Background: High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up (LTFU) in an HIV vaccine-preparedness study in Masaka, Uganda. Methods: Between July 2018 and March 2021, HIV sero-negative adults (18–45 years) at high risk of HIV infection were identified through HIV counselling and testing (HCT) from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria. Study procedures included collection of baseline socio-demographic data, quarterly HCT, and 6-monthly collection of sexual risk behaviour data. Retention strategies included collection of detailed locator data, short clinic visits (1–2 h), flexible reimbursement for transport costs, immediate (≤7 days) follow-up of missed visits via phone and/or home visits, and community engagement meetings. LTFU was defined as missing ≥2 sequential study visits. Poisson regression models were used to identify baseline factors associated with LTFU. Results: 672 participants were included in this analysis. Of these, 336 (50%) were female and 390 (58%) were ≤24 years. The median follow-up time was 11 months (range: 0–31 months). A total 214 (32%) participants were LTFU over 607.8 person-years of observation (PYO), a rate of 35.2/100 PYO. LTFU was higher in younger participants  = 1.29, 95% confidence interval (CI) 0.80–2.11), although this difference was not significant. Female sex , and recreational drug use  were significantly associated with increased LTFU. Engagement in transactional sex was associated with increased LTFU  but this difference was not significant. LTFU was higher in 2020–2021 (the period of COVID-19 restrictions) compared to 2018–2019 . Being Muslim or other  and self-identification as a sex worker  were associated with reduced LTFU. Conclusion: We observed a high LTFU rate in this cohort. LTFU was highest among women, younger persons, recreational drug users, and persons who engage in transactional sex. Efforts to design retention strategies should focus on these subpopulations. HIV remains a global public health problem with 1.5 million new infections reported in 2020 worldwide [A prophylactic HIV vaccine is still considered the best hope for controlling the epidemic. Several HIV vaccine-preparedness studies have been established in sub-Saharan Africa to describe the HIV epidemiology and assess the suitability and willingness of different populations to participate in future vaccine trials ,4. A criUnderstanding the predictors of LTFU is critical for informing strategies aimed at maximizing retention. Some HIV vaccine-preparedness studies in Uganda have assessed participant retention and factors associated with study dropout rate ,7. HowevWe used data from an ongoing HIV vaccine-preparedness cohort study, “The PrEPVacc Registration Cohort Study”. The study was set up at sites in Tanzania, Mozambique, South Africa, and Uganda to prepare a population of HIV-negative individuals at risk of acquiring HIV for possible participation in the PrEPVacc HIV vaccine efficacy trial ,10.In Uganda, the study is conducted at the Medical Research Council/Uganda Virus Research Institute and the London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit’s clinical research site in Masaka city, Masaka district. Study participants were recruited from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria in Masaka and the neighboring districts of Rakai, Kalungu, Lwengo, and Lyantonde, an area spanning a radius of approximately 80 km from Masaka city . To be eMissed visit: This was defined as a scheduled study follow-up visit whose ±7-day window closed without the participant attending the visit, and with no late visit attendance within a 3-month period from the scheduled visit.Late visit: This was defined as a visit that occurred after the visit window for a scheduled follow-up visit had closed but before the window for the next scheduled follow-up visit opened.LTFU: This was defined as missing two or more consecutive scheduled study visits and failure to attend further study visits after at least three documented attempts.Prior to the initiation of the study, the study team held meetings with the community advisory board and community leaders from target communities to inform them about the study and obtain their input into the design of study tools and implementation of planned activities. Following these meetings, study team counsellors offered community-based HIV counselling and testing (HCT) services as per the national HIV testing algorithm .Individuals who tested HIV-negative were provided with brief information about the study, and those willing were invited to the study clinic for screening and possible enrolment. At the screening visit, individuals were provided with more detailed study information and asked to provide written informed consent. Consenting individuals underwent repeat HCT, urine pregnancy testing (women), eligibility assessment, and enrolment if eligible. Enrolment procedures consisted of collection of participant locator information . Information was also collected on socio-demographics as well as HIV risk and risk-reduction behaviours.Participants were followed up every 3 months (one month = 28 days). Follow-up visit dates were estimated from the day of enrolment with a window of ±7 days for each visit. HCT was performed at each visit. Urine pregnancy testing (women) and collection of HIV risk and risk-reduction behaviour data were performed every 6 months. Retention strategies included: collection of detailed participant locator information at baseline, which was updated as necessary at follow-up visits; issuance of participant appointment cards with a detailed study visit schedule at the enrolment visit; use of phone calls, where possible, to remind participants of imminent or missed study visits; use of locator data to physically visit participants who were not contactable by phone and remind them to attend study visits; ensuring that study visits were as short (1–2 h) as practically possible to minimize study fatigue and allow participants to attend to other obligations; flexibility in reimbursing transport costs to accommodate changes in transport fares due to a change of residence or during known periods of peak demand on public transportation services; offer of psycho-social support and medical care for common illnesses to participants, their partners, and children; and community engagement meetings.Data were entered and managed in OpenClinica. Analysis was conducted in STATA . Participant baseline characteristics were summarized using frequencies and percentages. The LTFU rate was estimated as the number of participants who were LTFU, divided by the total person-years of observation (PYO), expressed as a rate per 100 PYO. LTFU rates were reported overall, by demographic characteristics, and by calendar period i.e., 2018–2019 (pre-COVID-19) and 2020–2021 (COVID-19 restrictions). PYO were defined as time from enrolment until the last attended visit. For participants who were LTFU, the last attended visit was the visit prior to being categorised as LTFU. Participants who were not yet due for their first follow up visit were excluded from the analysis. We included follow-up data through March 2021.p-value of ≤0.10 using backward elimination . Sex and age were included and retained in the multivariable model a priori. Rate ratios with 95% confidence intervals (CI) were reported for both univariable and multivariable analyses. Kaplan–Meier plots were also used to assess associations with LTFU over time.Univariable and multivariable Poisson regression models were fitted to identify factors associated with LTFU. Factors associated with LTFU in HIV prevention studies were identified (from literature) and investigated within the data available. All variables assessed at univariable analysis were initially included in the multivariable analysis model. Variables were retained in the multivariable model if they had a The study protocol was approved by the Uganda Virus Research Institute Research Ethics Committee (reference number: GC/127/18/03/637) and the Uganda National Council for Science and Technology (reference number: HS2392). Prior to conducting study procedures, written informed consent was obtained from all participants. Individuals who tested HIV-positive during study follow-up were provided with post-test counselling and referred for HIV care. Pregnant HIV-positive female participants were also referred for services to prevent of mother-to-child HIV transmission.p < 0.001) and to self-identify as commercial sex workers  compared to those who were included in the analysis.Of 1017 individuals who were screened for eligibility between July 2018 and March 2021, 728 (72%) were enrolled. The commonest reasons for ineligibility were being at low risk for HIV infection , HIV infection  and not being available for follow-up . Of those enrolled, 672 (92%) had follow-up data and were included in the LTFU analysis. Of these, 336 (50%) were female, 390 (58%) were aged ≤24 years, 365 (54%) were single, and 403 (60%) had at most a primary-school-level education. . ParticiThe median time of follow-up was 11 months (range: 0–31 months). A total 214 (31.8%) participants were LTFU over 607.8 PYO, an overall LTFU rate of 35.2/100 PYO. Of those LTFU, 78 (36%) did not attend any follow-up visit, or only attended one follow-up visit. The median time to LTFU for women was 1.5 years, while that for men was more than 2.5 years . The comWe found a LTFU rate of 35.2 per 100 PYO in this HIV vaccine-preparedness cohort study. This level of LTFU is higher than levels reported in previous HIV vaccine-preparedness studies in Uganda in which annual LTFU ranged between 15% and 30% ,8,12. SoConsistent with previous studies , we founAlthough LTFU was higher among younger participants than their older counterparts, the association was not statistically significant. Previous HIV vaccine-preparedness studies found LTFU to be highest in the youngest age groups ,8,15,16.Drug abuse and commercial sex are associated with life instability that may be associated with poor retention in longitudinal studies . This prA strength of this study is that participants were recruited from diverse backgrounds and geographical areas; hence the results may be more generalisable to a wider group of potential HIV prevention trial participants in this setting than those from more homogenous populations. One of the limitations of the study is that data were obtained by self-report. Hence, there is a possibility of response bias, particularly for stigmatising behaviours, e.g., transactional sex and use of recreational drugs. We did not collect data on distance to the study clinic, and therefore could not evaluate its impact on participant retention. However, other studies have identified distance to the study clinic as a significant barrier to retention ,25,26. WWe observed a substantial LTFU rate in this HIV vaccine-preparedness study despite using several retention strategies. LTFU was more common among sub-populations that are likely to have the highest risk of HIV infection, i.e., women, younger persons, recreational drug users and those engaging in transactional sex. As high-risk individuals are the primary target of HIV prevention studies, retention strategies that target these groups should be urgently designed and evaluated.


What are the clinical outcomes of patients with intracranial metastatic disease in the setting of stable extracranial disease (IMD-SE) compared with patients with brain metastases and progressive extracranial disease (IMD-PE)?This meta-analysis of 68 studies found prolonged overall survival in patients with IMD-SE compared with those with IMD-PE. Pooled median overall survival for patients with IMD-SE was 20.9 months, and weighted median overall survival was 17.9 months for patients with IMD-SE and 8.0 months for patients with IMD-PE.These results suggest that IMD-SE represents a subgroup of patients with intracranial metastatic disease who have favorable survival. This meta-analysis evaluates overall survival, progression-free survival, and intracranial progression-free survival in patients with stable vs progressive intracranial metastatic disease secondary to any primary cancer. Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis.To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer.Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021.Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE  and no prior second-line chemotherapy or brain-directed therapy were selected.Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022.The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS.2I = 56.5%) and low (2I = 0%), respectively.Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS  and iPFS  compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months , and for patients with IMD-PE it was 8.0 months . Pooled median OS for all patients with IMD-SE was 20.9 months ; for the subgroup with breast cancer it was 20.2 months , and for non–small cell lung cancer it was 27.5 months . Between-study heterogeneity for OS and iPFS were moderate (In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases. We performed a systematic review and meta-analysis to evaluate OS, progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE compared with patients with IMD-PE.PRISMA) reporting guideline and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline and was registered in PROSPERO (CRD42021261563). Study protocols and amendments can be accessed on the Open Science Framework (OSF).This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses .Data extraction was completed in duplicate by 4 reviewers . Conflicts were resolved through discussion. Corresponding authors were not contacted given resource constraints. Extracted data are available in the Supplement  for single-group and comparative studies, respectively. Secondary end points included iPFS.8 In studies which displayed Kaplan-Meier curves but reported no effect size estimates for OS and iPFS in formats amenable to pooling, median OS and iPFS were derived according to Guyot et al9 and used calculate HRs.9 Subgroup analyses were performed for primary cancer type, Agency for Healthcare Research and Quality (AHRQ) rating, IMD-SE definition, and whether HRs were reported or derived from published Kaplan-Meier curves.Random-effects meta-analyses using the Paule-Mandel estimator pooled HRs with 95% CI for OS and iPFS between IMD-SE and IMD-PE cohorts.10 to generate summary survival curves. Weighted median OS, iPFS, and PFS were estimated using the method reported by McGrath et al.11 All statistical analyses were performed from January to February 2022 using R version 4.0.3  and meta,12 metafor,13 metaSurvival,14 and metamedian11 packages  statistics86 Among included studies, there were 58 retrospective cohort studies, 7 prospective cohort studies, and 3 RCTs. Thirty-four reported on non–small cell lung cancer (NSCLC), 3 on breast cancer, 2 on small-cell lung cancer, 1 on melanoma, and 1 reported multiple lung cancers. Twenty-five studies reported multiple primary cancers, and 2 did not specify primary cancer type. There were 5325 patients with IMD-SE, 4822 meeting our IMD-SE criteria and 503 with stable ECD as defined by study authors, and 1466 patients with IMD-PE were included across all studies; the number of patients with IMD-SE and IMD-PE were not reported in 2 studies.31 Median follow-up was reported in 42 studies and ranged from 4.7 to 102 months   (P = .47).30 The weighted median OS estimate for patients with IMD-SE was 17.9 months , and for patients with IMD-PE it was 8.0 months   . Subgrouatients) .61 Two studies each reported separate patient cohorts that met our criteria of IMD-SE and another with stable or controlled ECD.30 Five studies compared OS in the setting of controlled vs uncontrolled ECD and were amenable to meta-analysis  for patients with IMD in the setting of controlled ECD without further details on extracranial metastatic burden or prior treatment and 8.0 months  in patients with IMD in the setting of uncontrolled ECD  for all patients with IMD-SE  (67Twenty-seven studies reported median OS in patients with IMD-SE.h IMD-SE A. Of notatients) B and 27.atients) C, respecatients) A.32,49,6Weighted median OS from any first-line treatment was 23.5 months  . Subgroup analysis similarly did not show significant differences among studies with high vs low risk of bias as determined by AHRQ ratings. Metaregression failed to identify associations between the effect size and number of patients, publication year, or risk of bias.Improved OS was associated with IMD-SE in patients with breast cancer, NSCLC, and melanoma compared with IMD-PE secondary to these cancer types , with no significant differences between cancer type , and influence analysis based on Baujat plot, leave-one-out meta-analysis, and GOSH statistics only identified 1 study, Mariya et al,27 as individually contributing to between-study heterogeneity , while direction and statistical significance of the summary effect size remained unchanged 65 patients with IMD-PE (2I = 0%) and no outliers were identified.Prolonged iPFS was associated with presence of IMD-SE  . The weih IMD-PE . BetweenThe weighted median PFS of patients with IMD-SE secondary to any primary cancer was 7.0 months; . The 28 To our knowledge, this is the first meta-analysis to delineate the clinical outcomes of patients with IMD-SE and emphasize the importance of ECD status on survival in patients with IMD. For example, Mariya et al27 reported a median OS of 32 months in NSCLC patients with IMD-SE compared with just 7 months in those with IMD-PE . These observations are reminiscent of the concept of oligometastasic disease, an intermediate state in which metastatic progression is seen in the setting of primary disease control.87 Although oligometastatic IMD has historically been defined as a state of limited intracranial disease burden , our results suggest a need to reevaluate this definition to incorporate ECD stability.This systematic review and meta-analysis captures a clear divergence of OS in patients with IMD and stable ECD from those with uncontrolled ECD, further supporting the notion that OS in patients with IMD may be limited by ECD progression.23 found improved OS with absent ECD compared with present ECD in patients with a single brain metastasis secondary to NSCLC or melanoma . Prolonged OS was also reported in patients with less than or equal to 4 brain metastases secondary to NSCLC without ECD compared with those with ECD by Pessina et al26  and Karlovits et al30 . Rodrigues et al31, which reported prolonged OS in patients without ECD compared with those with ECD, included patients with up to 7 brain metastases . Notably, Mariya et al27 reported that the most common cause of death in their study cohort was active ECD (76% of 58 patients). These findings suggest that the stability of ECD drives survival outcomes in patients with IMD even in the setting of multiple intracranial lesions.In this meta-analysis, 5 studies incorporated intracranial disease burden in their study design. Della Seta et al21 Limited evidence on the location of extracranial metastatic sites precluded study of its impact on patient outcomes. Four studies reported OS beyond 10 years in patients with IMD-SE67 Patient characteristics for this subgroup could not be extracted and therefore, covariates associated with these extended survival times remain unknown. Although prognostic tools do not take into consideration the extracranial disease site, a thorough assessment of the location of ECD could expand treatment options and warrant more aggressive management for patients with IMD who frequently receive conservative therapy given their poor prognosis.The prognosis of IMD-SE may also be influenced by ECD location, although this information was underreported among our included studies.88 In addition to the suggestion that ECD control may be associated with reduced intracranial disease progression, extended iPFS may be associated with delayed development of neurological symptoms and improved quality of life. This possibility is especially meaningful in the context of prolonged OS, although our analysis of iPFS is limited by differences in intracranial radiological response criteria between studies. Our median PFS estimate in patients with IMD-SE is similar to historical estimates in patients with IMD, ranging from 2 to 8.5 months, although we were unable to assess PFS differences between IMD-SE and IMD-PE.89We also found that patients with IMD-SE demonstrated a weighted median iPFS of 13.6 months, which is longer than that of patients with IMD-PE . This is in contrast to reports of iPFS in patients with brain metastases ranging from 2 to 9 months, although recent advancements in immunotherapies and targeted therapies in combination with local interventions have led to improvements in iPFS.This systematic review and meta-analysis has several limitations. First, given the retrospective nature of most included studies, our results are limited by study quality, which we deemed to be acceptable in our analysis. Our results may also be susceptible to selection bias; our analysis, however, did not show any publication bias. Second, data on IMD-SE were frequently reported among included studies in subgroup analyses in larger studies limiting extraction of patient and disease characteristics specific to these subgroups. The absence of data on previous first-line brain-directed and systemic therapies, which may affect patient outcomes, may have introduced selection bias. The absence of reporting on intracranial disease burden may have further introduced selection bias. Moreover, among studies that reported outcomes in patients with controlled ECD, disease control was not consistently defined. This ambiguity may increase between-study heterogeneity. Third, across several studies, the number of patients with IMD-SE was not balanced with the number of patients with IMD-PE, likely a consequence of the retrospective nature of these studies. Finally, the results of our study are largely driven by the survival outcomes of patients with NSCLC, which may generate bias given that patient prognosis is associated with primary cancer and histological subtype. These limitations support the need for uniform reporting on baseline characteristics and outcomes in IMD-SEAlthough outcomes in patients with IMD have been historically poor, our findings suggest that IMD-SE may be associated with prolonged overall and progression-free survival. Efforts are needed to characterize this patient subgroup, predict survival, and inform treatment strategies.


The COVID-19 pandemic is a unique period of stress that, in some cases, led to post-traumatic stress symptoms (PTSSs). Emotion regulation strategies are known to modulate the emotional response to stressful events. Expressive suppression (ES) is a maladaptive strategy related to the exacerbation of the physiological stress response. Heart rate variability (HRV), an index of cardiac autonomic balance strictly related to ES, was also shown to predict PTSSs. This was the first study to investigate whether the pre-pandemic ES use and resting-state HRV predicted pandemic-related PTSSs. Before the pandemic, 83  university students completed the Emotion Regulation Questionnaire (ERQ), self-report measures of anxiety and depressive symptoms, and a three-minute resting-state electrocardiogram recording. After 12 months, 61  participants completed a self-report measure of pandemic-related PTSSs and repeated the self-report psychological measures. Pre-pandemic anxiety symptoms prospectively predicted greater PTSSs. Moreover, a significant interaction between HRV and ES in predicting PTSSs emerged, whereby those who had higher levels of ES and reduced HRV showed higher PTSSs. These findings suggest that an integrated assessment of HRV and ES might be useful for identifying individuals who are more vulnerable to the development of PTSSs during crises. Multiple factors negatively impacted the mental health of the general population, such as the uncertainty and the fear of contagion, isolation, high mass-media coverage, and the social and economic crises2. Several global community-based studies documented elevated levels of anxiety, depression, and post-traumatic stress symptoms (PTSSs) related to the pandemic8. These symptoms might persist5 and develop into full-blown mental disorders. Meta-analytic evidence reported high rates of anxiety (31.9%), depression (33.7%), and stress (29.6%) in community samples globally9. The high psychological impact was also thoroughly documented in college students12, who experience a sensitive period for the development of mental disorders13. Because the distress caused by the COVID-19 pandemic, in some cases, led to the onset of post-traumatic stress disorder (PTSD), this global crisis can be considered a specific mass traumatic event17.Since its outbreak in late 2019, the SARS-CoV-2 (COVID-19) spread worldwide and reached pandemic proportions in March 202018, not all individuals that experience traumatic events show consequent psychological distress, but some individuals are more vulnerable to adverse psychological consequences in response to traumatic and stressful events19. Following a traumatic event, most individuals develop a temporary stress response, but relatively few individuals experience persistent psychological symptoms20. Several factors that predispose individuals to experience elevated and persistent levels of psychological distress when exposed to traumatic events have been identified, such as a family history of psychopathology, poor social support, maladaptive emotion regulation strategies, and prior depressive and anxiety symptoms27. Although a wealth of evidence suggests that the pandemic is having a negative impact on the population’s psychological well-being, the literature on the psychological factors that could play roles in buffering pandemic-related psychological distress is still lacking.However, in line with the diathesis-stress model29. Reappraisal is a cognitive strategy that changes the trajectory of emotional responses by reformulating an event’s meaning31. This strategy is effective in regulating the emotional stress response. For instance, individuals who habitually use reappraisal are characterized by lower levels of negative affect, reduced experience of negative emotions31, and increased resilience32. Expressive suppression is a response-focused strategy that consists of inhibiting emotions once they have already been generated31. Following traumatic events, the use of expressive suppression might prevent the necessary emotional processing of the event, leading to the development and persistence of symptoms34. In addition, a few longitudinal studies have demonstrated that expressive suppression predicts PTSS development and reduced psychosocial functioning after stressful and traumatic events37. Other studies reported that the habitual use of expressive suppression was associated with pandemic-related post-traumatic symptoms41. Notably, this maladaptive strategy does not lead to a reduced emotional experience; instead, it impedes the expression of emotions, whilst physiological response can remain elevated. It has been shown that the use of expressive suppression can be associated with somatic arousal and physiological strain43.The way individuals regulate their emotions when provoked by stressful and traumatic events, such as the pandemic, can determine subsequent adverse psychological outcomes. Particularly, emotion regulation strategies are known to modulate the emotional response to stressful events50). HRV is defined as the fluctuations in interbeat intervals over time, and it is considered a reliable measure of cardiac autonomic balance and reflects overall physical health51. Low resting HRV was shown to be associated with emotion dysregulation52 and, more specifically, with higher use of maladaptive emotion regulation strategies56. An explanation for this association could lay in the evidence that HRV is believed to be modulated by a network that involves brain structures known for emotion regulation . Notably, individuals with PTSD have greater cardiovascular risk62 and a reduced HRV64. Additionally, longitudinal studies demonstrated that cardiovascular diseases65 and low HRV before a traumatic event predicted greater PTSSs in response to the event69. Individuals with lower HRV during the pandemic showed significant reductions in psychological well-being, compared to those with higher HRV70. In addition, a longitudinal study on a sample of adolescents reported that the link between psychological distress and pandemic-related affective symptoms was moderated by HRV assessed before the pandemic71. However, a limited number of longitudinal studies were conducted to assess the predictive role of reduced HRV in the development of psychological distress due to a traumatic event69. Even though HRV appears to be related to the stress response, the nature and direction of this association are still unclear.A peculiar autonomic measure inversely related to impaired emotion regulation and associated positively with efficient emotion regulation is heart rate variability (HRV71). The investigation of premorbid features is crucial to identify individuals who might suffer from severe consequences following trauma exposure and who might benefit from close monitoring and treatment following exposure to a stressor. To address this gap, this longitudinal study’s objective was to investigate the role of pre-pandemic expressive suppression, reduced HRV, and the interaction of these in predicting pandemic-related PTSSs. The present study examined a sample of undergraduate college students, as they are considered a particularly vulnerable population to the development of distress following stressful life events13. A moderating role of HRV in the association between expressive suppression and pandemic-related PTSSs was expected, whereby those with lower HRV and greater habitual use of expressive suppression would show greater pandemic-related PTSSs. The role of pre-pandemic cognitive reappraisal, anxiety, and depressive symptoms was taken into account in the analyses.Given the individual differences in response to trauma-related stressors, the lack of longitudinal studies examining the interaction of psychological and autonomic measures in predicting maladaptive stress responses is surprising. Indeed, as indicated by the above-reviewed literature, emotion regulation and HRV are both associated with the response to stressors (e.g.74). Eighty-three  Italian Caucasian students at the University of Padua voluntarily took part in the study. A convenience sampling method was used: the sample was recruited from several large introductory courses in psychology at the University of Padua, Italy. Exclusion criteria included a past or current history of cardiovascular, psychiatric, and neurological diseases, as well as the intake of psychotropic medications. All participants were right-handed and had normal or corrected-to-normal vision. Participants were naive to the aim of the study and received monetary compensation for their participation. Of the original 83 participants who took part in the pre-pandemic assessment , 61  took part in the follow-up, which occurred 12 months after the first assessment (December 2020–February 2021). The attrition rate of this longitudinal study was within the expected range (26.5%)75, and participants’ reasons for dropouts were not registered. The present study was conducted with participants’ adequate understanding and written consent in accordance with the Declaration of Helsinki and was approved by the University of Padua’s local ethics committee (prot. no. 3612).The present study was conducted within an extensive research project, and some participants’ data was already presented in previous publications . Subsequently, participants were seated on a comfortable chair in a dimly lit, sound-attenuated room, and a three-minute resting electrocardiographic was recorded. The second experimental session was conducted online, approximately a year after the first visit, between December 2020 and February 2021. The second assessment included the administration of the same three psychological questionnaires and the Impact of Event Scale (IES-R), a commonly used tool to measure PTSSs related to any traumatic event78. The ERQ is a self-report questionnaire to assess the respondent’s tendency to use cognitive reappraisal or expressive suppression as a strategy to modulate one’s emotional responses. Cognitive reappraisal is an emotion regulation strategy that consists of re-evaluating an emotion-eliciting situation to change the meaning of the event and reduce its impact. On the other hand, expressive suppression consists of reducing the experiential and behavioral aspects of emotion. The measure is composed of 10 items that refer to the use of cognitive reappraisal  or expressive suppression (“I control my emotions by not expressing them”). Each item is rated on a 7-point Likert scale from “strongly disagree” to “strongly agree.” The questionnaire provides two scores, one for cognitive reappraisal (ERQ-R) and one for expressive suppression (ERQ-S). Higher scores indicate greater employment of the emotion regulation strategy78.Habitual use of expressive suppression and cognitive reappraisal was collected at both assessments using the ERQ79 was used exclusively during the follow-up assessment. The IES-R is a self-report measure composed of 22 items that refer to post-traumatic symptoms  provoked by any traumatic event. In this case, participants were asked to refer to the COVID-19 pandemic (e.g.81). Respondents are asked to rate how distressing each item has been during the previous week on a Likert scale from 0  to 4 (“extremely”). Scores lower than or equal to 23 indicate minimal post-traumatic stress symptoms, whereas scores above 24 indicate the presence of clinically significant PTSSs. Particularly, scores greater than 24 can be divided into mild-to-moderate symptomatology (ranging from 24 to 36) and severe symptomatology (higher than 37)82.To assess post-traumatic symptoms due to the COVID-19 pandemic, the IES-R84 was used at both assessments to measure the severity of depressive symptoms. Each of the 21 items is comprised of a group of statements that address a particular depressive symptom . Respondents are asked to read each statement and select the one that best describes how they have felt for the past two weeks. The statements are scored on a scale from 0 to 3 depending on their level of severity, with a higher sum (range 0–63) suggesting more severe symptoms84.The BDI-II86 was used at both assessments to measure anxiety levels. The BAI includes 21 items, each based on a 4-point Likert scale, and scores range from 0 to 63. Whereby, greater scores indicate greater anxiety symptoms86.The BAI87. To fit the assumptions for linear analyses, the SDNN was natural log-transformed88. The SDNN is a widely used and accurate measure of total HRV, especially in short-term recordings. In resting conditions, its primary source of variation is parasympathetically mediated respiratory sinus arrhythmia87.The electrocardiographic (ECG) signal was acquired using three Ag/AgCl electrodes positioned according to Einthoven’s lead II configuration. ECG recordings were collected at rest for 3 min, sampled at 1000 Hz, and band-pass filtered (0.3–100 Hz). The ECG signal was visually inspected and corrected for artifacts using a piecewise cubic spline interpolation method to generate missing or corrupted values into the normal-to-normal (NN) intervals. Then, R-peak detection was used to compute interbeat intervals and mean heart rate (HR). HRV indices were computed using Kubios HRV Analysis software 2.2 . Specifically, time-domain HRV indices were calculated through autoregressive spectral analysis. The standard deviation of the normal (NN) sinus-initiated interbeat intervals (SDNN) in ms was computed because it is considered a reliable HRV index in short-term recordingst-tests were conducted. Considering that the male sex was underrepresented, an independent t-test was conducted to examine whether sex influenced the dependent variable of interest (IES-R).All analyses were performed using RStudio Version 1.4.1717. As a preliminary analysis to assess potential changes in emotion regulation , anxiety (BAI), and depression scores (BDI-II) between the first assessment and the follow-up, two-sided paired samples 89.Then, Pearson correlations were performed for each study variable collected at baseline  and IES-R scores. The Benjamini–Hochberg procedure was applied to control the false discovery rate in the correlationsmctest package90, multicollinearity diagnostics were run by calculating the variance inflation factors (VIF). A p-value of 0.05 was the cut-off for significance. Significant interactions were explored by conducting a simple slope analysis at the mean and 1 standard deviation (SD) below and above the mean using the interactions package91.Finally, a multiple linear regression model was conducted to assess the main effect of pre-pandemic expressive suppression scores, HRV, and the interaction of these in predicting psychological distress due to the pandemic (assessed at the 1-year follow-up). Pre-pandemic BDI-II, BAI, and ERQ-R scores, as well as sex, were included in the model as covariates to avoid confounding effects. All variables were centered and scaled: the mean of each variable was subtracted by each value, and the resulting value was then divided by the standard deviation of its distribution. Using the 92 for a linear multiple regression model with seven predictors was performed to determine whether the sample size was large enough to detect a significant effect. This analysis revealed that the sample size was large enough to detect a moderate effect size (d = 0.56) with a power of 0.80.A sensitivity power analysis in G*Powerp = 0.40; initial sample: Mage = 20.5, SDage = 2.5; follow-up sample: Mage 20.6, SDage = 2.7) and gender (p = 0.20) between the subsample that participated in the follow-up and the subsample that did not. Regarding the psychophysiological measures, there were no differences in BAI scores (p = 0.666), BDI scores (p = 0.70), ERQ-S scores (p = 0.47), ERQ-R (p = 0.10) scores, and HRV  between the subsample that participated in the follow-up and the subsample that did not.Regarding the demographic characteristics, there were no differences in age , and the scores ranged from 2 to 88. Particularly, 34 participants had a score below 23 (absence of symptoms); 12 participants had a score between 24 and 36 (mild-moderate PTSSs); and 15 had a score greater or equal to 37 (severe PTSSs). Table 6.9, and t-tests examining sex differences in IES-R scores, a significant difference emerged, t(59) = 3.03, p = 0.004, showing higher PTSSs in females, compared to males. For this reason, sex was included in the regression model as a covariate to avoid confounding effects.Regarding symptoms of anxiety, results showed a significant difference in BAI scores between the two assessments, specifically displaying milder symptoms of anxiety in the follow-up, with respect to the first assessment. Concerning the independent sample 93.The average HRV values of the analyzed sample were 3.86 (SD = 0.45), which were within normative valuesCorrelations among baseline variables and IES-R scores are displayed in Table Considering that cognitive reappraisal did not predict IES-R scores, its interaction with HRV was not included in the model. Results from the regression model are displayed in Table 71). However, given that HRV and emotion regulation are strictly associated (e.g.44), their interaction may buffer a detrimental psychological outcome following elevated stress. The present results showed that greater expressive suppression and reduced HRV interacted to predict greater pandemic-related PTSSs prospectively.This longitudinal study’s objective was to investigate the role of the interaction between pre-pandemic expressive suppression and reduced HRV in predicting pandemic-related PTSSs. The study was based on the evidence that the premorbid habitual use of expressive suppression and a reduced HRV have independently been related to greater PTSSs following a traumatic event . This data is relevant because it underlies the importance of combining self-report psychological measures with psychophysiological measures in the assessment of PTSS risk.Notably, expressive suppression and HRV alone did not predict PTSSs. Instead, the maladaptive emotion regulation strategy was a significant predictor of PTSSs only in association with HRV. Indeed, individuals with elevated levels of expressive suppression but with higher HRV were less likely to develop greater PTSSs. This is in line with previous studies that demonstrated the role of higher HRV levels in protecting individuals who habitually used maladaptive emotion regulation strategies from the development of psychological disorders (e.g.96), premorbid anxiety symptoms predicted pandemic-related PTSSs. Hence, this supports that delivering preventive programs aimed at reducing anxiety in at-risk populations might be important for reducing the impact of exposure to aversive situations97. Interestingly, the use of expressive suppression and reappraisal did not change across the two assessments, and this provided further support for the notion that emotion regulation strategies can be considered a vulnerability trait31. Instead, anxiety levels were slightly reduced from the pre-pandemic assessment to the follow-up. However, BAI scores were within a nonclinical range, thus making it hard to interpret this finding.In line with previous studies  might limit the generalization of our findings to the general population. Second, the reasons for participants to dropout were not registered, and future studies should collect this information. Finally, the use of self-report tools for the clinical assessment, the lack of information about the presence of post-traumatic symptoms before the pandemic, and socioeconomic data might have influenced the results. Although the IES-R is a commonly employed and reliable measure of PTSSsThe present study granted novel evidence on psychophysiological vulnerability factors involved in the development of PTSSs following the COVID-19 pandemic. Understanding the psychophysiological underpinnings of vulnerability to PTSSs is essential to developing effective systematic screening programs for the prevention and treatment of PTSSs. Taken together, our evidence suggests that an integrated assessment of HRV and expressive suppression may constitute a more accurate predictor of PTSSs than the two independent measures alone do.


The emotional impacts of the COVID-19 pandemic and resulting public health emergency are only beginning to be understood.age = 19.63, SDage = 2.59) and 157 older  adults, between July 2020 and July 2021. We hypothesized that individuals with increased loneliness, depression, and/or decreased subjective numeracy (SN) and interpersonal trust would experience more COVID-19 fear. We also predicted that females and older adults would experience more COVID-19 fear given that age-related comorbidities are associated with increased illness severity.We assessed the contributions of emotional and cognitive factors and age-related comorbidities to greater COVID-19 fear in a community dwelling sample of 142 younger (Mp = 0.016), and poorer SN was associated with increased COVID-19 fear in both age groups . Further, higher interpersonal mistrust was associated with increased COVID-19 fear , as was identifying as female .Results showed that the extent of loneliness in older adults was more strongly related to fear of COVID-19 than it was in younger adults (β = 0.197, Given that self-described poor numeracy was a marker for greater COVID-19 fear, investigators and policy makers might consider mitigation opportunities addressing data literacy requirements imposed by the media. Further, outreach to mitigate loneliness, particularly of the elderly, might effectively lessen the negative psychological impact of this ongoing public health crisis. The isolating nature of these orders led to negative impacts on the psychological well-being of individuals of all ages (The coronavirus disease (COVID-19) pandemic triggered a host of unprecedented changes to societal function . In respall ages . With thall ages .During the initial pandemic response, reports of elevated distress related to COVID-19 were evident . Extant Recent findings reported greater loneliness in younger adults compared to older adults during the pandemic , which cAdditionally, physical health status may modify the risk of becoming severely ill from COVID-19, and thus may increase COVID-19 fear USA: . DiabeteSociocultural factors may also be related to fear of COVID-19. With the introduction of stay-at-home orders, media and internet consumption grew exponentially. Indeed, the Canadian Internet Use Survey revealed that 90% of those aged 15–35 years and 35% of those aged 65–75 years increased online activities during late 2020 to early 2021 . FurtherOne last factor that has been suggested to play a fundamental role in adherence to health directives and in susceptibility to misinformation is trust. A high level of trust in the government and society is associated with higher vaccination rates as observed in a sample of 177 countries with vaccine availability . In a stThe current study was designed to clarify several issues pertinent to fear of COVID-19. First, we hypothesize that regardless of age, increased loneliness and depression will be associated with increased fear of COVID-19. Likewise, we predict that participants with lower versus higher SN would show greater COVID-19 fear. Further, we investigate the contribution of interpersonal trust to COVID-19 fear, anticipating age invariance for this effect. Finally, we expect that fear of COVID-19 is higher in females, as has been reported for anxiety symptoms.Age was targeted specifically for its contribution to COVID-19 fear to address this apparent gap in the literature. We hypothesized that older adults would experience greater COVID-19 fear given their known vulnerabilities. We also explore whether age group moderates the anticipated effects of loneliness, depression, SN, and trust. Finally, the presence of diseases common in older adults might portend greater fear of COVID-19. Consequently, we explored whether older adults treated for diabetes , HTN Ha, and hign = 299.This study was conducted between July 2020–July 2021 during waves 2 and 3 of the COVID-19 pandemic. Participants were considered eligible for inclusion if they met the minimum age requirement for each age group . Participants who did not meet the English language eligibility requirement, assessed through four English as a Second Language questions, were excluded from the study. Participants who did not complete the fear of COVID-19 Scale and who had missing values were also excluded from the study, resulting in 305 total participants, 5 of whom were excluded for missing data, and 1 was excluded as they emerged as an extreme outlier for a total of age = 19.63, SDage = 2.59, 76.0% female) enrolled in introductory psychology courses were recruited through the Simon Fraser University Research Participation System. 157 healthy community-dwelling older adults  were recruited through snowball sampling, newspaper advertisement, and online advertisement . The rationale behind the division of the age groups has been guided by 142 healthy younger adults , and all participants signed informed consent.Participants completed a 1–1.5-hour remote testing session through Qualtrics Survey Software. The following measures were self-administered and were scored according to standardized procedures by trained research assistants.The Demographics portion of the self-report questionnaire asked participants about their demographic information . The Health Questionnaire, developed by the researchers e.g.,  asked paThe Subjective Numeracy Scale (SN) is an 8-item self-rated measure of participants’ understanding of basic mathematics and probability . ParticiThe University of California, Los Angeles (UCLA) Loneliness Scale Version 3  is a 20-The Center for Epidemiological Studies Depression Scale CES-D;  is a 20-The fear of COVID-19 Scale  is a 7-iThe Trust Scale  is a 7-i2). Hierarchical linear regression was used to determine the contribution of the primary continuous variables of interest to fear of COVID-19 . As well, Gender, Age Group, and the Age Group moderating effects on continuous variables were evaluated. Age group and Gender were entered on the first Block. On the second Block centered scores for CES-D, SN, UCLA-L, and Trust were entered. On the final block the interaction terms were entered. The final model involved refinement by deletion of all non-contributory Block 2 terms (p > 0.10) and any non-significant Age Group interactions (p > 0.05).All analyses were conducted using IBM SPSS Statistics software  were retained. In Block 3, we tested age moderation of the other independent variable effects . This model includes the only significant age interaction . A main effect of SN on fear of COVID-19  was revealed, indicating that lower SN was associated with higher fear. In addition, Age group interacted with loneliness (UCLA-L)  (p = 0.039), as was identifying as female .= 0.016) . The rest-tests were conducted in older adults to determine the association between health status variables with fear of COVID-19. A small group of older adults (n = 10) who reported being currently treated for DM showed a trend to report higher fear of COVID-19  compared to those who did not report treatment for DM (n = 147). There were no differences in fear of COVID-19 scores for either HTN or HC .Independent sample Overall, this study conducted during waves 2 and 3 (2020–2021) of the COVID-19 pandemic, showed that older adults experienced greater COVID-19 fear related to loneliness as compared to younger adults. Furthermore, we found that both younger and older individuals with a greater COVID-19 fear reported lower SN scores, and a link between interpersonal trust and COVID-19 fear. Specifically, increased interpersonal trust was associated with less COVID-19 fear. Finally, our outcomes shed light on the impact of other diseases during the COVID-19 pandemic. In this case, older adults treated for DM experienced a greater fear of COVID-19 compared to those without DM, while the presence of other diseases, such as HTN and HC, did were not associated with fear of COVID-19. Below, we discuss each of these findings in turn.Despite finding no significant mean differences in COVID-19 fear in older versus younger participants, older adults experienced COVID-19 fear as a stronger function of loneliness compared to that of younger adults. Given that in older versus younger adults COVID-19 fear appears more contingent upon loneliness, interventions might be focused accordingly. This aligns with our hypothesis suggesting that older adults are especially vulnerable to psychosocial consequences of stay-at-home orders and isolation caused by the COVID-19 pandemic, which may lead to decreased quality of life and mental well-being , as wellThe current findings also present novel associations between SN and fear of COVID-19 in both older and younger adults. Specifically, we revealed that those reporting lower SN experienced greater fear of COVID-19. While prior studies have reported that lower subjective numeracy is associated with lower scores on a measure of COVID-19 knowledge , and to Past research on the role of trust and COVID-19 behaviors is often both contradictory and dependent on the measures used see . HoweverLastly, as we predicted, despite that fact that COVID-19 related deaths have been reported to be higher in males compared to females , our fing’s < 0.11). While the DM effect  did not reach traditional statistical significance, the magnitude suggests that in those few older participants with DM (n = 10), their fear may be considered meaningfully higher in this exploratory analysis while other select health conditions were not contributory. This is unsurprising given that DM has been associated with nearly a two-fold increase in both morbidity and severity of COVID-19 compared to those without DM , which, despite the moderate effect size noted, renders the reliability of this finding questionable until replication. While our outcome measure of fear of COVID-19 was specifically designed to assess fear related to the ongoing pandemic . The patients/participants provided their written informed consent to participate in this study.AC wrote the initial draft and performed initial data screening and cleaning. MT performed the analyses. VP assisted with writing and administrative tasks. AT performed the analyses and assisted with writing. WT conceived the original idea and finalized the writing. All authors discussed the results and contributed to the final draft.


BackgroundThis study aims to assess the graft patency rate following coronary artery bypass graft (CABG) surgery using noninvasive CT angiography. Materials and methodsA total of 68 patients were retrospectively evaluated with CT angiography (group I: 34 patients with coronary endarterectomy (CE) and group II: 34 patients without CE). CE was performed in multi-segmental diffuse coronary artery disease (CAD) or when calcified or extremely thick plaques made anastomosis troublesome. A team of two experts, an interventional radiologist and a cardiac surgeon, did the evaluations of graft patency rate.ResultsA total of 205 bypass grafts were evaluated in 68 post-CABG status patients . Post CABG, CT angiography demonstrated a graft patency rate of about 90% in both study groups at five years follow up, which was statistically insignificant (P > 0.05) in terms of graft patency rate. Following CE, five-year angina-free survival rates were 89% and 91% in groups I and II, respectively.ConclusionCABG surgery with endarterectomy is reliable and effective. It achieves the desired surgical myocardial revascularization in patients with diffuse calcified CAD having no alternative options for adequate myocardial revascularization. Atherosclerosis is the most common form of arteriosclerosis and a complex multifocal progressive inflammatory arterial disease of medium and large-size arteries involving multiple genetic and environmental factors ,2. The mAccording to the American Heart Association (AHA), CABG surgery is the most common intervention in patients with ischemic heart disease (IHD). Techniques of CABG surgery can be divided into two categories: traditional on-pump CABG and off-pump CABG (OPCABG) surgery -8. CurreComparative studies on the long-term outcome of off-pump CABG with or without endarterectomy have not been done in Bangladesh. This study aimed to assess the long-term graft patency rate following OPCABG with endarterectomy, and provide details regarding triple anticoagulation  strategies for patients having CE due to diffuse calcified CAD.A retrospective study was performed between September 2019 and February 2020, and 68 patients were evaluated in two study groups. Group 1 had 34 patients who had CE with OPCABG surgery; Group 2 had 34 patients who had only OPCABG surgery. This study included only postoperative isolated off-pump CABG with or without endarterectomy patients who attended outpatient department follow-up after five years of surgery. However, patients with combined CABG and valvular or congenital cardiac procedures, redo CABG, and systemic diseases such as end-stage renal disease, hepatic failure, and respiratory failure were excluded from the study. The primary study endpoint was to evaluate left ventricular function and long-term graft patency rates at a five-year follow-up. To evaluate the primary outcome, patients underwent transthoracic echocardiography (TTE) and CT-based coronary angiogram. However, the secondary study endpoints considered the incidence of major adverse cardiac and cerebrovascular events (MACCE), postoperative myocardial infarction, and transient ischemic attack (TIA)/stroke during the five-year clinical follow-up. The departmental, academic, and National Research Ethics Committee (NREC) have given ethical clearance for this study. Informed written consent was obtained from the patients involved. A quality assurance system was employed to confirm the validity of the observations and findings to ensure the reliability of the data and to conclude that it was derived correctly from the raw data. Quality control measures were applied to each stage of data handling to ensure data consistency and correct processing.Indication and surgical technique of CEThe CE techniques have been published in detail elsewhere . A conclPostoperative anticoagulation therapyIn this study, we have used triple anticoagulation therapy with a target international normalized ratio (INR) of 1.5-2.5, according to the local hospital protocols described elsewhere . Triple Statistical analysisStatistical analyses were performed utilizing SPSS v25.0 . Data were expressed as mean ± SD for continuous variables, percentages, and frequency for categorical variables. Pearson’s chi-square evaluates categorical variables. The Kaplan-Meier curve estimates the cumulative survival rate. A p-value of ≤0.05 was considered significant.A total of 68 post-CABG patients  underwent CT angiographic evaluation in this review after five years of operation. A total of 205 bypass grafts (110 bypass grafts in group I and 95 grafts in group II) were evaluated in this study. Moreover, the total number of arterial and venous grafts among the study population was 82 and 123, respectively. Table Tables The patency of the bypass grafts and native coronary artery is vital in the long-term outcome after surgical myocardial revascularization. However, recently published papers observed that approximately 40% and 25% of post-CABG patients suffered from a recurrence of angina and graft restenosis at five-year follow-up, respectively -6. ThereHowever, Ghatanatti R and Teli A performed a meta-analysis of 43 recently published papers. They observed that endarterectomy with OPCABG surgery in diffuse calcified CAD has a better outcome . It was In this current study, a CT angiogram observed a ~91% graft patency rate at five-year follow-ups, similar to other recent study results ,8,21-24.This current study has a few limitations, such as this retrospective study was conducted in a single center with a five-year follow-up period. It is quite likely that there are subtle differences in the cohort of the patients that would cause the surgeon to elect to perform an endarterectomy instead of a more conventional CABG procedure, leading to a selection bias. Furthermore, as this current study is based on outpatient department post-CABG patients, the plausibility of bias related to selective reporting and measurement of study outcomes cannot be excluded. Despite these limitations, there is no simple method to answer questions about how to increase grafts' long-term patency to endarterectomized vessels, and this study offers potentially valuable insights. A randomized control trial with a large population and long-term follow-up are necessary to confirm our findings and define both groups' long-term clinical and functional results. Developing a well-trained cardiac, surgical, and anesthetic team and establishing modern equipment and adequate logistic support should be done in the cardiac institutes of Bangladesh to ensure up-to-date cardiac services and research for complex CAD.This study observed a standard and comparable long-term graft patency rate of ~90% following OPCABG surgery with or without endarterectomy in Bangladesh. Therefore, as a surgical option, CE is a viable procedure for desired surgical myocardial revascularization in diffuse calcified CAD patients and has good long-term graft patency and survival benefits. However, endarterectomy should be considered an adjuvant therapy to CABG surgery in patients with diffusely calcified coronary arteries, even when no alternative could achieve complete myocardial revascularization.


Patients with transposition of the great arteries (TGA) after an atrial switch or congenitally corrected TGA (ccTGA) are prone to systemic right ventricular (sRV) failure. Tricuspid valve (TV) regurgitation aggravates sRV dysfunction. Timely TV surgery stabilizes sRV function, yet the development of atrioventricular (AV)-conduction disturbances in the course of sRV failure can contribute to sRV dysfunction through pacing-induced dyssynchrony. This study aims to explore the incidence, timing, and functional consequences of AV-block requiring ventricular pacing after TV surgery in patients with sRV.Consecutive adolescent and adult patients with an sRV who underwent TV surgery between 1989 and 2020 and followed-up at our center were included in this observational cohort study.p = 0.000), as was the heart failure biomarker NT-pro-BNP  and the percentage of patients with ≥1 echocardiographic class of deterioration of systolic sRV function . Of the patients receiving chronic subpulmonary ventricular pacing (n = 12), 9 (75%) reached the composite endpoint of progressive heart failure . Only 4 (31%) patients with native AV-conduction (n = 13) reached this composite endpoint (p = 0.027).The data of 28 patients  were analyzed. The mean follow-up was 9.7 ± 6.8 years. Of the remaining 22 patients at the risk of developing high degree AV-block after TV surgery, 9 (41%) developed an indication for chronic ventricular pacing during follow-up, of which 5 (56%) within 24 months postoperatively . The QRS duration, a surrogate marker for dyssynchrony, was significantly higher in patients with chronic left ventricular pacing than in patients with native AV-conduction (217 ± 24 vs. 116 ± 23 ms, Patients with a failing sRV who undergo TV surgery are prone to develop AV-conduction abnormalities, with 41% developing an indication for chronic ventricular pacing during 10 years of follow-up. Patients with chronic subpulmonary ventricular pacing have a significantly longer QRS complex duration, have higher levels of the heart failure biomarker NT-pro-BNP, and are at a higher risk of deterioration of systolic sRV function and progressive heart failure. Over the past decades, surgical, interventional, and pharmaceutical strategies for patients with congenital heart disease (CHD) have improved with over 90% of patients currently reaching adulthood. This increase in survival, however, often comes at the price of long-term sequelae. A particularly challenging group within the adult patient with CHD population is formed by patients with a systemic right ventricle (sRV) in a biventricular circulation. This group entails patients with transposition of the great arteries (TGA) after atrial switch according to Mustard or Senning and patients with congenitally corrected TGA (ccTGA). In this context, the morphological right ventricle is in the subaortic position, supports the systemic circulation, and is exposed to a chronic pressure overload, ultimately resulting in systolic dysfunction of the sRV . Atriovede novo AV-block of ~2%  regurgitation . EbsteinThis study aims to explore the incidence, timing, and functional consequences of a high degree AV-conduction block requiring chronic ventricular pacing after TV surgery in patients with sRV.n = 3).This two-center, observational, retrospective cohort study was performed at the departments of Cardiology of the Leiden University Medical Center and Amsterdam University Medical Center, united in the Center for Congenital Heart Disease Amsterdam Leiden (CAHAL). Consecutive adolescent and adult patients (≥16 years of age) with an sRV in a biventricular circulation who underwent TV surgery at CAHAL between 1989 and 2020 were included for analysis. Patients with perioperative in-hospital mortality were excluded due to a lack of follow-up , postoperatively prior to hospital discharge, and at the last outpatient clinic visit before reaching the composite clinical endpoint of progressive heart failure  implantation/heart transplantation, or death) or the most recent follow-up available. The closing date for follow-up was March 2021.During the study, the data collected were medical history, complaints, pharmacological therapy, physical examination, cardiac implantable electronic device interrogation findings, electrocardiography (ECG), echocardiography, and laboratory investigations. For TV surgery, surgical technique [TV annuloplasty (TVP) or TV replacement (TVR)], and concomitant procedures and complications were documented. Data on vital status and cause of death were obtained.Serial echocardiograms were performed with commercially available ultrasound systems and were analyzed offline in Echo PAC . Echocardiographic parameters were assessed and measured offline by two independent cardiologists with expertise in congenital imaging.The primary outcome was the incidence and timing of high degree AV-block necessitating ventricular pacing. Chronic ventricular pacing was defined as > 40% subpulmonary left ventricular (LV) pacing, in accordance with the current ESC guidelines . SecondaAll tests and procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 2013 Helsinki declaration or comparable ethical standards. Appropriate local scientific board approval was obtained and the need for written informed consent was waived by the institutional medical ethical board. All patients provided consent for their data to be registered and published.T-test or the Mann–Whitney U-test, as appropriate. In the case of categories, a McNemar test or the chi-square test was used. For a comparison between the occurrence of the cumulative endpoint of CRT, VAD implantation/heart transplantation, or death, the chi-square test was used. The value of p < 0.05 was considered statistically significant.All statistical analyses were performed in IBM SPSS version 25 and the cumulative incidence curve was performed in R version 3.6.3 . Normally distributed continuous data are displayed as mean ± standard deviation (SD) and non-normally distributed continuous data are displayed as median and the first and third interquartiles [IQ1 and IQ3]. Proportions are displayed as numbers . The primary analysis focused on the incidence and timing of chronic ventricular pacing. A cumulative incidence curve was generated for pacing dependency after surgery. A comparison between patients with native AV-conduction and chronic ventricular pacing was performed using an unpaired-samples Data from 28 patients were included for analysis . Patientde novo. Of the remaining 22 patients at the risk of developing high degree AV-block after TV surgery, 9 (41%) developed an indication for chronic ventricular pacing during follow-up, of which 5 (56%) within 24 months postoperatively  (Five (18%) patients received chronic LV pacing preoperatively, of which two had undergone an upgrade to a CRT prior to TV surgery. One patient underwent a concomitant surgical CRT implantation scharge) . Of the There were no significant differences between the group of patients retaining native AV-conduction and those requiring chronic ventricular pacing with regards to baseline demographic characteristics, anatomy, preoperative ECG characteristics, echocardiography, surgical technique, and concomitant procedures or pharmacological therapy .During follow-up, 7 (25%) patients died, of which 6 deaths were heart failure-related and one patient died due to aspiration pneumonia. Three (11%) patients underwent VAD implantation as destination therapy due to progressive heart failure and being not eligible for heart transplantation. No patients received heart transplantation. During follow-up, 5  patients received CRT implantation or upgrade due to progressive heart failure. Of all the CRT implantations and upgrades, pre- and post-surgery, four patients (50%) required a hybrid and/or primarily surgical approach. One patient received a transvenous upgrade to CRT, yet successful resynchronization was not achieved due to a suboptimal lead location. Seven (26%) patients required a re-operation, other than for epicardial lead placement, of which three VAD implantations, three TVR procedures , and one pulmonary valve replacement.p = 0.000) . p = 0.004]. The global sRV function and percentage of patients with severely reduced sRV function were not significantly different between the groups (p = 0.001)  . Renal fe groups . However= 0.001) . The recAt the last follow-up, all patients were treated with at least one heart failure drug. Pharmacological therapy did not differ significantly among the groups . A totalp = 0.027) (Four (31%) patients with native AV-conduction reached the composite endpoint of upgrade or implantation of CRT, VAD implantation, or death, as compared with 9 (75%) patients requiring chronic ventricular pacing (= 0.027) .The main findings of this study are that (1) the incidence of AV-block necessitating chronic ventricular pacing in patients with sRV who have undergone TV surgery is 41% after 10 years of follow-up, and in 56% of the cases, high AV-conduction block occurs already within the first 24 months postoperatively; (2) the group receiving chronic left ventricular pacing has longer QRS complex duration, higher levels of the heart failure biomarker NT-pro-BNP, and has a higher percentage of patients with at least one echocardiographic class of deterioration of systolic sRV function; and (3) patients with chronic subpulmonary pacing due to AV-block are at a higher risk of progressive heart failure.Given the high prevalence of TR requiring surgical intervention and AV-conduction block in the group of patients with sRV failure, it is important to evaluate the incidence and consequences of chronic subpulmonary pacing after TV surgery, as some of its negative sequelae may be prevented by concomitant implantation of an epicardial sRV lead at the time of surgery and timely initiation of CRT. In the current study, we investigated the incidence, timing, and long-term functional consequences of AV-conduction block requiring ventricular pacing after TV surgery in patients with sRV.Patients with an sRV are prone to sRV dysfunction and failure . The morde novo AV-block of ~2%  after TV surgery. The group of patients with chronic subpulmonary pacing had significantly more events of the composite endpoint of progressive heart failure during follow-up. This might be due to the deterioration of sRV function due to pacing-induced dyssynchrony. As CRT has shown potential to reduce pacing-induced dyssynchrony, concomitant epicardial sRV lead implantation at the time of TV surgery may halt some of the negative pacing-induced effects on sRV dysfunction.This study is retrospective and observational by nature and involves a cohort of 28 patients. The relatively small study population is reflective of the rareness and complexity of the condition and is the largest study on the long-term outcomes after TV surgery in patients with sRV to date. Although the groups with native AV-conduction and chronic subventricular pacing are comparable, some heterogeneity of the study population should be considered when interpreting the results—the anatomy of ccTGA and TGA after atrial switch has important pathophysiological differences, as well as the different surgical strategies that might have evolved over time. As a consequence of the retrospective nature of this study, follow-up is susceptible to information bias and loss to follow-up. Another limitation to this study is the lack of an ideal counterfactual, as progressive sRV dysfunction is intricately related to TR requiring intervention and to AV-conduction abnormalities.Future research should focus on the mechanisms of AV-block post-surgery in patients with sRV, the correlation among ventricular pacing burden, electrocardiographic, echocardiographic, and invasive markers of dyssynchrony and sRV function, and heart failure progression (post TV surgery). Another future aspiration is to further investigate the therapeutic role of CRT and conduction system pacing in halting the progression of and stimulating reverse remodeling in sRV failure.Patients with a failing sRV who undergo TV surgery are prone to develop AV-conduction abnormalities, with 41% developing an indication for chronic ventricular pacing during 10 years of follow-up. Patients with chronic subpulmonary ventricular pacing have a significantly longer QRS complex duration, have higher levels of the heart failure biomarker NT-pro-BNP, and are at a higher risk of deterioration of systolic sRV function and progressive heart failure.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Medisch-Ethische Toetsingscommissie Leiden Den Haag Delft (METC LDD). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.AE and MJ contributed to study conception and design. MN and MR contributed to data collection. MN contributed to analysis of results. MN and AE contributed to interpretation of results. MN, MJ, PK, HV, BB, MR, DK, MH, MS, and AE contributed to draft manuscript preparation and reviewed the results. All authors approved the final version of the manuscript.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.


To evaluate whether the prognostic nutritional index (PNI) is related to the oxygen therapy requirement at hospital admission and to ascertain the prognostic effect of the PNI and the oxygen therapy requirement as predictors of hospital length of stay in patients with moderate to severe coronavirus disease 2019 (COVID-19).post-hoc analysis in hospitalized patients with moderate to severe COVID-19. The participants were categorized: (1) non-oxygen therapy (moderate COVID-19 not requiring oxygen therapy); (2) nasal cannula therapy ; and (3) high-flow therapy (severe COVID-19 requiring high-flow oxygen therapy). PNI was calculated for each patient according to the following equation: serum albumin [g/dL] × 10 + total lymphocyte count [per mm3] × 0.005. The participants were categorized into malnutrition (PNI <40), mild malnutrition (PNI 40–45), and non-malnutrition (PNI > 45).This is a P < 0.001) with significantly lower PNI compared to both groups even after adjusting for the center and C-reactive protein. Patients in the high-flow therapy group  and malnutrition status  showed a significant longer hospital length of stay compared to their counterparts. The multivariable Cox proportional hazard models showed significant associations between both oxygen therapy requirement and PNI categories and hospital discharge.According to PNI, malnutrition was more prevalent in the high-flow therapy group (94.9%; In addition to oxygen therapy requirement, low PNI was associated with longer hospital length of stay. Our findings suggest that PNI could be useful in the assessment of nutritional status related to the prognosis of patients with moderate to severe COVID-19. Nutritional assessment emerges as an indispensable management at hospital admission because malnourished patients imply a significantly longer hospital length of stay and high mortality rates . RegardiThe prognostic nutritional index (PNI) is based on serum albumin concentration and lymphocyte count , both usAccording to a recent meta-analysis , the pooSo far, there is no data concerning prospective PNI assessment in patients with COVID-19 according to illness severity. Thus, this is the first longitudinal multicenter study evaluating whether nutritional status, assessed by the PNI, is related to oxygen therapy requirement at hospital admission and ascertains the prognostic effect of the PNI and the oxygen therapy requirement on hospital length of stay in patients with moderate to severe COVID-19.post-hoc analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial  and the Ethics Committee of the Ibirapuera Field Hospital . All the procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individual participants included in the study before being enrolled. The manuscript had critical revisions and important intellectual content and was approved for publication by all the authors.The pre-specified inclusion criteria were: (1) age 18 years or older; (2) diagnosis of COVID-19 by polymerase chain reaction (PCR) testing for SARS-CoV-2 from nasopharyngeal swabs or computed tomography scan findings compatible with the disease , and subsequent COVID-19 confirmation; (3) diagnosis of flu syndrome with hospitalization criteria on hospital admission, presenting with respiratory rate >24 breaths per min, saturation <93% on room air or risk factors for complications , followed by COVID-19 confirmation. The patients who met these criteria were considered to have moderate to severe COVID-19.3 supplementation ; (6) pregnant or lactating women.The pre-specified exclusion criteria were: (1) inability to sign the written informed consent; (2) previous admission to invasive mechanical ventilation during hospitalization; (3) creatinine ≥2 mg/dL or requiring dialysis; (4) total calcium ≥10.5 mg/dL; (5) prior vitamin DThe criteria used for hospital discharge were: no need for supplemental oxygen in the last 48 h, absence of fever in the last 72 h , and oxygen saturation >93% on room air without respiratory distress .No patient received any SARS-COVID vaccine since at the time of data collection, there were no vaccines available for use in our population.Anthropometric characteristics (self-reported weight and height), acute COVID-19 symptoms, coexisting chronic diseases, patients' concomitant medications during hospitalization, oxygen supplementation requirement, imaging features, and serum 25OHD were assessed upon hospital admission. The investigation of coexisting chronic diseases was self-reported and, subsequently, all of them were checked according to the medical records of each patient, including previous medications. To provide a comprehensive demographic characterization, self-reported race data were also collected based on the following fixed categories: White, Black, Asian, and Pardo .The C-reactive protein was assessed by immunoturbidimetric assay, serum 25-hydroxyvitamin was assessed by chemiluminescent immunoassay , albumin was assessed by colorimetric assay, and lymphocyte count was assessed by automated assay. The analyses were performed according to the manufacturer's recommendations by the same technician in an accredited laboratory from the School of Medicine.In order to provide a broader knowledge of clinical illness, hospitalized patients were categorized into groups according to oxygen therapy requirement as follows: (1) non-oxygen therapy (moderate patients not requiring oxygen therapy); (2) nasal cannula therapy ; and (3) high-flow therapy (severe patients requiring high-flow oxygen therapy) .3) × 0.005. The patients were divided into 3 groups based on the PNI score: malnutrition (PNI <40), mild malnutrition (PNI = 40–45), and non-malnutrition (PNI > 45)  × 10 + total lymphocyte count (per mmNI > 45) . The cropost-hoc analysis regarding both the oxygen therapy requirement and PNI as predictors of hospital length of stay, the primary outcome. Hospital length of stay was previously defined as the total number of days that the patient remained hospitalized from study admission to hospital discharge, as published  and 25-hydroxivitamin D were handled by GEE models with no imputation data.Generalized estimating equations (GEE) were used for testing possible differences assuming groups as fixed factors, with marginal distribution, and a first-order autoregressive correlation matrix to test the main and interaction effects. Bonferroni's adjustment was performed for multiple comparisons in GEE analyses to maintain a family-wise 2-sided significance threshold of 0.05. Proportions were compared between groups using χP < 0.05 level. The proportionality assumption for Cox regression models was confirmed by assessing Schoenfeld residuals. For the Cox proportional hazard models (Cox regression model and time-dependent covariate cox regression model), the outcome was labeled as hospital discharge, aiming to facilitate the interpretation of the hazard ratio for discharge. Statistical analyses were performed with the IBM-SPSS software (USA), version 20.0. The significance level was set at 2-sided P ≤ 0.05.The Kaplan–Meier estimate curves for oxygen therapy requirement categories  and PNI categories  were compared using the log-rank, Breslow, and Tarone-Ware test for hospital length of stay (deaths were considered censored events). In order to avoid bias regarding the different weights to event in the survival curve analysis of each test, log-rank, Breslow, and Tarone-Ware were presented accordingly . Cox reg2, and the median from symptom onset to study enrollment was 10 days   . RegardiR, 8–13) , Table 1P < 0.01] and nasal cannula therapy groups  even after adjustment by the center and C-reactive protein . There was a significant mean difference for PNI between non-oxygen therapy and nasal cannula therapy groups in non-adjusted models . No significant mean difference for PNI was observed between non-oxygen therapy and nasal cannula therapy groups adjusted by the center  and adjusted by the center and C-reactive protein . The highest proportion of patients with malnutrition (94.9%) occurred in the high-flow therapy group ,  protein . SimilarP < 0.001] compared to nasal cannula therapy [7 days ] and non-oxygen therapy [4 days ] ] and non-malnutrition [6 days ] , 2, 4.8)] . Similar2, 7.8)] .P < 0.001] and nasal cannula therapy  compared to non-oxygen therapy ,  therapy . The unaTo the best of our knowledge, this is the first longitudinal multicenter study assessing prospectively the PNI tool as a predictor of hospital length of stay in patients with moderate and severe COVID-19 not admitted to the ICU. Additionally, the present study is the first to assess through a multicenter cross-sectional analysis whether nutritional status, according to the PNI, is associated with the oxygen therapy requirement at admission.According to the results, at least 90 percent of the patients with COVID-19 were malnourished at entry. These data were higher than previous evidence in patients with COVID-19 demonstrated by Doganci et al.  49.7% i 33.3% w 31.7% w, dividinThe worst nutritional status (low PNI) observed in the present study was significantly associated with increased COVID-19 severity, notably in severe patients requiring high-flow oxygen therapy compared to severe with nasal cannula oxygen therapy or moderate illness with no oxygen therapy. Our results are in agreement with individual studies , 26–28 aPatients requiring oxygen therapy, notably those undergoing high-flow therapy, as well as malnourished ones, had a longer hospital length of stay, herein. Furthermore, mild malnutrition patients presented a significant hazard ratio with greater potential to discharge compared to malnourished patients. These results were similar to those evidenced by Martinuzzi et al.  showing Our findings reinforce the PNI as a feasible tool associated with hospital length of stay, although other factors may have contributed to the lack of statistical significance in the other models analyzed here. In line with the Vavruk et al. , malnourTo date, the knowledge of PNI in patients with COVID-19 has been limited to cross-sectional , 16, smaIn addition, continuing an exploratory analysis of the evidence thus far, the small-scale cohort study assessing ICU patients  demonstrper se, could have mitigated PNI scores due to related comorbidities or their clinical condition, such as lymphopenia and hypoalbuminemia.Cinar et al.  retrospeThroughout hospitalization, it is well-established that the loss of lean body mass has deleterious impacts on the patient's prognosis, representing a crucial element that predisposes them to numerous adverse events in critical illnesses, including delayed recovery after discharge . A recenpost-hoc analysis, and complete data is an important limitation that need to be considered. This study does not rule out the possibility that early dietary manipulations at hospital admission could be an effective strategy to improve clinical status and patients' prognosis, so further randomized clinical trials that consider this perspective would be critical.Aside from the novelty of this prospective cohort with a feasible tool, the strengths of the present study include the enrollment of hospitalized patients with moderate to severe COVID-19; patients not admitted to the ICU performing different oxygen therapies; the use of a new parameter (PNI) as a surrogate marker for oxygen requirements/severity; the assessment of nutritional status that includes realistic markers of the immune system; and the appropriate statistical adjustment regarding possible confounding variables. Nevertheless, the relatively small sample size determined according to feasibilities, resources, patients' availability, In conclusion, among hospitalized patients with moderate to severe COVID-19, more than 90% were malnourished. Malnutrition was significantly associated with high-flow oxygen therapy requirement at hospital admission compared to nasal cannula oxygen therapy or non-oxygen therapy. Apart from oxygen therapy requirement, the worst prognostic nutritional index was associated with longer hospital length of stay, proving to be a feasible tool in the assessment of nutritional status related to the prognostic value of COVID-19 patients. Therefore, these findings do support the wide use of PNI tool in the context of hospitalizations, particularly in COVID-19, to aid multi-professional interventions ameliorating the patient's nutritional status.rosamariarp@yahoo.com). The codebook of this study will be made available upon request by qualified clinical researchers, including a statistician, with investigator support, for specified purposes dependent on the nature of the request and the intention use of the data.Deidentified participant data of this study must be requested from the corresponding author upon publication  and the Ethics Committee of the Ibirapuera Field Hospital . The patients/participants provided their written informed consent to participate in this study.RP had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. AF, BR, and RP: drafting of the manuscript. AF and BR: statistical analysis. RP: supervision. All authors designed research, conducted research, critical revision of the manuscript for important intellectual content, and have read and approved the final version of the manuscript.AF reports receiving grant support from the São Paulo Research Foundation , BR reports receiving grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES (88887.507119/2020-00), IM reports receiving grant support from FAPESP (grant 2019/24782-4), and RP reports receiving grants support from FAPESP (grant 2020/05752-4) and from Conselho Nacional de Desenvolvimento Científico e Tecnológico .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. 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