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Abstract Compared to healthy volunteers, participants with post‐acute sequelae of SARS‐CoV‐2 infection (PASC) demonstrated increased plasma levels of the prothrombotic protein NEDD9, which associated inversely with indices of pulmonary vascular function. This suggests persistent pulmonary vascular dysfunction may play a role in the pathobiology of PASC.

IMPORTANCE:. Which social factors explain racial and ethnic disparities in COVID-19 access to care and outcomes remain unclear. OBJECTIVES:. We hypothesized that preferred language mediates the association between race, ethnicity and delays to care. DESIGN, SETTING AND PARTICIPANTS:. Multicenter, retrospective cohort study of adults with COVID-19 consecutively admitted to the ICU in three Massachusetts hospitals in 2020. MAIN OUTCOME AND MEASURES:. Causal mediation analysis was performed to evaluate potential mediators including preferred language, insurance status, and neighborhood characteristics. RESULTS:. Non-Hispanic White (NHW) patients (157/442, 36%) were more likely to speak English as their preferred language (78% vs. 13%), were less likely to be un- or under-insured (1% vs. 28%), lived in neighborhoods with lower social vulnerability index (SVI) than patients from racial and ethnic minority groups (SVI percentile 59 [28] vs. 74 [21]) but had more comorbidities (Charlson comorbidity index 4.6 [2.5] vs. 3.0 [2.5]), and were older (70 [13.2] vs. 58 [15.1] years). From symptom onset, NHW patients were admitted 1.67 [0.71–2.63] days earlier than patients from racial and ethnic minority groups (p < 0.01). Non-English preferred language was associated with delay to admission of 1.29 [0.40–2.18] days (p < 0.01). Preferred language mediated 63% of the total effect (p = 0.02) between race, ethnicity and days from symptom onset to hospital admission. Insurance status, social vulnerability, and distance to the hospital were not on the causal pathway between race, ethnicity and delay to admission. CONCLUSIONS AND RELEVANCE:. Preferred language mediates the association between race, ethnicity and delays to presentation for critically ill patients with COVID-19, although our results are limited by possible collider stratification bias. Effective COVID-19 treatments require early diagnosis, and delays are associated with increased mortality. Further research on the role preferred language plays in racial and ethnic disparities may identify effective solutions for equitable care.

Abstract Background Stimulant use has increased across the US, with concomitant opioid and methamphetamine use doubling between 2011 and 2017. Shifting patterns of polysubstance use have led to rising psychostimulant-involved deaths. While it is known that individuals who use methamphetamine require greater access to treatment, there is still little known about methamphetamine use and treatment among individuals who are already engaged in outpatient substance use treatment. Objectives To characterize care-engaged individuals who use methamphetamine to guide harm reduction and treatment strategies. Methods Retrospective cohort study of individuals at a large academic medical center in Massachusetts with ≥ 2 positive methamphetamine oral fluid toxicology tests between August 2019 and January 2020. We performed descriptive analysis of sociodemographic, medical, and drug use characteristics and a comparative analysis of injection methamphetamine use versus other routes of use. Results Included were 71 individuals [56 male (80%), 66 non-Hispanic white (94%), median age 36 (IQR 30–42)]. Nearly all had opioid (94%) and stimulant use disorder (92%). Most had (93%) or were (83%) being treated with medications for opioid use disorder, but few received pharmacologic treatment for methamphetamine use disorder (24%). None received contingency management treatment. People who inject methamphetamine (68%) were more likely to have a history of overdose (91% vs. 70%; p = 0.02), have HCV (94% vs. 52%; p

Purpose: Code status orders impact clinical outcomes as well as patients’ and surrogates’ experiences. This is the first multicenter cohort examining code status orders of ICU patients with COVID-19 reported to date. Materials and methods: This is a retrospective cohort study including adult patients who tested positive for SARS-CoV-2 and were admitted to the ICU at three hospitals in Massachusetts from March 11, 2020 - May 31, 2020. We examined differences in code status orders at multiple timepoints and performed multivariable regression analysis to identify variables associated with code status at admission. Results: Among 459 ICU patients with COVID-19, 421 (91.7%) were Full Code at hospital admission. Age and admission from a facility were positively associated with DNR status (adjusted OR 1.10, 95% CI 1.05–1.15, p

Abstract The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9P) on the extracellular plasma membrane surface. We hypothesized that the SARS‐CoV‐2–ARDS pathophenotype involves increased pulmonary endothelial N9P. Paraffin‐embedded autopsy lung specimens were acquired from patients with SARS‐CoV‐2–​​​​​​ARDS (n = 13), ARDS from other causes (n = 10), and organ donor controls (n = 5). Immunofluorescence characterized the expression of N9P, fibrin, and transcription factor 12 (TCF12), a putative binding target of SARS‐CoV‐2 and known transcriptional regulator of NEDD9. We performed RNA‐sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O2) for 24 h. Immunoprecipitation‐liquid chromatography‐mass spectrometry (IP‐LC‐MS) profiled protein–protein interactions involving N9P relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19‐fold, p = 0.001; false discovery rate = 0.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS‐CoV‐2–ARDS versus donor control lungs (p

Background: Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. Methods: We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. Findings: Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. Interpretation: Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. Funding: The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542–02) from Harvard Catalyst.

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. Methods An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. Results The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. Conclusions The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.

Transcriptomic analysis of pulmonary microvascular endothelial cells from experimental models offers insight into pulmonary arterial hypertension (PAH) pathobiology. However, culturing may alter the molecular profile of endothelial cells prior to analysis, limiting the translational relevance of results. Here we present a novel and validated method for isolating RNA from pulmonary microvascular endothelial cells (PMVECs) ex vivo that does not require cell culturing. Initially, presumed rat PMVECs were isolated from rat peripheral lung tissue using tissue dissociation and enzymatic digestion, and cells were cultured until confluence to assess endothelial marker expression. Anti-CD31, anti-von Willebrand Factor, and anti-α-smooth muscle actin immunocytochemistry/immunofluorescence signal was detected in presumed rat PMVECs, but also in non-endothelial cell type controls. By contrast, flow cytometry using an anti-CD31 antibody and isolectin 1-B4 (from Griffonia simplicifolia) was highly specific for rat PMVECs. We next developed a strategy in which the addition of an immunomagnetic selection step for CD31+ cells permitted culture-free isolation of rat PMVECs ex vivo for RNA isolation and transcriptomic analysis using fluorescence-activated cell sorting. Heterogeneity in the validity and reproducibility of results using commercial antibodies against endothelial surface markers corresponded to a substantial burden on laboratory time, labor, and scientific budget. We demonstrate a novel protocol for the culture-free isolation and transcriptomic analysis of rat PMVECs with translational relevance to PAH. In doing so, we highlight wide variability in the quality of commonly used biological reagents, which emphasizes the importance of investigator-initiated validation of commercial biomaterials.