To the Editor: Despite the risk of rapid respiratory failure 1 and cardiac complications 2 due to Covid-19, it is unclear whether there is an association between Covid-19 and out-of-hospital cardiac arrest. The Lombardy region of Italy was among the first areas to have an outbreak of Covid-19 outside China, 3 and the first case there was diagnosed on February 20, 2020, in Lodi Province. 4 Using the Lombardia Cardiac Arrest Registry (Lombardia CARe), we compared out-of-hospital cardiac arrests that occurred in the provinces of Lodi, Cremona, Pavia, and Mantua during the first 40 days of the Covid-19 outbreak (February 21 through March 31, 2020) with those that occurred during the same period in 2019 (February 21 through April 1, to account for the leap year). We reviewed daily reports of new Covid-19 cases recorded by the National Department of Civil Protection 5 and cases of out-of-hospital cardiac arrest in the electronic database of the emergency medical system to identify either symptoms suggestive of Covid-19 (fever lasting ≥3 days before out-of-hospital cardiac arrest, with cough, dyspnea, or both) or positive results of testing to detect SARS-CoV-2 in pharyngeal swabs obtained before the out-of-hospital cardiac arrest or after death. (Details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.)During the study period in 2020, a total of 9806 cases of Covid-19 were reported in the study territory. During this period, 362 cases of out-ofhospital cardiac arrest were identified, as compared with 229 cases identified during the same period in 2019 (a 58% increase). Increases of various magnitudes in the numbers of cases of out-ofhospital cardiac arrest were seen in all four provinces (Table S1 in the Supplementary Appendix). The sex and age of the patients were similar in the 2020 and 2019 periods, but in 2020, the incidence

Aims An increase in out-of-hospital cardiac arrest (OHCA) incidence has been reported in the very early phase of the COVID-19 epidemic, but a clear demonstration of a correlation between the increased incidence of OHCA and COVID-19 is missing so far. We aimed to verify whether there is an association between the OHCA difference compared with 2019 and the COVID-19 epidemic curve. Methods and results We included all the consecutive OHCAs which occurred in the Provinces of Lodi, Cremona, Pavia, and Mantova in the 2 months following the first documented case of COVID-19 in the Lombardia Region and compared them with those which occurred in the same time frame in 2019. The cumulative incidence of COVID-19 from 21 February to 20 April 2020 in the study territory was 956 COVID-19/100 000 inhabitants and the cumulative incidence of OHCA was 21 cases/100 000 inhabitants, with a 52% increase as compared with 2019 (490 OHCAs in 2020 vs. 321 in 2019). A strong and statistically significant correlation was found between the difference in cumulative incidence of OHCA between 2020 and 2019 per 100 000 inhabitants and the COVID-19 cumulative incidence per 100 000 inhabitants both for the overall territory (ρ 0.87, P < 0.001) and for each province separately (Lodi: ρ 0.98, P < 0.001; Cremona: ρ 0.98, P < 0.001; Pavia: ρ 0.87, P < 0.001; Mantova: ρ 0.81, P < 0.001). Conclusion The increase in OHCAs in 2020 is significantly correlated to the COVID-19 pandemic and is coupled with a reduction in short-term outcome. Government and local health authorities should seriously consider our results when planning healthcare strategies to face the epidemic, especially considering the expected recurrent outbreaks.

Introduction An increase in the incidence of OHCA during the COVID-19 pandemic has been recently demonstrated. However, there are no data about how the COVID-19 epidemic influenced the treatment of OHCA victims. Methods We performed an analysis of the Lombardia Cardiac Arrest Registry comparing all the OHCAs occurred in the Provinces of Lodi, Cremona, Pavia and Mantua (northern Italy) in the first 100 days of the epidemic with those occurred in the same period in 2019. Results The OHCAs occurred were 694 in 2020 and 520 in 2019. Bystander cardiopulmonary resuscitation (CPR) rate was lower in 2020 (20% vs 31%, p<0.001), whilst the rate of bystander automated external defibrillator (AED) use was similar (2% vs 4%, p = 0.11). Resuscitation was attempted by EMS in 64.5% of patients in 2020 and in 72% in 2019, whereof 45% in 2020 and 64% in 2019 received ALS. At univariable analysis, the presence of suspected/confirmed COVID-19 was not a predictor of resuscitation attempt. Age, unwitnessed status, non-shockable presenting rhythm, absence of bystander CPR and EMS arrival time were independent predictors of ALS attempt. No difference regarding resuscitation duration, epinephrine and amiodarone administration, and mechanical compression device use were highlighted. The return of spontaneous circulation (ROSC) rate at hospital admission was lower in the general population in 2020 [11% vs 20%, p = 0.001], but was similar in patients with ALS initiated [19% vs 26%, p = 0.15]. Suspected/confirmed COVID-19 was not a predictor of ROSC at hospital admission. Conclusion Compared to 2019, during the 2020 COVID-19 outbreak we observed a lower attitude of laypeople to start CPR, while resuscitation attempts by BLS and ALS staff were not influenced by suspected/confirmed infection, even at univariable analysis.

IMPORTANCE Electrocardiography (ECG) is an important tool to triage patients with out-of-hospital cardiac arrest (OHCA) after return of spontaneous circulation (ROSC). An immediate coronary angiography after ROSC is recommended only in patients with an ECG that is diagnostic of ST-segment elevation myocardial infarction (STEMI). To date, the benefit of this approach has not been demonstrated in patients with a post-ROSC ECG that is not diagnostic of STEMI. OBJECTIVE To assess whether the time from ROSC to ECG acquisition is associated with the diagnostic accuracy of ECG for STEMI. DESIGN, SETTING, AND PARTICIPANTSThis retrospective, multicenter cohort study (the Post-ROSC Electrocardiogram After Cardiac Arrest study) analyzed consecutive patients older than 18

Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is likely to unveil new pathophysiological roles and novel emerging pharmacological properties for some of these GPCRs, including GPR17. This receptor shares structural, phylogenetic and functional properties with some chemokine receptors, CXCRs. Both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCR ligands have been demonstrated to have a role in orchestrating inflammatory responses and oligodendrocyte precursor cell differentiation to myelinating cells in acute and chronic diseases of the central nervous system. Here, by combining in silico modelling data with in vitro validation in (i) a classical reference pharmacological assay for GPCR activity and (ii) a model of maturation of primary oligodendrocyte precursor cells, we demonstrate that GPR17 can be activated by SDF-1, a ligand of chemokine receptors CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism. We also demonstrate that cangrelor, a GPR17 orthosteric antagonist, can block the SDF-1-mediated activation of GPR17 in a concentration-dependent manner. The ability of GPR17 to respond to different classes of GPCR ligands suggests that this receptor modifies its function depending on the extracellular mileu changes occurring under specific pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an inflammatory/immune component.

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Out-of-hospital cardiac arrest incidence in the different phases of COVID-19 outbreakTo the editor, Last February, Europe was affected by the first wave of the COVID-19 pandemic. Now a second outbreak has begun. Albeit a close relationship between the pandemic trend and the incidence of out-ofhospital cardiac arrest (OHCA) has been documented during the first surge in different countries such as Italy 1,2 the United States 3,4 and France, 5 some elements still remain unclarified.Our aims were (1) to confirm the correlation between the incidence of OHCA and COVID-19 across a longer time period including the downward phase of the pandemic; (2) to compare the incidence of OHCA in the post-and pre-pandemic peak and (3) to verify whether the incidence OHCA correlated more closely with daily COVID-19 diagnoses or with the rate of ICU admissions. We considered all events of OHCA enrolled in the out-of-hospital cardiac arrest register of the Lombardy region (Lombardia CARe; ClinicalTrials.gov Identifier: NCT03197142) from January 1st, 2020 to October 9th, 2020 that have occurred in the provinces of Pavia, Lodi, Cremona, Mantua and Varese (total area 9061 km 2 ; total population of 2,435,939 inhabitants). The daily new cases of COVID-19 in the entire Lombardy region, as well as the daily count of COVID patients admitted in the intensive care units (ICU), were collected from National Department of Civil Protection (http://www.protezionecivile.gov.it/). During the study period, 2488 OHCAs occurred and resuscitation was attempted in 1629 of them (65.5%). The median age was 78 years (IQR 66À86 years); the event occurred at home in 1392 (85.5%); a medical aetiology was found in 1519 (93%); the event was witnessed in 756 (46.4%); the rhythm was non-shockable in 1393 (85.5%) and bystander CPR occurred in 519 (32%). As shown in Fig. 1, the trend of OHCA has followed the trend of the pandemic during both the ascending and the descending phase. A statistically significant correlation was found across the 283 days of observation, reinforcing the deep relationship between the pandemic and OHCA incidence. The

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