Socially marginalized groups, including people living with HIV/AIDS (PLHIV), could be disproportionately affected by Coronavirus disease 2019 (COVID-19). Following an initial single-center survey conducted in 2020, we conducted a second survey of 11 antiretroviral therapy (ART) sites in Northern Vietnam between June 2021 and January 2022. We tested anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) nucleocapsid IgG antibodies and assessed prevention against COVID-19 and impacts of COVID-19 on access to ART, economic security, risky health behaviors, and mental health using self-reported questionnaires. In total, 7808 PLHIV on ART participated in the second survey. The overall prevalence of SARS-CoV-2 antibody was as low as 1.2%. There was no clear upward trend in COVID-19 infection among PLHIV compared with the rate of infection among the general population. HIV treatment was generally maintained and no increase in risky health behaviors was observed. The economic impacts were significant, with high unemployment rate, poorer economic security, and binge drinking strongly associated with depression. However, the prevalence of depression decreased by 11.2% compared with pre-COVID-19 levels. Social support, including for patients to continue HIV treatment and effective employment/financial assistance, may help to alleviate the negative socioeconomic impacts of COVID-19 and improve mental health among PLHIV. Socially marginalized groups according to race and ethnicity, sex, income, and geographic region often bear a disproportionately large burden7. People living with HIV/AIDS (PLHIV), who are often drug users, sexual minorities, and sex workers, face numerous socioeconomic challenges 9. PLHIV could be affected by COVID-19 in many ways, including elevated risk of severe COVID-19 outcomes and mortality11, interruption of HIV treatment and care13, and increased HIV risk behavior14.The pandemic of coronavirus disease 2019 (COVID-19) has been ongoing since early 2020 and the effects have been far-reaching, affecting not only individual health but also economies and health care systems15.In the early phase of the COVID-19 pandemic (June–July 2020), we conducted a cross-sectional study of anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) nucleocapsid (N) IgG antibodies and psychosocial and behavioral impacts of COVID-19 in a large HIV outpatient clinic at the National Hospital for Tropical Diseases (NHTD) in Hanoi, Vietnam. In that study of 1243 PLHIV, we found that the impacts of COVID-19 were small with respect to access to antiretroviral therapy (ART) but were substantial in terms of economic security and risky health behaviors, which were associated with psychological stress16. In response, many regions in Vietnam enforced strict citywide lockdowns and stay-at-home orders until the country entered a more normal stage in October 202117. After restrictions were eased, Vietnam recorded its first case of infection involving the SARS-CoV-2 Omicron variant in December 2021, leading to a peak of infection, with the highest number of new cases  recorded on 12 March 202216.Beginning in April 2021, Vietnam experienced its largest COVID-19 outbreak, the fourth epidemic wave in the country, which has resulted in over 11 million infections as of March 2023We scaled up our previous survey and conducted a second survey at 11 ART sites in Northern Vietnam during the period with strict social restrictions in the fourth COVID-19 outbreak during 2021. In the second survey, we aimed to explore the long-term impacts of COVID-19 and changes in the impacts of different pandemic phases. In particular, we assessed anti-SARS-CoV-2 N IgG antibodies and psychosocial and behavioral impacts of COVID-19 using a revised questionnaire. Our previous survey reported a prevalence of anti-SARS-CoV-2 N IgG antibodies of 0.2%, but this rate may have been underestimated partly owing to privacy violation concerns in SARS-CoV-2 testing. Additionally, the first survey showed that the economic impact of COVID-19 was enormous and associated with psychological distress and that improved social support may alleviate such psychological impact. However, the need for PLHIV to improve economic security and social support was not specifically evaluated in that survey. To address this limitation in our previous survey, the present survey included questions on barriers to COVID-19 testing, social support needs to continue ART and HIV care during the pandemic, perceived financial status, and preferred forms of assistance. The information from this study could help with understanding how PLHIV are affected by the COVID-19 pandemic and developing appropriate strategies to meet their needs.From June 2021 to January 2022, we conducted SARS-CoV-2 antibody testing and administered a self-report questionnaire survey on the psychosocial and behavioral impacts of COVID-19 among PLHIV (aged ≥ 18 years) at 11 ART facilities in Northern Vietnam. These facilities were involved in an HIV research project entitled, “Establishment of the “bench-to-bedside” feedback system for sustainable ART and the prevention of new HIV transmission in Vietnam,” which started in 2019 under a Japanese government program, the “Science and Technology Research Partnership for Sustainable Development” (SATREPS). These 11 ART facilities were selected in consultation with the Vietnamese Ministry of Health from multiple perspectives, including region, facility level, HIV prevalence, and support from other overseas donors. Additionally, owing to SATREPS being implemented within the framework of the Japanese government’s official development assistance, some facilities were selected with an intention to provide technical assistance to facilities with insufficient access to HIV services, such as viral load testing. The study sites include one national-level hospital (NHTD), seven provincial/city-level hospitals, and three district-level hospitals. Four of the 11 hospitals were located in Hanoi  and a 6R86 SARS-CoV-2 IgG Reagent Kit (Abbott Laboratories Inc.). In the questionnaire, the self-reported incidence was assessed by asking whether the respondent had been diagnosed with SARS-CoV-2 infection in a polymerase chain reaction (PCR) test or quarantined as a close contact of another person with such a diagnosis. The methods used for IgG antibody testing were the same as those in a previous study conducted in 2020 at the NHTD and are described elsewhereThe SARS-CoV-2 IgG assay is designed to detect IgG antibodies to the nucleocapsid (N) protein of SARS-CoV-2 whereas the main target of SARS-CoV-2 vaccines available in Vietnam is the spike (S) protein at the time of the survey. No study participant had received an inactivated whole-cell vaccine containing the N protein. Therefore, our antibody test results were not affected by vaccine history.The questionnaire included the total vaccine doses received so far, behaviors to prevent COVID-19 infection , changes in social contacts compared with those pre-COVID-19 , and willingness to have a diagnostic test when having symptoms of COVID-19 . Participants who said they were not willing to be tested were asked the reasons. The response options included “fear of HIV status being disclosed,” “fear of laboratory confirmation of COVID-19 infection,” and “fear of discrimination against people with COVID-19 infection,” and participants could select all applicable options.The questionnaire assessed participants’ experience of continuing ART during the outbreak  and their experience of receiving ART at another clinic that was not their regular hospital during the outbreak. Question responses were dichotomous. Additionally, participants were asked whether they had received any form of social support to continue ART and HIV care during the COVID-19 pandemic. Participants used free text to describe the type of social support that could be effective in ensuring continuity of ART during the pandemic. For the NHTD, all patients had scheduled visits to measure HIV viral load during June–July each year. We obtained visit status and reasons for missing a scheduled visit, as well as data on HIV viral load in June–July 2020 and 2021.18, in the past month and any change in alcohol consumption before and after the COVID-19 pandemic. As for drug use, participants were asked whether they had used illegal drugs in the past 3 months and whether there was a change in the amount of drug use before and after the pandemic. Finally, we queried changes in the number of sex partners and frequency of using a condom during sex, before and after the outbreak. For questions asking about these changes, possible responses were “no change,” “decreased,” and “increased.” For the items on alcohol intake and drug use, “non-drinker” and “non-drug user” were added to the response categories.Alcohol intake, drug use, and sexual behaviors were assessed. Regarding alcohol intake, participants were asked whether they had any episodes of binge drinking, defined as > 5 drinks on one occasionChanges in employment status were assessed using five categories . Participants’ pre- and post-COVID-19 household income and their current financial status were also assessed. Financial status was rated according to categories . We also asked whether participants had ever received financial assistance from any public authority. Finally, participants reported any forms of emergency assistance that could be helpful to support their lives using six options ; participants could select all applicable options.15. However, one limitation of our previous study was that there was no comparable prevalence of general distress using that cutoff score in the Vietnamese PLHIV population before and after the COVID-19 pandemic.In the first survey conducted at the NHTD during 2020, the Vietnamese version of the Depression, Anxiety and Stress Scale-21 (DASS-21-V) with a cutoff score of 34 was used to measure the general distress experienced by study participants19. To address limitations of the first survey and compare the prevalence of depression before and after the COVID-19 pandemic, we assessed depression using the CES-D, as well as general distress using the DASS-21-V, among participants in the second survey at the NHTD. The CES-D is a widely used self-reporting scale and there is strong evidence for both its reliability and validity in Vietnam’s HIV population, with a Cronbach’s alpha of 0.81 and sensitivity and specificity of 79.8% and 83.0%, respectively, with a cutoff score of 1620. The CES-D comprises 20 items answered on a four-point scale ranging from 0 (rarely or none of the time) to 3 , except for four items that are positively worded and scored in reverse. Regardless of whether questions were scored in reverse, if a respondent provided the same answer to all 20 items, the CES-D score was considered invalid and was excluded from the analysis. We used the Vietnamese version of the CES-D, which was previously available20. We defined a CES-D score of ≥ 16 as experiencing depression because this cutoff has been proven optimal for assessing depression in Vietnam’s HIV population20. The DASS-21-V comprises 21 items answered on a four-point scale ranging from 0  to 3 (applies to me very much or most of the time). According to the scoring instructions21, the total score is calculated by multiplying the sum of the responses by two. In line with the first survey, a cutoff score of 34 was used to measure general distress. This cutoff score was suggested by Tran et al. to detect general distress, including depression and anxiety, with a sensitivity of 79.1% and specificity of 77.0% in Vietnamese women22.Prior to the COVID-19 pandemic, the National Center for Global Health and Medicine began a collaboration with NHTD, a study site in the present research, to monitor clinical outcomes of PLHIV. Under this collaboration, we conducted a study to assess depression using the Center for Epidemiological Studies-Depression (CES-D) scale in an HIV patient cohort at the NHTD in 2016First, we descriptively evaluated the incidence of SARS-CoV-2 infection, prevention against COVID-19 infection, impact of COVID-19 on ART continuity, economic security, and risky health behaviors among all study participants. Next, to assess changes in the impacts of COVID-19 during different pandemic phases, we compared differences in responses between the two surveys conducted at the NHTD in 2020 and 2021 using the McNemar test. Additionally, a study on depression among PLHIV patients was previously conducted at the NHTD in 2016, prior to the COVID-19 pandemic. Using that available data, the prevalence of and factors associated with depression were compared between the 2016 survey (pre-COVID-19) and the present 2021 survey (post-COVID-19). Comparisons between the 2020 and 2021 surveys and the 2016 and 2021 surveys were conducted for the same questions or using the same scales among those who participated in both surveys . Univariate logistic regression models were used to investigate factors associated with depression, and crude odds ratios (ORs) were calculated. As supplementary analysis, we performed logistic regression models using all data, including from participants who gave the same response to all items on the CES-D.All analyses were performed using SAS 9.4 software . All tests were two-sided, with the significance level set at 5%. Missing data were excluded from the analyses.The study was approved by the Human Research Ethics Committee of the National Center for Global Health and Medicine (reference: NCGM-G-003560-02) and the Bio-medical Research Ethics Committees of the National Hospital for Tropical Diseases (reference: 12/HDDD-NDTU). We performed this study in accordance with Japan’s Ethical Guidelines for Medical and Health Research Involving Human Subjects, issued by the Japanese Ministry of Health, Labour and Welfare.Among 8633 HIV-infected outpatients under follow-up at 11 study sites, 7808 participated in the survey, with more than an 80% participation rate in each site and 90.4% as a whole  reported that they were salaried workers before the COVID-19 pandemic; 26.1% and 14.2% reported that they were self-employed and household workers, respectively  were practicing preventive measures, including wearing a mask (97.2%) and hand washing or gargling (94.0%). Additionally, 71.5% reported having less social contact than before the COVID-19 pandemic. Furthermore, most participants (95.2%) reported being willing to undergo diagnostic testing for SARS-CoV-2 infection when symptoms appeared; 280 (3.6%) were unwilling to be tested. The most frequently reported reasons for reluctance to undergo testing for COVID-19 were fear of HIV status being disclosed (52.5%) and fear of laboratory confirmation of COVID-19 infection (41.1%). Few participants were reluctant to be tested for fear of discrimination against those infected with SARS-CoV-2 (Table % were prMost study participants (99.1%) continued ART without interruption during the COVID-19 pandemic. Only a few participants (1.4%) reported that they temporarily received ART at another hospital during the COVID-19 outbreak. Most participants 73.2%) reported receiving social support to continue ART during the COVID-19 pandemic; the remaining participants (26.8%) reported receiving no support  reported binge drinking in the previous month, defined as having 5 or more drinks on one occasion. Additionally, 253 (3.2%) reported illicit drug use in the past 3 months. However, few participants reported an increase in alcohol consumption (0.7%) or illicit drug use (0.1%) after the COVID-19 pandemic; instead, more participants reported a reduction in the amount of alcohol consumption (16.3%) and illicit drug use (2.8%). Furthermore, fewer participants reported an increased number of sexual partners (0.7%) or decreased condom use when having sex (1.7%) than those who reported opposite changes   reported that they had reduced working hours and 1393 (17.8%) lost their job. Median household income after COVID-19 decreased by 2 million VND (33.3%) compared with pre-COVID-19 levels. Nearly two-thirds of participants reported that their financial situation was “a little challenging” (43.2%) or “very challenging” (22.5%). However, only 391 (5.0%) had ever received public financial assistance. More than half of participants (51.9%) reported cash benefits as being the most appropriate form of emergency assistance. Notably, participants from the study site in Hanoi reported higher unemployment due to COVID-19 compared with participants from other provinces (26.9% vs. 9.5%). However, there was no difference in perceived financial difficulties and likelihood of receiving financial support from public authorities . Table Regarding ART continuity, among 1288 HIV outpatients who were under follow-up at the end of 2019 before the COVID-19 pandemic, the number who missed a scheduled visit for known reasons increased significantly during the 1-year period between June–July 2020  and June–July 2021 . In June–July 2021, 129 PLHIV outpatients (10.0%) could not access the NHTD because of movement restrictions under the COVID-19 social distancing policy, and 106 patients (8.2%) were transferred to other hospitals to receive ART. However, there was no significant difference in missed scheduled appointments without a known reason (1.4% in 2020 vs. 1.2% in 2021). ART discontinuation was rarely reported in both surveys (0.9% in 2020 vs. 1.5% in 2021). Among those who were able to access the NHTD and underwent laboratory testing, HIV viral load was also minimally changed . During the prolonged COVID-19 pandemic, more participants reported receiving social support to continue ART and HIV care in the 2021 survey (82.3 in 2020 vs. 98.1% in 2021). As for risky health behaviors, more participants reported reduced alcohol consumption in the 2021 survey than in the 2020 survey; no significant change in illicit drug use was observed between the surveys. The responses to other questions, such as changes in sexual behaviors  and changes in economic conditions  differed between the two surveys. Therefore, the responses could not be directly compared.Mental health was assessed only among participants in the NHTD. Table In the logistic regression analyses for depression in the 2021 survey, 119 (10.7%) participants were excluded from the analyses because they provided the same responses to all 20 items on the CES-D. Table After the initial survey in 2020 at a single center, the second survey was expanded to 11 ART sites in Northern Vietnam. This extensive survey was conducted during the period with strict social restrictions during the largest outbreak of COVID-19 in Vietnam. Using a long-standing cohort of PLHIV before and during the COVID-19 pandemic, the second survey evaluated the long-term impacts of COVID-19 and changes in these impacts between different pandemic phases among PLHIV on ART.24 would facilitate sustainable access to ART during an emergency.HIV treatment was maintained amidst the stringent social restrictions imposed during the fourth COVID-19 epidemic wave. A comparison of two surveys conducted in 2020 and 2021 at the NHTD showed no increase in loss to follow-up for unknown reasons or virological failure. Only 1.2% of patients missed scheduled visits without a known reason, and more than 90% maintained an undetectable HIV viral load. Since the early days of the COVID-19 outbreak, the NHTD has made substantial efforts to follow up with patients via phone and apps, making tailored adjustments for patients to ensure that they continue to receive ART. Such support is believed to have been effective in preventing patients’ disengagement from HIV care. The Vietnam Administration for HIV/AIDS Control of the Ministry of Health issued a variety of decision documents outlining special measures to ensure HIV continuum of care during the COVID-19 pandemic. However, some participants in our study reported that they needed more flexibility in terms of delivery and pick up of medicine and multi-month prescriptions. Personalized support to meet patients’ needs and innovative strategies to strengthen ART delivery systems25, 27.7% in Guinea-Bissau26, 30.6% in Kenya27, and 54.6% in India28). To our knowledge, ours is the only study to investigate the seroprevalence of SARS-CoV-2 in PLHIV in Vietnam. It is evident that the seroprevalence of SARS-CoV-2 varies greatly between countries and regions within a country, depending on the prevalent virus strain, outbreak phases, and timing of survey. The fact that this study was conducted before emergence of the SARS-CoV-2 Omicron variant in Vietnam, and that the strong social restriction measures were continued by the Vietnamese government, may have contributed to the low prevalence compared with other countries.The 2021 survey revealed a SARS-CoV-2 antibody positivity rate of 1.2%. This prevalence was lower than that found in previous studies of PLHIV conducted in other countries over a similar period  and 2,275,727 (2.32%) at the beginning of June 2021 and at the end of January 2022, respectively36. However, a study from China observed a rebound in HIV risk behaviors among men who have sex with men after lockdown measures were lifted37. Furthermore, a study from Vietnam found worrying signs that stay-at-home orders and financial challenges regarding buying drugs could facilitate unsafe injection, group methamphetamine use, and unsafe sex among people who use drugs38. Moreover, whereas a decrease in alcohol consumption was reported, binge drinking was associated with depression in this study. Alcohol consumption is culturally perceived as a masculine trait in Vietnam, and there is high social pressure to drink heavily39. In our previous work, we found that substance use, including drinking alcohol, was a stress-coping strategy in the PLHIV population in Vietnam, and it was strongly associated with depression40. In particular, as the COVID-19 pandemic continues, limited social contact may lead to feelings of loneliness43, which can be exacerbated in PLHIV who often already have such negative feelings45. The prolonged COVID-19 pandemic could accelerate alcohol consumption as a mean to cope with emotional stress and chronic uncertainty47. Therefore, continuous monitoring of risky health behaviors is important.The tendencies to reduce risky health behaviors  were also consistent with findings from the first survey in 2020 and from those in other countries48. Additionally, more than 60% of study participants reported experiencing financial difficulty whereas only a few had received public financial assistance. The Vietnam government issued Resolution No. 68 to support employees and employers facing difficulties owing to the COVID-19 pandemic , totaling 1.14 billion USD. However, owing to the complexity and length of the application process, many gave up seeking aid49. Given the difficulties for PLHIV to find employment in general, there is a need to accelerate intensive employment assistance as well as capacity development such that these individuals can earn a stable income, which will help to minimize the negative impact of COVID-19 and future crises in this population. Additionally, the government of Vietnam should create financial assistance mechanisms to support those most in need in a timely and efficient manner during times of emergency. One example would be a system like that in the United States, which allows people in need to learn what types of financial aid they are eligible for through websites and apps and allows them to apply online50.The economic impact of COVID-19 has remained enormous in the PLHIV population. Overall, the unemployment rate of 17.8% (26.9% in Hanoi vs. 9.5% in other provinces) found in the present survey was far higher than national data in 2021 52, a change in employment status and poor financial status were strongly associated with depression. However, the prevalence of depression decreased by more than 10% in our NHTD cohort, in comparison with that of the pre-COVID survey in 2016. This is contrary to the available literature showing an increased risk of mental health problems globally during the COVID-19 pandemic53 as well as in Vietnam54. There is no apparent reason for this decline in prevalence. However, nearly all NHTD patients (98.1%) reported receiving social support to continue ART and HIV care in the 2021 survey. Additionally, our previous studies found that social support is a strong protective factor against depression in Vietnamese PLHIV19. Therefore, the reduced prevalence of depression in the present study may be partly explained by enhanced social support during the fourth COVID-19 outbreak. The variable social support was not statistically associated with depression in this study; however, our finding could be due to the fact that nearly all patients in the NHTD received social support. We found significant hospital-to-hospital variation in the proportion of patients who reported receiving social support to continue HIV treatment during the pandemic. Further investigation is needed regarding the reasons for this variation and specific social support characteristics that could protect against depression.Consistent with other studies conducted among the general population in VietnamThis study has several limitations. First, we adopted a cross-sectional design; therefore, we were unable to determine any causal relationships. Second, COVID-19 outbreaks and the responses varied widely by region and by survey timing, which may limit the generalization of our findings to other regions and pandemic phases. Additionally, the 11 ART facilities that participated in this study were selected in consultation with Vietnam's Ministry of Health from multiple perspectives, including region and facility level. However, the representativeness of PLHIV participating in this study across Northern Vietnam has not been fully validated. Third, the impacts of COVID-19 may be greater for those who were unable to participate in the survey than for those who participated. Continuous follow-up and monitoring would be required for those patients. Fourth, mental health was assessed only among participants from the NHTD, a national-level facility in Hanoi. To further investigate the protective role of social support against depression, future research should expand the number of study sites and include various social support settings. Additionally, more rigorous evaluation of social support characteristics is required. Finally, whereas our study provides important information on the impacts of COVID-19 among PLHIV from the patient’s perspectives, the engagement of families, health care professionals, communities, local governments, and policy makers is essential to make decisions about effective interventions to reduce adverse effects of COVID-19. A variety of research methods, including face-to-face interviews with stakeholders, can help to identify the strategies that are particularly relevant to PLHIV living in Vietnam.In conclusion, the overall prevalence of SARS-CoV-2 antibodies was low at 1.2%; there was no clear upward trend in COVID-19 infection among PLHIV compared with the rate of infection among the general population. Amidst the stringent social restrictions imposed during the largest outbreak of COVID-19 in Vietnam, HIV treatment was generally maintained and no increase in risky health behaviors was observed. The economic impacts on PLHIV remained significant, with a high unemployment rate, poorer economic security, and binge drinking strongly associated with depression. However, the prevalence of depression was decreased compared with that during the pre-COVID-19 period. Social support, including for patients to continue HIV treatment and effective employment/financial assistance, may help to alleviate the negative socioeconomic impacts of the COVID-19 pandemic and improve mental health among PLHIV.Supplementary Tables.


Whether vigorous intensity exercise increases risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown.To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported non-vigorous activity.Investigator-initiated, prospective observational study. Participants were enrolled 5/2015 to 2/2019, median follow up of 38 months completed 2/2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous intensity exercise.Multicenter, observational registry with recruitment at 42 high-volume HCM centers in the United States and internationally. Patients could also self-enroll through the central site.Individuals 8-60 years old diagnosed with HCM, or genotype-positive without left ventricular hypertrophy (phenotype-negative), without conditions precluding exercise, were enrolled.Amount and intensity of physical activityThe primary pre-specified composite endpoint included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate ICD shocks. All outcome events were adjudicated by an Events Committee blinded to the patient’s exercise category.Among the 1660 participants, 252 were classified as sedentary (15%), 709 (43%) participated in moderate, and 699 (42%) in vigorous intensity exercise . Seventy-seven individuals (4.6%) reached the composite endpoint: 44 (4.6%) of those classified non-vigorous, and 33 (4.7%) classified vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years. In multivariate Cox regression analysis of the primary composite endpoint, individuals engaging in vigorous exercise did not experience a higher rate of events compared to the non-vigorous group with adjusted hazard ratio (HR) of 1.01. The upper 95% one-sided confidence level (UCL) is 1.48, below the pre-specified boundary of 1.5 for non-inferiority.Among individuals with HCM, or those who are genotype-positive/phenotype -negative, who are managed in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or the sedentary. These data will inform discussion between the patient and their expert care provider around exercise participation. In others it is expressed as a complex trait with contributions from both polygenic and acquired factors. Some patients with HCM may experience symptoms of heart failure, atrial and/or ventricular arrhythmias, while others have normal longevity and good quality of life.2 As HCM is a well-recognized cause of SCD in previously-undiagnosed young individuals, including athletes,3 there has been intense debate over the last four decades over medical recommendations around participation at any level of physical activity, including recreational exercise and competitive sports, for individuals diagnosed with HCM. U.S. and European consensus guidelines dating back to 19854 have recommended against vigorous recreational physical activity and ineligibility for sports participation for all patients with HCM – a conservative approach in light of the lack of any outcomes data. However, restriction from exercise has adverse consequences. Individuals with HCM exercise less than the general population, and report a higher prevalence of obesity, heightened anxiety, and reduced emotional well-being.6Exercise has well-established physical and mental health benefits and is an integral part of life for millions of people worldwide. However, for individuals with hypertrophic cardiomyopathy (HCM), the possibility that physical activity may heighten risk of sudden cardiac death (SCD) has led to exercise restriction and disqualification from competitive sports. HCM is defined by unexplained left ventricular hypertrophy (LVH) and has a worldwide prevalence of ~1:500 individuals.7 now recognizing the benefits of mild-moderate intensity recreational exercise in patients with HCM. This new Class I recommendation was supported by evidence from the RESET-HCM clinical trial, in which adult patients who followed prescriptions of moderate intensity exercise showed significant improvements in exercise capacity and physical functioning.8 Although the study was underpowered for safety, there were no major adverse events and no increase in non-fatal arrhythmias in the exercise trained group compared to the usual activity group. The 2020 ACC/AHA HCM guidelines, 7 and the 2019 European guideline9, also introduced a new recommendation that participation in vigorous recreational exercise and competitive sports participation could be considered using a framework of shared decision-making10 for all7 or some9 patients with HCM. However, the ACC/AHA recommendation remains a “Class 2B” due to limited data on whether vigorous physical activity increases risk of ventricular arrhythmic events in patients with HCM. There remains uncertainty even for those who carry a genetic variant without left ventricular hypertrophy (LVH) (i.e. genotype positive/phenotype negative), particularly in light of post-mortem studies that have identified pathogenic genetic variants in 5-10% of sudden cardiac death victims without structural abnormalities at autopsy12 The guidelines prioritize thess knowledge gaps as a major unmet need. The prospective, multinational, NIH-funded LIVE-HCM study was designed to provide data to inform patient-provider decisions, with its primary objective to determine whether engagement in vigorous exercise, including competitive sports, is associated with increased risk for life-threatening ventricular arrhythmias and/or mortality in individuals with HCM.Recommendations are evolving, with the most recent AHA/ACC 2020 guidelinesThis was an investigator-initiated prospective observational study. This study was approved by the Yale Human Investigation Committee and by institutional review boards of participating sites. All patients provided signed informed consent.Individuals 8-60 years old with a diagnosis of overt HCM (phenotype positive), or genotype-positive/phenotype-negative, were eligible to participate. Individuals were excluded if they had conditions precluding vigorous exercise (advanced HCM-related symptoms (New York Heart Association class III or IV), or non-HCM-related conditions), as were those with LVH due to syndromic conditions or infiltrative disease. Individuals unable to complete online or phone questionnaires due to language or cognitive barriers were also excluded.Patients were enrolled either through participating high-volume HCM centers (N=42), in the United States, United Kingdom, Canada, Australia, and New Zealand, or through contacting the central site  directly , between 5/2015 and 2/2019. Information was disseminated to patients by the advocacy organization Hypertrophic Cardiomyopathy Association  other patient group Internet sites and mailing lists, and via mailings to physicians. For site-enrolled patients, diagnosis of HCM and eligibility were confirmed by the site. For self-enrolled patients, after consent and medical release forms were signed, diagnosis and eligibility were confirmed by chart review, interpretation of echocardiogram images by a Core Lab at the Mayo Clinic or of cardiac magnetic resonance (CMR) images at the University of Michigan. Derivation of the final cohort of 1660 participants is shown in Patients who consented were contacted by the central study team and sent a link to online questionnaires via a REDcap database. Records were obtained from sites and via medical release forms from physicians. Demographic, clinical, and genetic data were abstracted and entered into the REDcap database. Participants received a link to a brief survey querying the occurrence of outcome events every six months. If outcome events were reported, study coordinators contacted participants for details and records were obtained. If patients did not complete the planned 36 months of outcome surveys, records were obtained from sites or physicians to assess for events. Vital status was confirmed for all patients via sites or national death registries. Follow up was complete in 2/2022.13 which has been validated against both direct15  and indirect, (frequent detailed activity records) 15 criteria, and has high test-retest reliability16. Participants identified physical activities performed in the past year, indicating the months per year, times per month, and the average time per event they performed each activity. Activities were assigned a metabolic equivalent (MET) intensity level defined as the oxygen cost of physical activity in ml·kg-1·min-1 divided by the oxygen cost at rest (3.5 ml·kg-1·min-1). MET values were obtained from the 2011 Compendium of Physical Activities.17 Participation in at least one activity at METS > 6.0 for > 60 hours per year, was categorized as vigorous. 18 This level of intensity is beyond what has been recommended for patients with HCM for exercise. 19 Those participating in activities at METS > 4 and < 6 for > 60 hours per year, but not meeting criteria for vigorous, were categorized as moderate, and those not meeting either of these criteria, as sedentary. Those in moderate and sedentary groups were categorized as non-vigorous for the primary analysis. Patients were also queried about current participation in competitive level athletics. A subset of those meeting criteria for vigorous exercise performed at least one activity competitively, and were categorized as the vigorous-competitive subgroup.The primary independent variable, exercise level, was based on the Minnesota Leisure Time Activity Questionnaire,20All outcome events were reviewed and adjudicated by a Clinical Events Committee blinded to the patient’s exercise category. The primary pre-specified composite endpoint included death, resuscitated sudden cardiac arrest (SCA), syncope adjudicated to be definitely or likely arrhythmic, and appropriate ICD shocks, with or without syncope. All ICD shock events were reviewed by two electrophysiologists. If electrograms could not be obtained, reports of electrograms from the record were reviewed. Deaths were classified as sudden-arrhythmic/cardiac (SCD), non-sudden cardiac, or non-cardiac using standard definitions.22 10% dropout and 90% power at the 0.05 one-sided significance level to declare non-inferiority of vigorous and moderate to sedentary at the upper boundary for a hazard ratio (HR) of 1.5. These estimates were based on expected proportions of exercise intensity based on published data in patients with HCM and the general population: 25% vigorous, 25% moderate and 50% sedentary. 5, 23 However, the ratio of individuals performing vigorous compared to sedentary and moderate activity was higher than expected. Therefore, prior to analysis, we revised the comparison to compare the vigorous group to the moderate and sedentary groups combined, defined for this analysis as “non-vigorous”. Our achieved sample size  provides 91% power at the one-sided 0.05 significance level to declare non-inferiority of vigorous to non-vigorous at the 1.5 HR boundary.Sample size was determined using the Log Rank Non-Inferiority module of PASS . Original sample size was estimated at 2250 participants based on a 21 month recruitment period, total study time of 57 months, an event rate of 11.5% over 3 years, 24 This margin is within the range reported in large trials in the literature.For studies comparing interventions, it is customary to use data comparing the “standard” intervention to placebo, but analogous data are not available for exercise risk. Our rationale for using a HR of 1.5 as the upper bound was two-fold. First, consensus, derived from clinical judgment amongst our steering committee and investigators, was that 1.5 represented a clinically relevant margin. Second, 1.5 has been suggested as appropriate in trials in which no data are available on standard-placebo differences.7 which differed between groups (effect size > 12%) including history of arrest in the entire overt HCM group, followed by, septal thickness,  To determine, among those with overt HCM, whether apical variant HCM, or presence of a pathogenic mutation, impacted any associations of exercise with the composite endpoint, interaction testing was performed.The primary outcome variable is a composite endpoint of time to first of either death, SCA, appropriate ICD shock (for ventricular arrhythmia) or arrhythmic syncope. Time was determined from date of enrollment to date of either first event, transplant ) or of date last survey or clinical follow up (censor). Kaplan-Meier plots were constructed showing event-free survival. Our non-inferiority hypothesis was that participants reporting vigorous activity at enrollment were no more likely to have an event than those reporting non-vigorous activity (i.e. not inferior within the specified margin based on a HR of 1.5). Event likelihood was compared between groups using Cox regression including activity level (vigorous vs non-vigorous activity) as well as covariates for age, sex, race, recruitment method (site or self), age at diagnosis and presence of an ICD. Linear contrasts were estimated to compare the hazards of the vigorous group with the moderate/sedentary group. A non-inferiority boundary for the hazard ratio of 1.5 was used with non-inferiority concluded when the upper boundary of the 95% one-sided Wald confidence interval was less than 1.5. Pairwise non-inferiority comparisons of vigorous to moderate and sedentary groups are also provided per the original analysis plan. Post hoc sensitivity analyses were performed excluding first, genotype-positive/phenotype-negative individuals, and then, participants with exertional dyspnea or chest pain (NYHA II). A similar analysis was performed to compare the vigorous-competitive subgroup to non-vigorous group. Subsequent models included controlling for known clinical risk factors for sudden cardiac deathDemographic, clinical, and genotype data are shown for vigorous and non-vigorous groups  and withThe subgroup of vigorous competitive athletes were younger, more likely to be genotype-positive/phenotype-negative, more likely to have apical HCM, and less likely to have an ICD. Traditional risk factors for SCD did not differ. Forty-seven were age 8-13 participating in leagues, 74 were age 14-22, among whom 54 participated on varsity, junior varsity, or traveling teams, and 138 were age 23-60, participating in leagues or organized events. The most common sports were baseball/softball, running/track, soccer, and basketball .As shown in Characteristics of participants experiencing SCD (N = 8) or SCA (N = 6) are shown in In multivariate Cox regression analysis of the primary pre-specified composite endpoint, individuals engaging in vigorous exercise did not experience a higher rate of events compared to those in the non-vigorous group with an adjusted hazard ratio (HR) of 1.01. The upper 95% one-sided confidence level (UCL) is 1.48, below the pre-specified boundary of 1.5 for non-inferiority .In a pre-specified secondary analysis, those engaging in vigorous-competitive exercise also did not experience an increased arrhythmic risk compared to the non-vigorous group with HR 0.71, UCL 1.32. . In pre-Post-hoc analyses were performed in subgroups with characteristics which differed by an effect size of >12% between the vigorous and non-vigorous groups. First, genotype-positive/phenotype negative patients were excluded. Among this subgroup of phenotype-positive patients, similar point-estimates for the HR for vigorous activity compared to the non-vigorous group were seen. Controlling for known risk factors for sudden cardiac death which differed between groups , did not impact the findings. Next, those with NYHA II were excluded. In this subgroup of asymptomatic, phenotype positive patients, findings were similar. In neither the primary nor any of the sub-analyses, was either non-vigorous or vigorous exercise demonstrated to be superior . Among tAlthough all SCD and SCA events occurred in males , the oveThere were 203 individuals age 14-22 years, among whom 56 individuals were competing in varsity sports/traveling teams, (42 with overt HCM), 50 engaging in other vigorous exercise, either recreationally or at lower levels of competition, and 97 engaging in moderate exercise or who were sedentary. Demographic and clinical characteristics are shown in In this prospective study of 1660 individuals with HCM or who are genotype-positive/phenotype-negative (8%), those engaged in vigorous exercise did not experience a heightened risk of death, cardiac arrest, appropriate ICD shocks or arrhythmic syncope compared to individuals engaging in low to moderate intensity physical activity. Individuals who were participating in high-intensity competitive sports were also not at heightened risk. Overall absolute event rates were low, with fewer than 5% reaching the composite outcome over 3 years of follow-up. Post hoc analysis limited to those with overt HCM showed a similar HR although non-inferiority was not demonstrated based on the pre-specified boundary. In neither the primary patient population, nor any subgroup comparison, was either vigorous or non-vigorous exercise shown to be safer (superior). Most life-threatening events occurred during activities of daily living. Among the subgroup of 42 younger, highly competitive athletes with overt HCM, there was one event , which did not occur during competitive exercise. In total, these findings do not support universal restriction of vigorous intensity exercise in patients with HCM.25, which has driven guideline recommendations for 4 decades. These conservative recommendations were based on early observational series showing that HCM was a common cause of SCD among athletes and that most events occurred during exercise3. Subsequent series of SCD in athletes have suggested that HCM is accountable for a smaller proportion of events, and that few SCD occur during exercise28. Recent series of athletes with HCM who continue to participate in sports have shown no adverse events, 31 with the exception of one report including 2 athletes with HCM who died during high-intensity exercise after returning to play.32 In a prior study of athletes with ICDs, including 77 with HCM, the athletes were equally likely to experience ventricular arrhythmias during non-sports-related activity, as during sports. 34 A retrospective cross-sectional study of individuals with HCM 35 did not show increased ventricular arrhythmias in those with higher cumulative hours of exercise. These studies have been limited however, by small size, older populations, retrospective nature, and/or lack of a control group of less active individuals.These prospective data challenge long-held beliefs that vigorous and competitive exercise increase the likelihood of arrhythmia for individuals with HCM36 In this study, the 42 high school and varsity college athletes with overt HCM had a lower rate of events than moderate/sedentary individuals of similar age. This age-group is too small for meaningful statistical analysis with or without controlling for potential confounding differences. However, it is reassuring that the overall event rate is low, and that the single event was non-fatal and did not occur during competition. Despite these limitations, these data will inform shared-decision making as endorsed by recent guidelines7. Ongoing and future studies of highly competitive athletes will also be informative in guiding these decisions.The safety of highly competitive athletics, such as varsity high-school and college competition, for individuals with HCM has been debated. 37 This is consistent with the role of the autonomic nervous system in arrhythmogenesis. Catecholamines are arrhythmogenic, while vagal tone, which increases with regular exercise, is protective against ventricular arrhythmia. 38 In the current study, 3 individuals had SCA during vigorous exercise. However, SCA and SCD occurred predominantly at other times, regardless of engagement in vigorous exercise. One national-claims-database analysis suggested an association of vigorous exercise with lower mortality in an older population of individuals with HCM, although detailed exercise and clinical data were not available.39 The current study did not show graded improvement in mortality with increasing exercise as shown in the general population. However, there was no increase in mortality or total arrhythmic endpoints seen, and the relatively young age and short timeframe may not have allowed demonstration of the longer-term benefits of exercise.In the general population, exercise can increase the immediate risk of SCD, even in habitual exercisers, yet habitual exercise lowers the lifetime risk of SCD and mortality compared to those who do not exercise regularly--termed the “paradox of exercise”. 41 although some show a “J shaped curve” with higher mortality at highest levels of intensity. 42 More than one third of participants were instructed by physicians to perform no exercise at all, or only light-intensity activities. These data do not support this overly conservative approach. However, future studies will be needed to determine what exercise volume and intensity will be most beneficial for patients with HCM.Whether there is an “optimal” duration, frequency, and/or intensity of exercise for individuals with HCM cannot be determined from these data, as the purpose of the study was to provide information on risk for those wishing to exercise, and the study was not powered to show superiority in any exercise classification group. In the general population, most studies show a graded benefit with increasing intensity of exercise, 7 Recent molecular autopsy series suggest a potentially non-zero risk of SCD for these individuals, with identification of pathogenic genetic variants for HCM in 5-10% of young SCD victims despite absence of hypertrophy or structural abnormalities. 12 As it is unclear whether these genetic findings were the primary trigger for SCD, prospective outcome studies in genotype positive/phenotype negative individuals continue to be warranted. The absence of events in this group in the present study is reassuring and supportive of current guideline recommendations, but continued surveillance of these individuals is advisable.The rationale for including the genotype-positive/phenotype-negative group in the prespecified primary analysis group was lingering uncertainty about risk in these individuals, which our data have shown, significantly impacts patient care. Close to half of genotype positive, phenotype negative participants reported receiving recommendations for some or complete exercise restriction. Although engaging in vigorous exercise and competitive sports is considered reasonable for genotype-positive/phenotype-negative individuals by US and European guidelines (Class 2a), both documents acknowledge limited data in this group. As fewer patients exercising vigorously were symptomatic compared to those who exercise moderately or were sedentary, post-hoc analysis was performed in asymptomatic patients with overt HCM (71%), excluding those with exertional symptoms which may have precluded more intense exercise. Even after removing symptomatic patients, the point-estimate for vigorous exercise was similar, and neither exercise group was superior to the other. While we cannot exclude the possibility that patients exercising vigorously were less severely affected, it is also possible that deconditioning due to exercise restriction may have increased symptomatic burden, as suggested by improvements in physical functioning and quality of life seen in the RESET trial.5 as well as data on exercise practices in Americans in general. 43 It is likely that individuals interested in exercise were more interested in study participation. However, the over-representation of individuals engaged in vigorous exercise allowed robust comparisons and exploratory subgroup analyses.LIVE participants may not be representative of all patients with HCM. While recruitment materials were aimed at individuals engaging in any level of physical activity, the percentage of those engaged in vigorous exercise was higher than expected based on prior surveys of patients with HCM7 Whether the data can be extrapolated to patients managed outside of these centers cannot be determined.While almost a quarter of participants were self-enrolled, most had received care at high-volume HCM centers with expertise in management and risk-assessment of patients with HCM, as recommended by current guidelines.2 While the reason for this is unclear, prior data on safety of sports for individuals with HCM and ICDs may have led to higher enrollment of participants with ICDs who were more active than the average patients with HCM.The percentage of participants with ICDs is higher than in most published HCM cohorts. Individuals exercising vigorously differed in some ways from those exercising less vigorously or were sedentary. However, most known risk factors for sudden death did not differ between the groups, and controlling for those that did, did not impact the findings. The possibility of survival bias,  cannot be excluded. However, while the subgroup of younger individuals (14-22 years) was too small for meaningful analysis, it is reassuring that there were fewer events in the competitive/other vigorous exercisers than those exercising moderately or sedentary.Among individuals with HCM, or those who are genotype-positive/phenotype - negative, who are managed in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or the sedentary. These data will inform discussion between patients and physicians regarding vigorous exercise participation, in the context of overall expert assessment and management of HCM, using an individualized shared decision-making framework.Supplemental figures and tables


This study examined the association between smoking status and death from COVID-19.This study used nationwide cohort data collected from the Korean National Health Insurance Service, linking to information on all individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The smoking status of subjects who participated twice in national health screenings between 2015 and 2018 was measured. This study investigated death from COVID-19 among those who tested positive from 1 January to 30 May 2020.This study included 4259 patients who tested positive for SARS-CoV-2 in Korea. After adjusting for all potential confounding factors, current smokers  and recent quitters  were associated with an increased risk of death from COVID-19 compared to never smokers. Compared with current smokers, long-term quitters  and never smokers  were associated with a reduced risk of death from COVID-19.Smoking was associated with an increased risk of death among patients with COVID-19. Given the lower possibility of death in long-term quitters with COVID-19, continuous smoking cessation among smokers or recent quitters is needed. Various risk factors for infection and severe outcomes of COVID-19 have been investigated3. Although smoking is a major cause of incident chronic diseases and premature death worldwide4, the effect of smoking status on COVID-19 outcomes is unclear. The low prevalence of current smoking among hospitalized patients with COVID-19 has been a consistent finding across most previous studies7. Previous studies demonstrated that past or current smoking was associated with higher odds of COVID-19 infection relative to never smoking9. A recent cohort study in England showed that former or current smokers were associated with a higher risk of death from COVID-1910. However, evidence for an association between smoking and death from COVID-19 has been mixed13.Globally, there were millions of confirmed cases of COVID-19, including more than 7 million deaths, according to the World Health Organization (WHO)14. Furthermore, the association between past smoking and death from COVID-19 may differ by smoking cessation period. Although evidence for the beneficial effect of smoking cessation on reducing the risk of death from COVID-19 may have significant implications during the COVID-19 pandemic, little is known about the association between smoking cessation and among patients with COVID-19. COVID-19 in Korea was primarily prevalent in specific regions  in the first half of 2020 and spread mainly in the metropolitan area and the whole country in the second half of 2020. During this study period, from January to May 2020, 11468 confirmed cases were reported. The distribution of characteristics such as sex and age among the study subjects included in this study was similar to that of the Korean population. This study investigated the association between smoking status and death from COVID-19 among patients with COVID-19 using nationwide cohort data.The results from the meta-analysis were extracted from data on the ‘point prevalence’ of smoking status (i.e. assessment of smoking status at one particular time only). Since smoking behavior may change over time, repeatedly measuring information for smoking status within a specific period may be more reasonable15. Korea Centers for Disease Control and Prevention (KCDC) database have epidemiological information for all individuals who underwent laboratory SARS-CoV-2 tests and the information for results of SARS-CoV-2 test in KCDC data is linked to the NHIS database16.This study used data from the Korean National Health Insurance Service (NHIS), which is linked to information about the national health examination. The NHIS covers mandatory health insurance for all Korean citizens, and all insured individuals are required to have a standardized biennial health examination . Since Korea has a single-payer national health system, the NHIS has all insured individuals’ demographic characteristics information , results from national health screening , all medical records regarding diagnoses, treatments, and prescribed drugs, and death informationAmong the 230327 individuals who tested positive for SARS-CoV-2 from 1 January to 30 May 2020, this study eliminated subjects who tested negative for SARS-CoV-2 (n=222257). This study also excluded participants aged ≤19 years (n=357) and eliminated study subjects who did not undergo a national health examination twice between 2015 and 2018 (n=3451). This study excluded subjects who had missing data for smoking status (n=3), and the final study sample included 4259 patients who tested positive for SARS-CoV-2 .The outcome of this study was death from COVID-19 among patients with COVID-19. The death information was ascertained from data of Statistics Korea and KCDC.17.This study used information on smoking status surveyed from the self-reported questionnaire in the national health examination. The survey items regarding smoking status composed of current smoking, past smoking, and non-smoking. This study utilized information from the participants’ responses for two surveys on smoking status between 2015 and 2018 and study participants were classified into 4 groups: never smokers, recent quitters (≤2 years since smoking cessation), long-term quitters (>2 years since smoking cessation), and current smokers18. Study participants were categorized into Daegu and Gyeongbuk regions and other regions. Household income was divided by the 5th quintile out of the total 20th quintile. BMI (kg/m2) was divided into groups as follows: 18.5 (underweight), 18.5–22.9 , 23.0–24.9 (overweight), 25.0–29.9 (Class I obesity), and ≥30 kg/m2 (Class II obesity), based on the recommendation for Asian populations of the WHO19. Blood pressure was estimated once on the right arms of seated individuals who had rested for >5 minutes. Serum glucose levels and total cholesterol were measured by blood sampling after overnight fasting. eGFR was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation for creatinine20. A history of hypertension (I10–15), diabetes mellitus (E10–14), dyslipidemia (E78), stroke (I60–63), ischemic heart disease (I20–25), chronic obstructive pulmonary disease , chronic kidney disease (N18), cancer (C00-97), asthma (J45–J46), chronic liver disease , and mental illness (F00-99) were confirmed by the reporting of at least 2 claims within 1 year during the 3-year period before the COVID-19 test using the International Classification of Disease, Tenth Revision (ICD-10) code21.Potentially confounding factors included sex, age, residential area, household income, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, total cholesterol, estimated glomerular filtration rate (eGFR), and comorbidities. During the initial period in South Korea, there was an explosive outbreak of COVID-19 in the Daegu and Gyeongbuk regionsFor patients with COVID-19, Pearson chi-squared test and ANOVA test were utilized to compare sociodemographic and clinical characteristics by smoking status. To explore the association between smoking status and the risk of death from COVID-19, this study used both current smoking and never smoking as the reference group, and multivariable logistic regression models with three incremental levels of adjustment as follows: Model 1: unadjusted; Model 2: adjusted for sex, age, household income, residential area, income level, and BMI; and Model 3: adjusted for all covariates.All patient-related data were anonymized to ensure confidentiality. The study protocol was approved by the Institutional Review Board of Yonsei University (7001988-202006-HR-917-01E) and the requirements for informed consent were waived because the NHIS data were established following anonymization by guidelines for rigorous confidentiality.The general characteristics of study subjects who were tested positive for SARS-CoV-2 by smoking status are shown in 11 found that past smokers compared with never smokers were at increased risk of mortality among patients having COVID-19, whereas current smokers were not associated with risk of mortality. However, Patanavanich and Glantz12 showed that smoking was associated with an increased risk of death from COVID-19. Both of these studies are meta-analysis studies and methodological differences such as inclusion criteria of research data may attribute to conflicting results. Williamson et al.13, reporting from a large UK study, showed a decreased risk for death in current smokers compared with never smokers when fully adjusted, possibly indicating a 22. Considering that significant association between recent quitters, but not long-term quitters, and death from COVID-19, there seems to be a possibility that the negative factors of smoking accumulated recently may be associated to fatal outcomes, and further research is needed.This nationwide cohort study investigated association between smoking status and death from COVID-19 among patients with COVID-19. This study found that current smokers and recent quitters were associated with an increased risk of death from COVID-19 compared to never smokers. Compared with current smokers, long-term quitters, and never smokers were associated with reduced risk of death from COVID-19. This study found that current smokers and recent quitters were associated with an increased risk of death from COVID-19 compared to never smokers. Simons et al.23, it is necessary to take this into account in the interpretation of the results of this study. Furthermore, this study period was prior to: 1) the development of effective treatments; 2) a vaccine to reduce disease severity in those infected with SARS-CoV-2; and 3) the emergence of novel variants. All of these are likely to change the severity of disease once infected and have the potential to affect smokers, former smokers, and never smokers differently, particularly if, for example, vaccine uptake and health seeking behavior are very different between these cohorts. Finally, this study included only Korean adults, and further study is warranted to explore the associations in other ethnicities or countries.This study has several limitations. First, this study may include potential selection bias because it included subjects who underwent two national health examinations between 2015 and 2018, thus approximately 55% of all adults who tested positive for SARS-CoV-2 between 1 January and 30 May 2020. Second, information on smoking status was collected from a self-reported questionnaire, which is subject to recall and reporting bias. Since smoking status also changes over time, the smoking status measured in this study may differ from that at the time of the SARS-CoV-2 test. In addition, although this study divided individuals into recent and long-term quitters, the exact period of smoking cessation was not ascertained. Further studies are needed to investigate the associations according to the duration of smoking cessation. Third, since the percentages of current smokers (4.1% vs 16%) were significantly different between COVID-19 and non-COVID-19 patientsThis study demonstrated that current smokers and recent quitters were associated with an increased risk of death from COVID-19 compared to never smokers. Given the higher possibility of death in smokers who tested positive for SARS-CoV-2 relative to never smoking, smoking is an independent risk factor for COVID-19. Furthermore, long-term quitters were associated with a reduced risk of death from COVID-19 compared with current smokers, suggesting the necessity of continuous smoking cessation among smokers or recent quitters to prevent the fatal risk of COVID-19.


The first-pass recanalization of endovascular treatment (EVT) is closely correlated with clinical outcome of patients with large vessel occlusion (LVO) stroke. The aim of the study was to explore whether intra-arterial tenecteplase (TNK) during the first pass of EVT can increase first-pass successful reperfusion and improve the neurological outcome in AIS-LVO patients.ClinicalTrials.gov Identifier: NCT04202458) was a prospective, single-arm, single center study. Twenty-six eligible AIS-LVO patients with large-artery atherosclerosis etiology were consecutively enrolled from December 2019 to November 2021. Intra-arterial TNK (4 mg) after microcatheter navigation through the clot was administered, followed by TNK (0.4  mg/min) given continuously for 20  min after the first retrieval attempt of EVT without confirmation of the reperfusion status by DSA. The 50 control patients comprised of a historical cohort before the BRETIS-TNK trial (from March 2015 to November 2019). Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b.The BRETIS-TNK trial (p = 0.14), and the difference became statistically significant after propensity score matching . There was no difference in symptomatic intracranial hemorrhage between the BRETIS-TNK and control groups . There was a trend toward higher proportion of functional independence at 90 days in the BRETIS-TNK comparing with the control group .The first-pass successful reperfusion rate was higher in the BRETIS-TNK vs. control group (53.8% vs. 36%, This is the first study to report that intra-arterial TNK during the first pass of EVT seems safe and feasible in AIS-LVO patients. Acute ischemic stroke (AIS) is one of the most important causes of neurological morbidity and mortality in the world, especially in patients with large vessel occlusion (LVO) . EndovasDuring EVT for AIS-LVO patients with large-artery atherosclerosis (LAA) etiology, additional retrieval attempts may be needed to achieve recanalization, which may result in endothelial damage and microvascular impairment, hence decreasing the likelihood of successful reperfusion , 16. A gIn this context, we hypothesized that intra-arterial TNK during the first attempt of EVT may increase the rate of first-pass successful reperfusion and improve the neurological outcome in AIS-LVO patients with LAA etiology. The current study was designed to explore the safety, feasibility, and possible efficacy of the combination in this population.3); (4) severe hepatic or renal dysfunction  or requiring dialysis; (5) severe uncontrolled hypertension (systolic blood pressure over 200 mmHg or diastolic blood pressure over 110 mmHg which was unable to be controlled); (6) patients allergic to any ingredient of drugs in our study; (7) unsuitable for the clinical study as assessed by the clinician. Intravenous thrombolysis was not excluded in this study. Due to non-randomized design, historical control patients who met the same inclusion/exclusion criteria before BRETIS-TNK trial beginning were screened from our EVT database and these data were collected between March 2015 and November 2019.The BRETIS-TNK study NCT 04202458) was a prospective, single-arm, single center study in which AIS-LVO patients with LAA etiology according to TOAST classification 2458 was ; (3) LVOEVT procedures were performed in a biplane neuroangiography suite  under local anesthesia as described previously . BrieflyThe primary outcome was the proportion of successful reperfusion defined as modified Thrombolysis In Cerebral Infarction (TICI) 2b-3 when continuous TNK infusion finished after the first-pass. The secondary outcomes were the proportion of final successful reperfusion, good clinical outcome  at 90 days and early neurological improvement (ENI), which was defined as more than 4 point decrease in NIHSS within 24 h , all-caupost-hoc test for continuous and normally distributed variables or chi-square tests. The primary and secondary outcomes were estimated using a binomial regression model adjusted for the admission NIHSS and onset to reperfusion time (ORT). Further, we performed a 1:1 propensity score matching based on the nearest-neighbor matching algorithm with a caliper width of 0.1 of the propensity score to reduce the possibility of selection bias in the historical control cohort. The propensity score was estimated using a logistic regression model adjusted for age, admission NIHSS, ORT, location of occlusion, and iv-thrombolysis, which may influence the successful reperfusion or functional outcome , as medians with interquartile range (IQR), or absolute and relative frequency distribution, unless otherwise specified. Comparisons of baseline demographic, clinical, imaging, and procedural characteristics were evaluated by one-way analysis of variance on ranks followed by Dunn’s method for discontinuous or nonnormal variables or student t test followed by Bonferroni  outcome , 27–29. p = 0.81], intravenous thrombolysis rate , premorbid mRS (p = 0.42), baseline NIHSS score , last known normal to puncture time , percentage of MCA occlusions , ASPECTS at baseline , the puncture to reperfusion time , total number of retrieval attempts , and thrombectomy techniques (direct aspiration or stent-retriever as the first attempt)  . Aspiratp = 0.14), proportion of patients with ENI , and good clinical outcome  in the BRETIS-TNK group vs. control group although not statistically significant (p = 0.78). As for safety, there were comparable rates of intracranial hemorrhage including sICH between the two groups (p = 0.86)  .p = 0.03) after propensity score matching. The other outcomes were consistent with those before propensity score matching  was noted in the control group vs. 38.5% in the BRETIS-TNK group, which may have contributed to the low reperfusion rate and less favorable outcome in the control group. We included patients with both tandem occlusion and intracranial LAA, which may affect outcome given the difference in treatment effect between two groups. Finally, in the present study, an infusion of intra-arterial TNK (0.4 mg/min) via the relocated aspiration catheter was administrated no matter whether the first passage was successful or not. Based on this design, we did not perform DSA after removal of the stent retriever and aspiration catheter to minimize the potential adverse effects of contrast agent, which prevented us from distinguishing how many patients acquire recanalization due to the one thrombectomy maneuver or TNK administration. Given this limitation and the safety concern, different doses of TNK infusion will be used based on the status of vessel patency after retrieval maneuver in the BRTIS-TNK II (NCT05657444), aiming to further explore the efficacy and safety of intra-arterial TNK administration during EVT.To our knowledge, this is the first report that intra-arterial TNK as adjunct to mechanical thrombectomy seems safe and feasible in AIS-LVO patients with LAA etiology. However, because of study limitations, these findings should be interpreted as preliminary and a prospective multicenter randomized trial is warranted.Publicly available datasets were analyzed in this study. This data can be found at: The data that support the findings of this study are available from the corresponding author upon reasonable request.The studies involving human participants were reviewed and approved by the Ethics Committee of the General Hospital of Northern Theatre Command. The patients/participants provided their written informed consent to participate in this study.Z-AZ, JQ, LW, X-HS, Y-GZ, WL, XL, X-LL, LL, M-RC, and H-SC contributed to the acquisition of the data and the drafting of the manuscript. Z-AZ, LW, and H-SC conducted data analysis. H-SC contributed to the study design and critically edited the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Shenyang Science and Technology Bureau (20–205–4-007), the Science and Technology Project Plan of Liao Ning Province (2020JH1/10300002). H-SC received the fundings.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.