Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial

Background Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. Method/Design 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. Discussion The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. Trial Registration: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health

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

Broadband Quantum Enhancement of the LIGO Detectors with Frequency-Dependent Squeezing

Quantum noise imposes a fundamental limitation on the sensitivity of interferometric gravitational-wave detectors like LIGO, manifesting as shot noise and quantum radiation pressure noise. Here, we present the first realization of frequency-dependent squeezing in full-scale gravitational-wave detectors, resulting in the reduction of both shot noise and quantum radiation pressure noise, with broadband detector enhancement from tens of hertz to several kilohertz. In the LIGO Hanford detector, squeezing reduced the detector noise amplitude by a factor of 1.6 (4.0 dB) near 1 kHz; in the Livingston detector, the noise reduction was a factor of 1.9 (5.8 dB). These improvements directly impact LIGO's scientific output for high-frequency sources (e.g., binary neutron star postmerger physics). The improved low-frequency sensitivity, which boosted the detector range by 15%-18% with respect to no squeezing, corresponds to an increase in the astrophysical detection rate of up to 65%. Frequency-dependent squeezing was enabled by the addition of a 300-meter-long filter cavity to each detector as part of the LIGO A+ upgrade

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

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

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

Gestational diabetes and the incidence of diabetes in the 5 years following the index pregnancy in South Indian women

This study was carried out to examine the incidence of diabetes and the factors associated with this in a cohort of South Indian women 5 years after they were examined for gestational diabetes (GDM). Women (N=630) whose GDM status was determined (Carpenter-Coustan criteria; GDM: N=41) delivered live babies without major anomalies at the Holdsworth Memorial Hospital, Mysore. Of these, 526 women (GDM: N=35) available for follow-up after 5 years underwent a 2-h oral glucose tolerance test and detailed anthropometry. Diabetes was determined using WHO criteria, and Metabolic Syndrome using IDF criteria recommended for south Asian women. The incidence of diabetes (37% versus 2%) and Metabolic Syndrome (60% versus 26%) was considerably higher in women with previous GDM compared to non-GDM women. GDM women who developed diabetes had lower gestational insulin area-under-the-curve (P=0.05). They had larger waist-to-hip ratio, skinfolds, body mass index, and lower 30-min insulin increment at follow-up than other GDM women. In all, history of diabetes in first-degree relatives was independently associated with higher incidence of diabetes (P<0.001). Our findings suggest high diabetes and cardiovascular risks in women with previous GDM. Follow-up of these women after delivery would provide opportunities to modify adverse lifestyle factor

Broadband quantum enhancement of the LIGO detectors with frequency-dependent squeezing

Quantum noise imposes a fundamental limitation on the sensitivity of interferometric gravitational-wave detectors like LIGO, manifesting as shot noise and quantum radiation pressure noise. Here, we present the first realization of frequency-dependent squeezing in full-scale gravitational-wave detectors, resulting in the reduction of both shot noise and quantum radiation pressure noise, with broadband detector enhancement from tens of hertz to several kilohertz. In the LIGO Hanford detector, squeezing reduced the detector noise amplitude by a factor of 1.6 (4.0 dB) near 1 kHz; in the Livingston detector, the noise reduction was a factor of 1.9 (5.8 dB). These improvements directly impact LIGO’s scientific output for high-frequency sources (e.g., binary neutron star postmerger physics). The improved low-frequency sensitivity, which boosted the detector range by 15%–18% with respect to no squeezing, corresponds to an increase in the astrophysical detection rate of up to 65%. Frequency-dependent squeezing was enabled by the addition of a 300-meter-long filter cavity to each detector as part of the LIGO A + upgrade