ObjectiveTo investigate differences in manifestations and outcomes of coronavirus disease 2019 (COVID-19) infection between those with and without rheumatic disease.MethodsWe conducted a comparative cohort study of patients with rheumatic disease and COVID-19 (confirmed by severe acute respiratory syndrome coronavirus 2 PCR), compared in a 1:2 ratio with matched comparators on age, sex and date of COVID-19 diagnosis, between 1 March and 8 April 2020, at Partners HealthCare System in the greater Boston, Massachusetts area. We examined differences in demographics, clinical features and outcomes of COVID-19 infection. The main outcomes were hospitalisation, intensive care admission, mechanical ventilation and mortality.ResultsWe identified 52 rheumatic disease patients with COVID-19 (mean age, 63 years; 69% female) and matched these to 104 non-rheumatic disease comparators. The majority (39, 75%) of patients with rheumatic disease were on immunosuppressive medications. Patients with and without rheumatic disease had similar symptoms and laboratory findings. A similar proportion of patients with and without rheumatic disease were hospitalised (23 (44%) vs 42 (40%)), p=0.50) but those with rheumatic disease required intensive care admission and mechanical ventilation more often (11 (48%) vs 7 (18%), multivariable OR 3.11 (95% CI 1.07 to 9.05)). Mortality was similar between the two groups (3 (6%) vs 4 (4%), p=0.69).ConclusionsPatients with rheumatic disease and COVID-19 infection were more likely to require mechanical ventilation but had similar clinical features and hospitalisation rates as those without rheumatic disease. These findings have important implications for patients with rheumatic disease but require further validation.

Background CDC states that a severe or immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine is a contraindication for the second dose. Objective To assess outcomes associated with excipient skin testing after a reported allergic reaction to mRNA COVID-19 vaccine dose one. Methods We identified a consecutive sample of patients with reported allergic reactions after the first dose of mRNA COVID-19 vaccine who underwent allergy assessment with skin testing to polyethylene glycol (PEG) and, if appropriate, polysorbate 80. Skin testing results in conjunction with clinical phenotyping of the first dose mRNA COVID-19 vaccine reaction guided second dose vaccination recommendation. Second dose mRNA COVID-19 vaccine reactions were assessed. Results 80 patients with reported first dose mRNA COVID-19 vaccine allergic reactions (n=65, 81% immediate onset) underwent excipient skin testing. 14 (18%) had positive skin tests to PEG (n=5) and/or polysorbate 80 (n=12). Skin testing result did not impact tolerance of second dose in patients with immediate or delayed reactions. Of 70 (88%) patients who received their second mRNA COVID-19 vaccine dose, 62 (89%) had either no reaction or a mild reaction managed with antihistamines, but two patients required epinephrine. Three patients with positive PEG-3350 intradermal (methylprednisolone) testing tolerated second dose mRNA COVID-19 vaccination. Refresh Tears caused non-specific irritation. Conclusion Most individuals with a reported allergic reaction to dose one of the mRNA COVID-19 vaccines, regardless of skin test result, received the second dose safely. More data are needed on the value of skin prick testing to PEG (Miralax) in evaluating patients with mRNA COVID-19 vaccine anaphylaxis. Refresh Tears should not be used for skin testing.

Mucocutaneous reactions, such as pruritus, urticaria, and angioedema, may occur after COVID-19 messenger RNA (mRNA) vaccination. To our knowledge, the incidence of these reactions and recurrence with subsequent vaccination has not been described. Cutaneous reactions may contribute to unnecessary avoidance of future vaccination doses.Methods | We prospectively studied Mass General Brigham employees who received an mRNA COVID-19 vaccine (first dose: December 16, 2020, to January 20, 2021; follow-up through February 26, 2021; eMethods in the Supplement). Institutional review board approval was provided by the Mass General Brigham human research committee with a waiver of informed consent. For 3 days after vaccination, employees completed daily symptom surveys through a multipronged approach, including email, text message, phone, and smartphone application links. Cutaneous reactions included rash or itching (other than the injection site), hives, and/or swelling of the lips, tongue, eyes, or face (eAppendix in the Supplement).We calculated the number and frequency of selfreported cutaneous reactions with 95% confidence intervals using symptom survey respondents by dose as the denomi-nator. We compared frequencies using χ 2 tests. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute), and statistical significance was set at P< .05.

ObjectiveIn earlier studies, patients with rheumatic and musculoskeletal disease (RMD) who got infected with COVID-19 had a higher risk of mechanical ventilation than comparators. We sought to determine COVID-19 outcomes among patients with RMD 6 months into the pandemic.MethodsWe conducted a cohort study at Mass General Brigham in Boston, Massachusetts, of patients with RMD matched to up to five comparators by age, sex and COVID-19 diagnosis date (between 30 January 2020 and 16 July 2020) and followed until last encounter or 18 August 2020. COVID-19 outcomes were compared using Cox regression. Risk of mechanical ventilation was compared in an early versus a recent cohort of patients with RMD.ResultsWe identified 143 patients with RMD and with COVID-19 (mean age 60 years; 76% female individuals) and 688 comparators (mean age 59 years; 76% female individuals). There were no significantly higher adjusted risks of hospitalisation (HR: 0.87, 95% CI: 0.68–1.11), intensive care unit admission (HR: 1.27, 95% CI: 0.86–1.86), or mortality (HR: 1.02, 95% CI: 0.53–1.95) in patients with RMD versus comparators. There was a trend towards a higher risk of mechanical ventilation in the RMD cohort versus comparators, although not statistically significant (adjusted HR: 1.51, 95% CI: 0.93–2.44). There was a trend towards improvement in mechanical ventilation risk in the recent versus early RMD cohort (10% vs 19%, adjusted HR: 0.44, 95% CI: 0.17–1.12).ConclusionsPatients with RMD and comparators had similar risks of poor COVID-19 outcomes after adjusting for race, smoking and comorbidities. The higher risk of mechanical ventilation in the early RMD cohort was no longer detected in a recent cohort, suggesting improved management over time.

Ribonucleic acid (RNA) is capable of hosting a variety of chemically diverse modifications, in both naturally-occurring post-transcriptional modifications and artificial chemical modifications used to expand the functionality of RNA. However, few studies have addressed how base modifications affect RNA polymerase and reverse transcriptase activity and fidelity. Here, we describe the fidelity of RNA synthesis and reverse transcription of modified ribonucleotides using an assay based on Pacific Biosciences Single Molecule Real-Time sequencing. Several modified bases, including methylated (m6A, m5C and m5U), hydroxymethylated (hm5U) and isomeric bases (pseudouridine), were examined. By comparing each modified base to the equivalent unmodified RNA base, we can determine how the modification affected cumulative RNA polymerase and reverse transcriptase fidelity. 5-hydroxymethyluridine and N6-methyladenosine both increased the combined error rate of T7 RNA polymerase and reverse transcriptases, while pseudouridine specifically increased the error rate of RNA synthesis by T7 RNA polymerase. In addition, we examined the frequency, mutational spectrum and sequence context of reverse transcription errors on DNA templates from an analysis of second strand DNA synthesis.

Platelet ACKR3/CXCR7 surface expression is enhanced and influences prognosis in coronary artery disease-(CAD) patients, who exhibit a distinct atherothrombotic platelet lipidome. Current investigation validates the potential of ACKR3/CXCR7 in regulating thrombo-inflammatory response, through its impact on the platelet lipidome. CAD patients-(n=230) with enhanced platelet-ACKR3/CXCR7 expression exhibited reduced aggregation. Pharmacological CXCR7-agonist-(VUF11207) significantly reduced pro-thrombotic platelet response in blood from ACS patients-(n=11) ex vivo. CXCR7-agonist administration reduced thrombotic functions and thrombo-inflammatory platelet-leukocyte interactions post myocardial infarction-(MI) and arterial injury in vivo. ACKR3/CXCR7-ligation did not affect surface availability of GPIbα, GPV, GPVI, GPIX, αv-integrin, β3-integrin, coagulation profile-(APTT, PT), bleeding time, plasma-dependent thrombin generation-(thrombinoscopy) or clot formation-(thromboelastography), but counteracted activation-induced phosphatidylserine exposure and procoagulant platelet-assisted thrombin generation. Targeted-(micro-UHPLC-ESI-QTrap-MS/MS) and untargeted-(UHPLC-ESI-QTOF-MS/MS) lipidomics analysis revealed that ACKR3/CXCR7-ligation favored generation of anti-thrombotic lipids-(dihomo-γ-linolenic acid-DGLA, 12-hydroxyeicosatrienoic acid-12-HETrE) over cyclooxygenase-COX-1-(thromboxane-TxA2), or 12-lipoxygenase-LOX-(12-HETE) metabolized pro-thrombotic, and phospholipase derived atherogenic-(lysophosphatidylcholine-LPC) lipids, in healthy subjects and CAD patients, contrary to anti-platelet therapy. Through 12-HETrE, ACKR3/CXCR7-ligation coordinated with Gαs-coupled prostacyclin receptor-(IP) to trigger cAMP-PKA mediated platelet inhibition. ACKR3/CXCR7-ligation reduced generation of lipid agonists-(arachidonic acid-AA,TxA2), lipid signaling intermediates-(lyophosphatidylinositol-LPI, diacylglycerol-DG), which affected calcium mobilization, intracellular signaling, consequently platelet interaction with physiological matrices and thrombo-inflammatory secretion-(IL1β,IFN-γ,TGF-β,IL-8), emphasizing its functional dichotomy from pro-thrombotic CXCR4. Moreover, CXCR7-agonist regulated heparin-induced thrombocytopenia-(HIT)-sera/IgG-induced platelet and neutrophil activation, heparin induced platelet aggregation-(HIPA), generation of COX-1-(TxA2), 12-LOX-(12-HETE) derived thrombo-inflammatory lipids, platelet-neutrophil aggregate formation, and thrombo-inflammatory secretion (sCD40L, IL-1β, IFN-γ, TNF-α, sP-selectin, IL-8, tissue factor-TF) ex vivo. Therefore, ACKR3/CXCR7 may offer a novel therapeutic strategy in acute/chronic thrombo-inflammation exaggerated cardiovascular pathologies, and CAD.

The annual dynamics of N 2 O emissions from a tea field in southern subtropical China was observed in situ weekly in 2010 using a static closed chamber -gas chromatography (GC) method for three treatments: non-fertilised (CK), conventional (CON) and rice straw mulching (SM). The annual N 2 O emissions for CK, CON and SM were 7.1, 17.2 and 16.7 kg N/ha/year, respectively. The N 2 O emission factors for the CON and SM treatments were estimated as 2.23% and 1.91% of the total fertiliser N applied, respectively. Rice straw mulching exhibited a potential to reduce the N 2 O emissions from the tea field, but not statistically significant (P = 0.82). The daily N 2 O fluxes were positively correlated with the air temperature. The cumulative precipitation of the previous five days was significantly correlated with the daily N 2 O fluxes of CON. The soil water contents were significantly correlated with the daily N 2 O fluxes in the three treatments. The N 2 O fluxes from CON had a more significant correlation with the soil NH 4 + -N contents than with the soil NO 3 --N contents, while the N 2 O fluxes from SM showed an inverse pattern. The N 2 O fluxes from CK did not show any significant relationship with the soil mineral N content.

Objective The objective of this study was to evaluate causes of death in a contemporary inception cohort of ANCA-associated vasculitis patients, stratifying the analysis according to ANCA type. Methods We identified a consecutive inception cohort of patients newly diagnosed with ANCA-associated vasculitis from 2002 to 2017 in the Partners HealthCare System and determined vital status through the National Death Index. We determined cumulative mortality incidence and standardized mortality ratios (SMRs) compared with the general population. We compared MPO- and PR3-ANCA+ cases using Cox regression models. Results The cohort included 484 patients with a mean diagnosis age of 58 years; 40% were male, 65% were MPO-ANCA+, and 65% had renal involvement. During 3385 person-years (PY) of follow-up, 130 patients died, yielding a mortality rate of 38.4/1000 PY and a SMR of 2.3 (95% CI: 1.9, 2.8). The most common causes of death were cardiovascular disease (CVD; cumulative incidence 7.1%), malignancy (5.9%) and infection (4.1%). The SMR for infection was greatest for both MPO- and PR3-ANCA+ patients (16.4 and 6.5). MPO-ANCA+ patients had an elevated SMR for CVD (3.0), respiratory disease (2.4) and renal disease (4.5). PR3- and MPO-ANCA+ patients had an elevated SMR for malignancy (3.7 and 2.7). Compared with PR3-ANCA+ patients, MPO-ANCA+ patients had a higher risk of CVD death [hazard ratio 5.0 (95% CI: 1.2, 21.2]; P = 0.03]. Conclusion Premature ANCA-associated vasculitis mortality is explained by CVD, infection, malignancy, and renal death. CVD is the most common cause of death, but the largest excess mortality risk in PR3- and MPO-ANCA+ patients is associated with infection. MPO-ANCA+ patients are at higher risk of CVD death than PR3-ANCA+ patients.