A prothrombotic coagulopathy is commonly found in critically ill COVID‐19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID‐19 respiratory failure is a relatively ...preserved lung compliance and high Alveolar‐arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low‐compliance in ARDS. The COVID‐19 pandemic is overwhelming the world’s medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID‐19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.
COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement. The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to ...assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events.
Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied. Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure.
Forty-four patients with COVID-19 were included in the analysis. Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes. A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021). A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005). Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004).
Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19. Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.
Display omitted
Antimicrobial resistance (AMR) is a serious threat to global public health. WHO emphasises the need for countries to monitor antibiotic consumption to combat AMR. Many low-income and middle-income ...countries (LMICs) lack surveillance capacity; we aimed to use multiple data sources and statistical models to estimate global antibiotic consumption.
In this spatial modelling study, we used individual-level data from household surveys to inform a Bayesian geostatistical model of antibiotic usage in children (aged <5 years) with lower respiratory tract infections in LMICs. Antibiotic consumption data were obtained from multiple sources, including IQVIA, WHO, and the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). The estimates of the antibiotic usage model were used alongside sociodemographic and health covariates to inform a model of total antibiotic consumption in LMICs. This was combined with a single model of antibiotic consumption in high-income countries to produce estimates of antibiotic consumption covering 204 countries and 19 years.
We analysed 209 surveys done between 2000 and 2018, covering 284 045 children with lower respiratory tract infections. We identified large national and subnational variations of antibiotic usage in LMICs, with the lowest levels estimated in sub-Saharan Africa and the highest in eastern Europe and central Asia. We estimated a global antibiotic consumption rate of 14·3 (95% uncertainty interval 13·2–15·6) defined daily doses (DDD) per 1000 population per day in 2018 (40·2 37·2–43·7 billion DDD), an increase of 46% from 9·8 (9·2–10·5) DDD per 1000 per day in 2000. We identified large spatial disparities, with antibiotic consumption rates varying from 5·0 (4·8–5·3) DDD per 1000 per day in the Philippines to 45·9 DDD per 1000 per day in Greece in 2018. Additionally, we present trends in consumption of different classes of antibiotics for selected Global Burden of Disease study regions using the IQVIA, WHO, and ESAC-net input data. We identified large increases in the consumption of fluoroquinolones and third-generation cephalosporins in North Africa and Middle East, and south Asia.
To our knowledge, this is the first study that incorporates antibiotic usage and consumption data and uses geostatistical modelling techniques to estimate antibiotic consumption for 204 countries from 2000 to 2018. Our analysis identifies both high rates of antibiotic consumption and a lack of access to antibiotics, providing a benchmark for future interventions.
Fleming Fund, UK Department of Health and Social Care; Wellcome Trust; and Bill & Melinda Gates Foundation.
Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic ...heparin would improve pulmonary function in these patients.
Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?
Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time aPTT, 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao
to Fio
ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao
to Fio
ratio improvement of > 50% or Pao
to Fio
ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality.
Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao
to Fio
ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao
to Fio
ratio at 48 h (16.9% control interquartile range (IQR), -8.3% to 36.8% vs 29.8% tPA bolus IQR, 4.5%-88.7%; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 IQR, 0.0-9.0 vs 12.0 IQR, 0.0-19.0; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit.
The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality.
ClinicalTrials.gov; No.: NCT04357730; URL: www.
gov.
This randomized trial showed no effect of early adenotonsillectomy, as compared with watchful waiting, on the primary outcome of attention and executive functioning in children with obstructive sleep ...apnea. Many secondary outcomes favored early surgery.
The childhood obstructive sleep apnea syndrome is associated with numerous adverse health outcomes, including cognitive and behavioral deficits.
1
The most commonly identified risk factor for the childhood obstructive sleep apnea syndrome is adenotonsillar hypertrophy. Thus, the primary treatment is adenotonsillectomy, which accounts for more than 500,000 procedures annually in the United States alone.
2
Nevertheless, there has been no controlled study evaluating the benefits and risks of adenotonsillectomy, as compared with watchful waiting, for the management of the obstructive sleep apnea syndrome.
The Childhood Adenotonsillectomy Trial (CHAT) was designed to evaluate the efficacy of early adenotonsillectomy versus watchful waiting with supportive . . .
Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal ...women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.
Materials with switchable absorption properties have been widely used for smart window applications to reduce energy consumption and enhance occupant comfort in buildings. In this work, we combine ...the benefits of smart windows with energy conversion by producing a photovoltaic device with a switchable absorber layer that dynamically responds to sunlight. Upon illumination, photothermal heating switches the absorber layer-composed of a metal halide perovskite-methylamine complex-from a transparent state (68% visible transmittance) to an absorbing, photovoltaic colored state (less than 3% visible transmittance) due to dissociation of methylamine. After cooling, the methylamine complex is re-formed, returning the absorber layer to the transparent state in which the device acts as a window to visible light. The thermodynamics of switching and performance of the device are described. This work validates a photovoltaic window technology that circumvents the fundamental tradeoff between efficient solar conversion and high visible light transmittance that limits conventional semitransparent PV window designs.
Abstract Objective To investigate how consensus is operationalized in Delphi studies and to explore the role of consensus in determining the results of these studies. Study Design and Settings ...Systematic review of a random sample of 100 English language Delphi studies, from two large multidisciplinary databases ISI Web of Science (Thompson Reuters, New York, NY) and Scopus (Elsevier, Amsterdam, NL), published between 2000 and 2009. Results About 98 of the Delphi studies purported to assess consensus, although a definition for consensus was only provided in 72 of the studies (64 a priori). The most common definition for consensus was percent agreement (25 studies), with 75% being the median threshold to define consensus. Although the authors concluded in 86 of the studies that consensus was achieved, consensus was only specified a priori (with a threshold value) in 42 of these studies. Achievement of consensus was related to the decision to stop the Delphi study in only 23 studies, with 70 studies terminating after a specified number of rounds. Conclusion Although consensus generally is felt to be of primary importance to the Delphi process, definitions of consensus vary widely and are poorly reported. Improved criteria for reporting of methods of Delphi studies are required.
Early/fast very low frequency (VLF) events evidence the direct impulsive coupling of lightning energy to the overlying mesosphere and lower ionosphere, and they are readily detected as rapid (<20 ...msec) changes to the amplitude and phase of VLF transmitter signals propagating within the Earth-ionosphere waveguide. Typical early/fast VLF events exhibit 0.1-1.0 dB amplitude changes, but can be smaller (<0.1 dB) or significantly larger (>10 dB). Large (>6 dB) early/fast events have not yet been satisfactorily simulated, and past work has suggested that large amplitude early/fast VLF events may only be detected when the receiver is located in a VLF propagation "null." VLF propagation "nulls" result from the destructive interference of propagating waveguide modes, and they would result in deceptively large relative changes in field amplitude by reducing the magnitude of the ambient field, rather than by increasing the magnitude of the scattered field. In this paper, we present a new method to quantify the degree of destructive modal interference at the location of the VLF receiver, and we apply this method to analyze the impact of modal interference on the detected amplitude changes associated with 235 early/fast VLF events occurring over the Midwestern United States on 21 September 2016. No meaningful dependence on destructive modal interference is detected. We conclude that contemporary models of lightning-ionosphere interactions and/or VLF scattering require modification in order to accurately reproduce observations of large early/fast VLF events.
PDF
