Intravenous Aviptadil and Remdesivir for Treatment of COVID-19-Associated Hypoxaemic Respiratory Failure in the USA (Tesico): A Randomised, Placebo-Controlled Trial

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised

INNOVATION AND PERFORMANCE DURING THE EVOLUTION OF COMPLEMENTARY TECHNOLOGIES

Ph.DDOCTOR OF PHILOSOPH

Analysis of optimal reconfiguration of shipboard power systems

In power system reconfiguration, the status (ON/OFF) of switches are optimized such that maximum power is delivered to loads after the occurrence of a fault. The optimized reconfiguration is achieved by prioritizing power delivered to vital loads over semi-vital and nonvital loads. The formulation presented in this paper considers a new balanced hybrid (AC and DC) shipboard power system (SPS). Analysis of the nonconvex reconfiguration formulation is done by an appropriate nonconvex solver and by convex approximation. Unlike the nonconvex solution that is based on branch-and-bound methods, convex approximation significantly reduces complexity. It is shown that for the hybrid SPS reconfiguration problem, low complexity convex approximations are effective in finding optimal solutions. Cumulative distribution function (CDF) of the power delivered to loads is presented to showcase the system robustness against random fault scenarios. A combined objective of maximizing power delivery and minimizing the number of switching actions is included in the analysis. Tradeoff between power delivered and number of switching operations after reconfiguration has been discussed at steady state. A separate analysis is also included to observe the intermediate dynamic switch states while the reconfiguration is in progress to capture the tradeoff more prominently

Saving for Microenterprises

This project investigates the role of fintech in encouraging saving for microenterprise. The article is published as open access: https://onlinelibrary.wiley.com/doi/10.1002/sej.147

Fintech and banks as complements in microentrepreneurship

10.1002/sej.1470Strategic Entrepreneurship Journa

Sister cities, cross-national FDI, and the subnational FDI location decision

We investigate how intergovernmental ties at subnational levels between home and host countries influence the intensity and location of foreign direct investment (FDI) inflows. We focus on an intriguing type of subnational tie, namely, International Friendship (Sister) Cities. A sister city is a decentralized form of intergovernmental relationship that provides a platform by which a multinational corporation (MNC) can approach a local government, customers, and clients to acquire localized information and political capabilities. We argue that cities with a sister-city relationship attract more FDIs than other similar cities within a host country. The benefit extends to the national level as MNCs have higher FDI levels in host countries with a greater number of sister cities with their home country. We further investigate whether the effect of sister cities on an MNC’s country selection is greater when host-country subnational governments have a higher degree of autonomy relative to the national government, and lesser when governments have a higher level of policy uncertainty. Using data from the 1990–2009 period, we find consistent support for our ideas as tested at two levels of analysis: a city-level matched sample analysis on Japanese FDI inflows, and a country-level analysis on Japanese MNCs’ country selectio

Learning Relational Structure for Temporal Relation Extraction

Recently there has been a lot of interest in using Statistical Relational Learning (SRL) models for Information Extraction (IE). One of the important IE tasks is extraction of temporal relations between events and time expressions (timex). SRL methods that use hand-written rules have been proposed for various IE tasks. In contrast, we propose an approach that employs structure learning in SRL to learn such rules. Although not required, our method can also incorporate expert advice either as features or initial theory to learn a more accurate model. We present preliminary results on the TempEval-2 task of classifying relations between events and timexes.

Partial digeorge syndrome with hypertrophied arytenoids in a neonate: Expanding the clinical phenotype

Background: DiGeorge Syndrome (DGS) is caused by the 22q11 deletion. There is wide variation in the phenotypic presentation due to incomplete penetrance. Since dysmorphism is subtle in neonates, a high index of suspicion should be kept. Clinical Description: A 2.8 kg term baby girl born of a cesarean section developed stridor and respiratory distress and was referred to our hospital at 14 days for the persistence of symptoms. The manifestations were severe, requiring respiratory support, and not explainable by clinical findings, radiological atelectasis, and normal echocardiography. The baby had hypocalcemia (that had been noted and treated earlier), hypoparathyroidism and Vitamin D deficiency, for which standard therapy was started. Airway endoscopy revealed hypertrophied arytenoids which have not been reported in DGS before. Management: The presence of abnormal laryngeal with hypocalcemia prompted us to consider DGS. The likelihood became stronger when a chest ultrasonogram detected athymia. The identification of 22q microdeletion by fluorescence in situ hybridization confirmed the diagnosis. It was decided to perform supraglottoplasty to avoid the postoperative complications associated with direct vocal cord repair. The postoperative period was uneventful. The immunological profile was normal, besides a low count of normal CD4+ naïve cells. The final diagnosis was partial DGS. Conclusion: Genetic testing for 22q11 deletion should be done in the presence of laryngeal pathology and any of the following: congenital cardiopathy, velopharyngeal insufficiency, thymic hypoplasia, and neonatal hypocalcemia