no history of IDH events and 10 healthy subjects as controls. RESULTS: IDH patients had higher Bmax values than non-IDH patients (mean before HDS, +86%; after HDS, +112%), whereas non-IDH patients had lower Bmax values than controls (mean -72%). K(D) values were not significantly different between patients and controls. The levels of mRNA increased significantly during HDS but without an increase in receptor expression on the cell membranes. APLs were higher in hemodialyzed patients than in controls. CONCLUSION: We found that A(2A) receptors are more expressed in IDH patients than in non-IDH patients, whereas APL was high in all patients. Both high APL and a relative increase in A(2A) receptor expression may favor IDH events

Hydroxychloroquine and azithromycin tolerance in haemodialysis patients during COVID-19 infection

International audienceBackground. Haemodialysis patients are at risk of developing severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: coronavirus disease 2019 (COVID-19). In March 2020, hydroxychloroquine (HCQ) and azithromycin (AZI) were proposed as potential treatments of COVID-19, but with warnings concerning their possible toxicity. No data are available regarding the toxicity of this treatment in haemodialysis patients.Methods. We report the use of HCQ and AZI in a cohort of COVID-19 haemodialysis patients with focus on safety concerns.Results. Twenty-one patients received 200 mg HCQ thrice daily during 10 days, and AZI 500 mg on Day 1, and 250 mg on the four following days. HCQ plasma concentrations were within the recommended range (0.1-1.0 mu g/mL) in all patients except one, in which maximum concentration was 1.1 mu g/mL. HCQ concentration raised until the third day and remained stable thereafter. No cardiac event occurred in spite of progressive lengthening of corrected QT interval (QTc) during the treatment. One patient experienced a long QTc syndrome (QTc >500 ms) without any arrhythmia episode, although HCQ concentration was in the target range. Five (23.8%) patients experienced hypoglycaemia, a well-known HCQ side-effect. SARS-CoV-2 RNA remained detectable in nasopharyngeal swabs for a long time in haemodialysis patients (mean time 21 days).Conclusions. HCQ and AZI are safe in haemodialysis patients at these doses but can lead to long QTc syndrome and hypoglycaemia. HCQ concentrations were not correlated with side effects. We recommend monitoring of the QTc length throughout treatment, as well as glycaemia. SARS-CoV-2 could persist for longer in haemodialysis patients than in the general population

The "Dose-Effect" Relationship Between 25-Hydroxyvitamin D and Muscle Strength in Hemodialysis Patients Favors a Normal Threshold of 30 ng/mL for Plasma 25-Hydroxyvitamin D.

International audienceMuscle strength is weakened in maintenance hemodialysis patients. Strength is both a measure of a functional parameter and of frailty as it is independently associated with mortality. In the general population, observational studies show that plasma 25-hydroxyvitamin D (25[OH]D) is positively correlated with muscle strength and function. We analyzed the determinants of muscle strength measured by handgrip and 25(OH)D in a maintenance hemodialysis population.In this observational cross-sectional study, data from all hemodialysis patients from our nephrology department were recorded in July 2014. Daily nutritional oral intake, handgrip strength, body composition measured by bioimpedancemetry analysis, as well as biological and dialysis parameters, were obtained from medical files. We used a linear regression model to assess nutritional, biological, and dialysis parameters as well as body composition associated with handgrip strength.The median age (interquartile range) of the 130 included patients was 77.3 (69.5-84.7) years, 57.7% were men, and 50.8% had diabetes mellitus. Median handgrip strength value (interquartile range) was 14.3 (10.6-22.2) kg. In univariate analyses, the factors associated with handgrip strength were age, gender, albumin, transthyretin, predialysis creatinine and urea, normalized protein nitrogen appearance, lean mass, and muscle mass measured by bioimpedancemetry analysis as well as phase angle, and 25(OH)D. In multivariate analyses, lower age, male gender, higher albumin, higher muscle mass, and 25(OH)D level ≥ 30 ng/mL were independently correlated with muscle strength measured by handgrip.This study found a positive correlation between plasma 25(OH)D and muscle strength measured by handgrip in hemodialysis patients. We report a "dose-effect" relationship between 25(OH)D and handgrip strength under 30 ng/mL, which is no more present above 30 ng/mL. Prospective randomized studies are needed to prove that supplementation with cholecalciferol, leading to 25(OH)D levels ≥ 30 ng/mL, improves muscle strength in hemodialysis patients

The “Dose-Effect” Relationship Between 25-Hydroxyvitamin D and Muscle Strength in Hemodialysis Patients Favors a Normal Threshold of 30 ng/mL for Plasma 25-Hydroxyvitamin D

International audienceObjective: Muscle strength is weakened in maintenance hemodialysis patients. Strength is both a measure of a functional parameter and of frailty as it is independently associated with mortality. In the general population, observational studies show that plasma 25-hydroxyvitamin D (25[OH]D) is positively correlated with muscle strength and function. We analyzed the determinants of muscle strength measured by handgrip and 25(OH)D in a maintenance hemodialysis population. Methods: In this observational cross-sectional study, data from all hemodialysis patients from our nephrology department were recorded in July 2014. Daily nutritional oral intake, handgrip strength, body composition measured by bioimpedancemetry analysis, as well as biological and dialysis parameters, were obtained from medical files. We used a linear regression model to assess nutritional, biological, and dialysis parameters as well as body composition associated with handgrip strength. Results: The median age (interquartile range) of the 130 included patients was 77.3 (69.5-84.7) years, 57.7% were men, and 50.8% had diabetes mellitus. Median handgrip strength value (interquartile range) was 14.3 (10.6-22.2) kg. In univariate analyses, the factors associated with handgrip strength were age, gender, albumin, transthyretin, predialysis creatinine and urea, normalized protein nitrogen appearance, lean mass, and muscle mass measured by bioimpedancemetry analysis as well as phase angle, and 25(OH)D. In multivariate analyses, lower age, male gender, higher albumin, higher muscle mass, and 25(OH)D level >= 30 ng/mL were independently correlated with muscle strength measured by handgrip. Conclusions: This study found a positive correlation between plasma 25(OH)D and muscle strength measured by handgrip in hemodialysis patients. We report a "dose-effect'' relationship between 25(OH)D and handgrip strength under 30 ng/mL, which is no more present above 30 ng/mL. Prospective randomized studies are needed to prove that supplementation with cholecalciferol, leading to 25(OH)D levels >= 30 ng/mL, improves muscle strength in hemodialysis patients.

The "Dose-Effect" Relationship Between 25-Hydroxyvitamin D and Muscle Strength in Hemodialysis Patients Favors a Normal Threshold of 30 ng/mL for Plasma 25-Hydroxyvitamin D.

International audienceMuscle strength is weakened in maintenance hemodialysis patients. Strength is both a measure of a functional parameter and of frailty as it is independently associated with mortality. In the general population, observational studies show that plasma 25-hydroxyvitamin D (25[OH]D) is positively correlated with muscle strength and function. We analyzed the determinants of muscle strength measured by handgrip and 25(OH)D in a maintenance hemodialysis population.In this observational cross-sectional study, data from all hemodialysis patients from our nephrology department were recorded in July 2014. Daily nutritional oral intake, handgrip strength, body composition measured by bioimpedancemetry analysis, as well as biological and dialysis parameters, were obtained from medical files. We used a linear regression model to assess nutritional, biological, and dialysis parameters as well as body composition associated with handgrip strength.The median age (interquartile range) of the 130 included patients was 77.3 (69.5-84.7) years, 57.7% were men, and 50.8% had diabetes mellitus. Median handgrip strength value (interquartile range) was 14.3 (10.6-22.2) kg. In univariate analyses, the factors associated with handgrip strength were age, gender, albumin, transthyretin, predialysis creatinine and urea, normalized protein nitrogen appearance, lean mass, and muscle mass measured by bioimpedancemetry analysis as well as phase angle, and 25(OH)D. In multivariate analyses, lower age, male gender, higher albumin, higher muscle mass, and 25(OH)D level ≥ 30 ng/mL were independently correlated with muscle strength measured by handgrip.This study found a positive correlation between plasma 25(OH)D and muscle strength measured by handgrip in hemodialysis patients. We report a "dose-effect" relationship between 25(OH)D and handgrip strength under 30 ng/mL, which is no more present above 30 ng/mL. Prospective randomized studies are needed to prove that supplementation with cholecalciferol, leading to 25(OH)D levels ≥ 30 ng/mL, improves muscle strength in hemodialysis patients