Emergency ventilator for COVID-19.

The COVID-19 pandemic disrupted the world in 2020 by spreading at unprecedented rates and causing tens of thousands of fatalities within a few months. The number of deaths dramatically increased in regions where the number of patients in need of hospital care exceeded the availability of care. Many COVID-19 patients experience Acute Respiratory Distress Syndrome (ARDS), a condition that can be treated with mechanical ventilation. In response to the need for mechanical ventilators, designed and tested an emergency ventilator (EV) that can control a patient's peak inspiratory pressure (PIP) and breathing rate, while keeping a positive end expiratory pressure (PEEP). This article describes the rapid design, prototyping, and testing of the EV. The development process was enabled by rapid design iterations using additive manufacturing (AM). In the initial design phase, iterations between design, AM, and testing enabled a working prototype within one week. The designs of the 16 different components of the ventilator were locked by additively manufacturing and testing a total of 283 parts having parametrically varied dimensions. In the second stage, AM was used to produce 75 functional prototypes to support engineering evaluation and animal testing. The devices were tested over more than two million cycles. We also developed an electronic monitoring system and with automatic alarm to provide for safe operation, along with training materials and user guides. The final designs are available online under a free license. The designs have been transferred to more than 70 organizations in 15 countries. This project demonstrates the potential for ultra-fast product design, engineering, and testing of medical devices needed for COVID-19 emergency response.

At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension.

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis.

BACKGROUND: Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. METHODS: We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. FINDINGS: Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15-1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00-1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). INTERPRETATION: Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. FUNDING: Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial.

BACKGROUND: We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. METHODS: This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. RESULTS: Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. CONCLUSIONS: SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.

Speckle patterns with atomic and molecular de Broglie waves.

We have developed a nozzle source that delivers a continuous beam of atomic helium or molecular hydrogen having a high degree of transverse coherence and with adequate optical brightness to enable new kinds of experiments. Using this source we have measured single slit diffraction patterns and the first ever speckle-diffraction patterns using atomic and molecular de Broglie waves. Our results suggest fruitful application of coherent matter beams in dynamic scattering and diffractive imaging at short wavelength and with extreme surface sensitivity.

Randomized controlled trial of three different doses of aerosol beclomethasone versus systemic dexamethasone to promote extubation in ventilated premature infants.

Our objective was to determine the safety and efficacy of aerosol beclomethasone vs. systemic dexamethasone for extubation in premature infants at high risk for chronic lung disease (CLD). Intubated preterm infants who were identified as being at high risk for moderate-severe CLD on day 14 of life were randomized to one of four groups. The control group received systemic dexamethasone and aerosol placebo, while the other three groups received either high (2.40-3.69 microg/kg/day delivered to lungs), medium (1.0-1.85 microg/kg/day), or low (0.48-0.74 microg/kg/day) dose aerosol beclomethasone and systemic placebo. Those receiving aerosol steroids who remained ventilator-dependent after 7 days were switched to standard 42-day tapering doses of systemic dexamethasone. The primary outcome was extubation within 1 week of starting steroids, using predefined criteria. Secondary variables included changes in lung function, rates of side effects, and tracheal aspirate white blood cell counts. Sixty-one infants with birth weights of 761 +/- 18 g (mean +/- SEM) and gestational ages of 25.7 +/- 0.2 weeks were randomized to one of the four groups. Seven of 15 infants in the control systemic dexamethasone group were successfully extubated compared with 3/16 in the high-dose beclomethasone group, 1/15 in the medium-dose group, and 2/15 in the low-dose group (P < 0.01). Only dexamethasone subjects demonstrated improvements in lung function over the study period. These infants also had significant increases in blood pressure and blood glucose levels, as well as a decline in their tracheal aspirate white blood cell count. In conclusion, aerosol beclomethasone at the very low doses used in this study did not facilitate extubation in intubated premature infants at high risk for moderate-severe CLD.