Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial

Background: Non-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS. Methods: We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913. Findings: Between Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11·0 months [95% CI 8·3-13·6] vs 22·5 months [13·6-not reached]; adjusted hazard ratio 2·27, 95% CI 1·22-4·25; p=0·009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5·9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2·5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious. Interpretation: Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow both the frequency and the time derivative of the frequency of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search, we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets. © 2022. The Author(s). Published by the American Astronomical Society

Search for Gravitational Waves Associated with Gamma-Ray Bursts Detected by Fermi and Swift during the LIGO-Virgo Run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC-2020 March 27 17:00 UTC). We conduct two independent searches: A generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate. © 2022. The Author(s). Published by the American Astronomical Society

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of binary black hole coalescences confidently observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include the effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that have already been identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total source-frame mass M > 70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz emitted gravitational-wave frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place a conservative upper limit for the merger rate density of high-mass binaries with eccentricities 0 < e ≤ 0.3 at 16.9 Gpc−3 yr−1 at the 90% confidence level

Cohort profile: Mysore Parthenon Birth Cohort

The Mysore Parthenon Birth Cohort was established to examine the long-term effects of maternal glucose tolerance and nutritional status on cardiovascular disease risk factors in the offspring. During 1997-98, 830 of 1233 women recruited from the antenatal clinics of the Holdsworth Memorial Hospital (HMH), Mysore, India, underwent an oral glucose tolerance test. Of these, 667 women delivered live babies at HMH. Four babies with major congenital anomalies were excluded, and the remaining 663 were included for further follow-up. The babies had detailed anthropometry at birth and at 6-12-monthly intervals subsequently. Detailed cardiovascular investigations were done at ages 5, 9.5 and 13.5 years in the children, and in the parents at the 5-year and 9.5-year follow-ups. This ongoing study provides extensive data on serial anthropometry and body composition, physiological and biochemical measures, dietary intake, nutritional status, physical activity measures, stress reactivity measures and cognitive function, and socio-demographic parameters for the offspring. Data on anthropometry, cardiovascular risk factors and nutritional status are available for mothers during pregnancy. Anthropometry and risk factor measures are available for both parents at follow-up

Accelerometers for measuring physical activity behavior in Indian children

Objective: To examine the validity of accelerometers forcharacterizing habitual physical activity patterns in Indianchildren.Design: Cohort study.Setting: Holdsworth Memorial Hospital, Mysore.Subjects: Children (N=103, mean age 6.6 years) selectedfrom an ongoing birth cohort study.Methods: Physical activity was measured over 7 daysusing accelerometers (MTI Actigraph) and concurrentparent-maintained activity diaries. Actigraph counts perminute representing sedentary (&lt;10), light (&lt;400),moderate (&lt;3000) and vigorous (?3000) activity weredetermined using a structured activity session in aseparate group of 10 children. In 46 children chosen forvalidating accelerometers, time spent in different activitylevels according to diaries was determined. EnergyExpenditure (EE) was calculated from diaries using afactorial method.Results: Ninety-eight children wore the monitor for ?4days. Total counts and time spent in different activity levelswere similar in boys and girls (P&gt;0.2). Among 46 childrenchosen for comparisons, time spent in sedentary (r =0.48,P=0.001), light (r=0.70, P&lt;0.001) and moderate activities(r=0.29, P=0.054) according to diaries correlated withthose derived from counts, and total Actigraph countscorrelated with EE (r=0.42, P=0.004). Bland-Altmananalysis showed systematic bias, and wide limits ofagreement between these methods for time spent indifferent activity levels.Conclusions: Accelerometers are a well tolerated andobjective way of measuring activity behavior in free-livingchildren. Though accelerometer counts correlate with timespent in activity of varying intensity and energyexpenditure derived from parent-maintained diaries, widelimits of agreement show that the limitations ofaccelerometers need to be recognized in interpreting thedata that they generate

Adiposity and cortisol response to stress in Indian adolescents

SETTING: Holdsworth Memorial Hospital, Mysore, India.OBJECTIVE: We examined associations of different adiposity measures with cortisol responses during the Trier Social Stress Test for children (TSST-C).DESIGN: Descriptive study.PARTICIPANTS: Adolescents aged 13.5y from a birth cohort were recruited (N=269, 133 boys).METHODS: The stressor (TSST-C) was 5-minutes each of public speaking and mental arithmetic tasks in front of two unfamiliar 'judges'. Salivary cortisol concentrations were measured at baseline and at regular intervals after TSST-C. Weight, height, sub scapular and triceps skinfold thickness, and waist and hip circumference were measured, and percentage body fat was estimated (fat%; bioimpedance). Body mass index (BMI) and Waist-to-hip ratio (WHR) were calculated. All variables were converted into within-cohort SD scores before analysis. Stress-induced change in cortisol concentrations from baseline (cortisol response) was examined in relation to adiposity.RESULTS: Stress increased cortisol concentrations significantly from baseline (mean (SD): 5.5 (6.4) ng/mL; P&lt;0.001). Higher WHR was associated with lower cortisol response at 20 and 30-minutes after stress (~0.13 SD decrease in cortisol response per SD higher WHR, P&lt;0.05). Higher fat% was also associated with lower cortisol response only in girls 20-minutes post-stress (0.23 SD lower response per SD higher fat%, P=0.004). Sum of skinfold thickness and BMI were not associated with cortisol responses.CONCLUSION: Abdominal adiposity is associated with reduced hypothalamic-pituitary-adrenal axis reactivity to stress in this adolescent population.</p