Pulsar Timing and its Application for Navigation and Gravitational Wave Detection

Pulsars are natural cosmic clocks. On long timescales they rival the precision of terrestrial atomic clocks. Using a technique called pulsar timing, the exact measurement of pulse arrival times allows a number of applications, ranging from testing theories of gravity to detecting gravitational waves. Also an external reference system suitable for autonomous space navigation can be defined by pulsars, using them as natural navigation beacons, not unlike the use of GPS satellites for navigation on Earth. By comparing pulse arrival times measured on-board a spacecraft with predicted pulse arrivals at a reference location (e.g. the solar system barycenter), the spacecraft position can be determined autonomously and with high accuracy everywhere in the solar system and beyond. We describe the unique properties of pulsars that suggest that such a navigation system will certainly have its application in future astronautics. We also describe the on-going experiments to use the clock-like nature of pulsars to "construct" a galactic-sized gravitational wave detector for low-frequency (f_GW ~1E-9 - 1E-7 Hz) gravitational waves. We present the current status and provide an outlook for the future.Comment: 30 pages, 9 figures. To appear in Vol 63: High Performance Clocks, Springer Space Science Review

New clinical prediction model for early recognition of sepsis in adult primary care patients:a prospective diagnostic cohort study of development and external validation

Background Recognising patients who need immediate hospital treatment for sepsis while simultaneously limiting unnecessary referrals is challenging for GPs.Aim To develop and validate a sepsis prediction model for adult patients in primary care.Design and setting This was a prospective cohort study in four out-of-hours primary care services in the Netherlands, conducted between June 2018 and March 2020.Method Adult patients who were acutely ill and received home visits were included. A total of nine clinical variables were selected as candidate predictors, next to the biomarkers C-reactive protein, procalcitonin, and lactate. The primary endpoint was sepsis within 72 hours of inclusion, as established by an expert panel. Multivariable logistic regression with backwards selection was used to design an optimal model with continuous clinical variables. The added value of the biomarkers was evaluated. Subsequently, a simple model using single cut-off points of continuous variables was developed and externally validated in two emergency department populations.Results A total of 357 patients were included with a median age of 80 years (interquartile range 71–86), of which 151 (42%) were diagnosed with sepsis. A model based on a simple count of one point for each of six variables (aged >65 years; temperature >38°C; systolic blood pressure ≤110 mmHg; heart rate >110/min; saturation ≤95%; and altered mental status) had good discrimination and calibration (C-statistic of 0.80 [95% confidence interval = 0.75 to 0.84]; Brier score 0.175). Biomarkers did not improve the performance of the model and were therefore not included. The model was robust during external validation.Conclusion Based on this study’s GP out-of-hours population, a simple model can accurately predict sepsis in acutely ill adult patients using readily available clinical parameters

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease

No specific effect of fluoxetine treatment on fasting glucose, insulin, lipid levels, and blood pressure in healthy men with abdominal obesity

In this paper we investigated the effect of fluoxetine (60 mg/d) on serum lipids, glucose and insulin concentrations and blood pressure by means of a randomized, double-blind placebo controlled trial. Thirty-eight overweight (BMI: 26-30 kg/m2), nondiabetic, nonhypertensive men with an abdominal fat distribution (waist/hip ratio: > 0.97) received dietary advice and placebo or fluoxetine for 12 weeks. The changes in serum parameters and blood pressure in the fluoxetine treated group were not different from the placebo treated group, despite a significantly larger weight loss in the fluoxetine group. In both groups serum total-cholesterol concentrations, serum LDL-cholesterol concentrations and the HDL/LDL ratio were significantly improved after treatment. Reductions in fasting glucose concentration and systolic blood pressure were only significant in the placebo group. A reduction of serum triglycerides and an increase of HDL-cholesterol were found in the fluoxetine treated group. In the total study population the changes in serum lipids seemed to be more strongly related to the change in total body fat or subcutaneous abdominal fat (assessed by MRI) compared to the change in visceral fat. The improvement of most of the serum lipids was related to the change in total body fat independent of the mechanism for attaining this fat loss. Our results indicate that fluoxetine treatment has no specific effect beyond that expected for weight loss on serum lipid, glucose and insulin concentrations, and blood pressure in overweight men

The effect of fluoxetine on body weight, body composition and visceral fat accumulation

In this study the effect of fluoxetine versus placebo treatment on body weight, body composition and abdominal fat areas, assessed from three magnetic resonance imaging scans at umbilicus level, was investigated. Thirty-eight abdominal overweight men aged 41 +/- 7 years (mean +/- s.d.), BMI 27.9 +/- 1.2 kg/m2 and WHR 0.97 +/- 0.03 were given dietary advice and a placebo (n = 20) or fluoxetine treatment (n = 18, 60 mg/day) for 12 weeks after a placebo run-in of two weeks. Measurements were carried out during run-in and at week 12 of treatment. The treatment groups did not differ at the start of the study. After treatment, weight loss (on average) was observed in both groups: -2.4 +/- 0.6 kg and -5.9 +/- 0.7 kg for the placebo and fluoxetine groups, respectively. Weight loss was significantly larger in the fluoxetine group (P = 0.0004). The reduction of fat mass tended to be larger (P = 0.08), and the reduction of fat-free mass was considerably larger in the fluoxetine group (P = 0.0005). Absolute (and proportional) changes in visceral and subcutaneous fat areas (cm2) were +2 +/- 26 (+1%) and -9 +/- 26 (-4%) in the placebo group, and -9 +/- 30 (-3%) and -30 +/- 27 (-13%) in the fluoxetine group. In both groups the proportional change in subcutaneous fat area was larger than the change in visceral fat (P < 0.02). Only in the fluoxetine group was the decrease in subcutaneous fat area significant, and larger compared to the placebo group (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS