The personality trait of neuroticism represents vulnerability for mental distress to somatic health problems. There are few studies of neuroticism in prostate cancer patients. This study examines the levels of self-reported adverse effects (AEs) after robot-assisted radical prostatectomy (RALP) in Norwegian men with high or low levels of neuroticism. Neuroticism is also compared to relevant factors concerning their associations with various AEs.Among 982 men who had RALP at Oslo University Hospital, Radiumhospitalet between 2005 and 2010, 79% responded to a mailed questionnaire in 2011. They rated AEs by completing the EPIC-26 questionnaire, and neuroticism on the Eysenck Personality Questionnaire (EPQ). Men with < 1 year’s follow-up, treatment failure, and incomplete EPQ responses were omitted, leaving 524 men for analysis. The EPQ responses were dichotomized into low and high level of neuroticism. Stepwise multivariate linear regression analyses were used for examination of associations with the EPIC-26 domain scores.High neuroticism was reported by 20% (95% CI 17–23%) of the patients. On the EPIC-26 dimensions men with high neuroticism had significantly lower mean scores than men with low neuroticism. Most of these between-group differences were clinically significant. In multivariate regression analyses, high neuroticism contributed significantly to all EPIC-26 domains.Increased levels of AEs after RALP are significantly associated with high neuroticism. A short screening test should be added to the current EPIC-26 instrument to identify patients with high neuroticism. In these patients, pre-operative counseling should take into account their risk of increased AE experiences.The online version of this article (10.1007/s11255-020-02688-4) contains supplementary material, which is available to authorized users. Curative treatments of prostate cancer (PCa) have relatively high rates of well-known adverse effects (AEs) with urinary incontinence and erectile dysfunction being most common after robot-assisted laparoscopic prostatectomy (RALP) , 2. AEs Neuroticism is the propensity to experience negative emotions, including anxiety, fear, depression, guilt, disgust, irritability, worry, and reduced self-confidence when exposed to stress . High neNeuroticism has, however, hardly been studied in men with PCa , and parOn this background, we wanted to expand the knowledge of the associations between neuroticism, AEs, and other PCa-relevant variables in a cross-sectional sample of Norwegian men treated with RALP. We selected men with ≥ 1 year’s follow-up time after RALP and without treatment failure. Separating that sample into two groups with either high or low neuroticism, we posed two research questions: (1) Are there significant between-group differences of post-treatment on EPIC-26 subs-scale and domain scores? (2) Is high neuroticism significantly associated with the EPIC-26 domain scores post-treatment in forced entry stepwise multivariate linear regression analyses?This is a cross-sectional questionnaire-based study of men who previously had RALP at Oslo University. Hospital, The Norwegian Radium Hospital. No corresponding questionnaire was administered before surgery. The study was approved by the Regional Committee for Medical and Health Science Research of South-East. Norway (REK # 2010/1511). All participants have given written informed consent.From January 2005 to August 2010, 988 men underwent RALP at our hospital. By March 2011, a questionnaire was mailed to the 982 survivors, and 777 responded (79% response rate). We omitted 91 men who had follow-up time < 1 year, 146 who reported treatment failure , and 16 with incomplete neuroticism data, leaving 524 men as our main study sample.Neuroticism was self-rated on an abridged version of The Eysenck Personality Questionnaire (EPQ) with six items concerning long-term personality characteristics. The items concerned frequent worry, easily hurt feelings, loss of interests, reaction to embarrassing experiences, loss of motivation, and worry that terrible things might happen. Each item is rated as present (1) or absent (0). The sum score ranged from zero to six, and was dichotomized into the high (sum score 3–6) and low neuroticism (sum score 0–2) group as described by the third Health Study of North-Trøndelag County (The HUNT-3 study) . InternaThe EPIC-26 considered AEs of the last 4 weeks covering the urinary, bowel, sexual, and hormonal domains after PCa treatment. The urinary domain included the incontinence and the irritation/obstruction sub-scales. The scores were converted from 0 (worst) to 100 (best) and domain means were calculated  and low neuroticism by 417 [80% (95% CI 76–83%)]. No significant between-group differences were observed concerning the medical PCa-related variables. Significantly more men belonging to the high neuroticism group had short education and more reported comorbidity than the low neuroticism group  in the high neuroticism compared to the low neuroticism groups. All between-group domain differences of the EPIC-26 and the urinary irritation subscale were clinically significant . The dai2) varied from 6.6% for the urinary to 29.5% for the hormonal domain. The high neuroticism step made significant contributions to the models for all four EPIC-26 domains. The socio-demographic step made significant contribution to the sexual and hormonal domains, while the PCa-related step only contributed to the sexual domain, and the comorbidity step to the hormone domain.High neuroticism was negatively associated with each of the five EPIC-26 domain scores, and the highest explained variances emerged for the sexual and hormonal domain scores.The multivariable analyses of our four-step regression model with the EPIC-26 domains as dependent variables are displayed in Table Considering significant single variables, increasing age was negatively associated with the sexual domain score, as was short education with the hormonal domain score. Performance of bilateral nerve sparing RALP and increasing follow-up time were associated with increased sexual domain score, while comorbidity was significantly associated with decreased hormonal domain score.In Table N = 146) (see supplement). The proportion with high neuroticism was 25% (95% CI 18–32%), which did not differ from our main sample (p = 0.30). The recurrence sample showed less significant between group differences between the high and low neuroticism groups than the main sample.The comparisons between the high and low neuroticism groups were also performed in the group reporting recurrences . In the stepwise multivariate linear regression model, high neuroticism made significant contributions to the total explained variance of all the EPIC-26 domain scores. Taken together these main findings build a strong case for the relevance of neuroticism for self-reported AEs on the EPIC-26 experienced by men treated with RALP.The sensitivity analyses performed on them patient with recurrence were less convincing concerning these between-group differences. However, the high neuroticism group consisted only of 36 patients representing an increased risk of type II statical errors leading to fewer significant differences.A major question raised by our results is why high neuroticism has such a strong association with self-rated AEs after RALP. One answer concerns neuroticism as the propensity to experience all sorts of negative emotions and feelings of vulnerability for stress related to the diagnosis of PCa, the treatment, and the development of AEs , 9. AnotWe included two categorical variables based on the EPIC-26 ratings. Use of pads showed no significant difference between the high and low neuroticism groups. This could be since urine mechanics hardly are associated with high neuroticism. In contrast, the high neuroticism group had a significantly higher prevalence of inability to perform intercourse, which we consider a personality-sensitive issue. The association of increased EPIC-26 bowel domain scores and high neuroticism in our patients puzzles us. Bowel problems as post-RALP AEs have traditionally not been associated with RALP but rather with radiation therapy. We hypothesize that this association is due to the bladder–gut–brain axis having personality as an important factor previously described . Our finNeuroticism as a relatively permanent trait over time is closely related to anxiety and depression as emotional states, eventually as an important etiologic factor for these states . A meta-Previous studies have focused on the association between post-operative AEs and technical issues of RALP and medical pre-treatment measures, e.g. nerve-sparing and risk groups , 26. TheR2) in percent represents better fit of the model [Stepwise linear regression statistics, as performed in our study, compare the contributions of predefined steps of independent variables to outcomes which are the four domains of EPIC-26. The steps selected had their theoretical rationale based on previous research on RALP and AEs. Therefore, we chose relevant socio-demographic variables as our first step, whereas the second step contained relevant medical PCa-related variables. Somatic comorbidity, and high neuroticism also influence AEs after RALP, so they were selected as the next steps. In our statistical model, using the forced entry method, increasing explained variance Below is the link to the electronic supplementary material.


Several studies on the nutritional status of chronic kidney disease patients living on haemodialysis revealed high prevalence of malnutrition (18–94%). A hospital-based study in Nepal revealed 66.7% mild to moderately malnourished and National Kidney Center reported common protein-energy malnutrition problem among haemodialysis patients. As almost all patients undergoing maintenance haemodialysis looked malnourished, this study was carried out to explore prevailing dietary knowledge and practice of the patients.A descriptive cross-sectional survey of 471 patients undergoing haemodialysis from June 2015 to July in 2015 was carried out. After stratification through a systematic random sampling method, 40 (67%) patients from National Kidney Center and 20 (33%) from Bir Hospital were selected, interviewed face to face by using structured questionnaire. Ethical and institutional approval and patients' consent were obtained.The level of knowledge score found to be medium and practice score was even low. Seventy percent knew about renal diet but only 36 (60%) believed in it. After having kidney disease 42 (70%) had changed their dietary practice. Surprisingly, 38 (63.3%) said they ate the food what the other member in their family ate.Considerable limited knowledge (medium) and practices (low) scores were found. Had they have taken adequate dietician's support, they might have taken right kind and right amounts of foods and benefitted in controlling potassium, phosphate and protein at the recommended level. Plant-based diet could assist in end stage renal disease in a number of ways: an edge of protection against diet cost, reduce inter-related co-morbidities or complications (hypertension and diabetes). Ethical approval was obtained from concerned Research Committee of National Kidney Center of Health Care Foundation-Nepal and National Academy of Medical Sciences (NAMS)- Bir Hospital authority.18During the study- a total of 60 patients at Bir Hospital and 411 patients at National Kidney Center were undergoing haemodialysis treatment. With a margin of error of 0.10, a confidence level of 90% and a population proportion of 0.5 -we calculated a sample size of 60. The systematic sampling method was adopted after stratification , in which individual patient was selected for interview and then the subsequent patient was chosen applying a systematic interval until the desired sample size was reached.Where z: Value of z at confidence interval of 90%, z = 1.645p = 50% prevalenceq = 1-pe = margin of error- 10%Since it was a new study in the context of Nepal- the questionnaires were generated by reviewing similar studies conducted in other countries and also reviewing various relevant articles on ESRD and diet. Then the content experts in the field of nutrition science reviewed the questions and objectives before using it. The study was undertaken after doing a pilot test of questionnaires in 20 patients undergoing haemodialysis treatment at National Kidney Center. The reliability test of the tool was done, where Cronbach Alpha Coefficient was (r = 0.75). It showed that repeatability was good indicating that these tools would produce stable and consistent results on knowledge on ESRD- renal diet-attitude towards it and dietary practice. Face validity appeared to measure what it intended to measure.Subsequently- the purpose of the research was explained to each participant individually prior to the interview. All were assured of privacy and confidentiality. Those who could read and write gave written consent and verbal consent was obtained from those who could not read and write.Since high-quality cross-sectional studies are susceptible to bias- we considered controlling selection bias by considering eligibility . Then- applied simple random sampling after stratification so that every patient, at both the strata - had an equal chance of being included. In order to control information bias- we did not take minor (<108 years)-those unwilling to participate in this study- did not speak and understand the Nepali language- who were getting psychiatric treatment additionally and known case of depression in medical record file.At first, obtained data was entered in to the Microsoft Excel 2007 and analysed by using Statistical Package for the Social Sciences- version 18.0. An association between knowledge and practice with their selected demographic variables are presented in frequency distribution and percentages.The demographic characteristics of ESRD patients undergoing haemodialysis treatment at National Kidney Center and Bir Hospital studied were age- sex- ethnicity-education level and marital status- where 34 (56.7%) revealed aged 50 years and above- 40 (66.67%) were male and only 20 (33.33%) were female.About 45 (75%) of the respondents said they knew about renal diet. Among the respondents- 24 (40%) said they did not believe in renal diet. About 41 (69.3%) said meat was not good for the ESRD patient and 44 (73.3%) said “red meat is harmful for ESRD” case. Forty-seven (78.3%) said drinking excess milk was not good for chronic kidney disease. Among the respondents, only 30 (50%) of them said that they knew which particular fruits could be consumed daily. Similarly, about 28 (47.7%) said they did not know spinach was harmful for ESRD patients living on haemodialysis. More than a quarter of subjects 16 (26.7%) did not know the need of salt intake reduction. Only 31 (51.7%) of them knew that they could enjoy food during haemodialysis. Thirty-six (60%) of the ESRD patients knew and visited the dietician for a dietary counselling .This study resulted that 36 (60%) of the patients had no knowledge about the potassium containing food items and 47 (78.3%) did not have idea about controlling the level of potassium in blood . SimilarAmong the respondents, 42 (70%) said they changed dietary practice after having kidney disease . NotablyIt is evident that about 11 (68%) respondents considered that the meat was not good for kidney disease, whereas 12 (20%) told they consumed meat every day, 23 (38.3%) said they knew about the source of potassium food item, but 34 (56.7%) consumed potatoes and yam in excess amount. Only 13 (21.7%) knew about controlling the potassium level in blood and 42 (70%) of them did not apply potassium leaching process in their daily life . Forty-fThe government of Nepal has nutritional program running under the umbrella of Ministry of Health and Population. But disease-specific guidelines for non-communicable diseases like diabetes, hypertension and CKD are not available as yet. Balancing the nutritional status among CKD patients is very vital to those undergoing haemodialysis treatment. Generally, as haemodialysis patients have reduced appetite, their attending physician or nephrologists are the first point to get nutritional advice.19 Generally, in early stage of chronic kidney disease, there may not be any signs or symptoms. As chronic kidney disease progresses to end-stage renal disease, signs and symptoms might appear.20 Then, the one and only immediate solution is to put the patients on dialysis.When kidneys can't do their function themselves, human body can't remove extra fluids and waste products from bloodstream, restore electrolyte levels, and help in controlling blood pressure. Dialysis does some of the work of the kidneys by filtering harmful wastes, salts and fluid from the blood.20The chronic diseases - heart disease, diabetes, some kinds of cancer, dental disease, and adult bone loss, all have a connection to poor diet. These diseases cannot be prevented by a good diet alone; they are to some extent determined by a person's genetic constitution, activities, and lifestyle. Within the range set by individual's genetic inheritance, however, the likelihood of developing these diseases is strongly influenced by persons' daily choices.21 this study aimed at determining the dietary knowledge and practice among those patients living on haemodialysis treatment at National Kidney Center and National Academy of Medical Sciences- Bir Hospital - Kathmandu- Nepal.The ESRD patients' energy requirement vary greatly, depending on the underlying cause of the renal failure and any other comorbidity. As nutritional status is an important predictor of outcome in ESRD patients living on maintenance HD-Though the nutritional status of individuals depends on multi-factors e.g. food accessibility- affordability-nutrition knowledge- the nutritional education-adherence of education and practice can make a huge difference.22 A study done on at Nepal Medical College and Teaching Hospital-Kathmandu revealed that 57% were male. Ghimire M et al. studied 50 ESRD patients- in which they found the age ranging from 18–79 years and males 64%.23 The majority of the respondents were male (66.67%) in our study- which indicates that male are still ahead of female in seeking treatment. Both the male and female patients can live on maintenance haemodialysis and contribute immensely in the nation-building activities given that they are well and balanced-nourished.In this study about 43% respondents aged 18 to 50 years were living on HD-which is a highly productive age group. Aged 50 and above revealed 57% with the ESRD. But in an earlier study conducted in Nepal reported that aged 41–60 constituted 45.8%- where the majority respondents were male (64.6%).24 This trend seem to be quite relevant to our study- where higher age group male are found compared to women. According to Centers for Disease Control and Prevention- the risk of CKD also increases with an increasing age and men with CKD are 50% more likely than women to have kidney failure.25Another largest retrospective cohort conducted in Nepal (1991–2000) found that the mean age of patients were 46.7±16.7 years with age ranging from 8 to 89 years. Of which- 905 (65%) patients were male. Similar to other studies in India -Saudi Arabia  and Japan .26 Ghimirey A et al. found that stage V CKD (ESRD) patients having co-morbid conditions of hypertension in 79.6% and diabetes mellitus in 15.6% and in 4.7% both hypertension with diabetes mellitus. But none of the patients were on medications for the management of their disease states.27The patients said they knew and also felt about the pre-symptoms before their ESRD was diagnosed. About 46% said that swelling was seen on legs-eyelids, face flowed by nausea, vomiting 13.3%, loss of appetite- headache and Insomnia 10%- back pain 3.3% and weight loss 1.7%. In fact- a person can lose a lot of kidney function before symptoms of kidney disease occur.32 The scenario of our context might not be exception to it. In addition to the above- it could be due to lack of awareness of patients on renal diet and the involvement of the clinical dietician in managing ESRD care. Since this study was the cross-sectional pattern- it does not allow for the establishment of cause and effect relationships. Therefore- future studies aiming at exploring casual relation would be of helpful.It is reported that diet-related decisions are influenced by multiple factors, including taste, financial constraints, individual preferences- social status- education level-societal norms- health- and relationships- trust in food sources- and convenience. Dietary preferences and behaviours are highly individual.33In this study- majority of patients 91.7% said that less water intake would help in managing kidney disease. Patients should limit fluid 1 to 1.5 litres a day and water intake to avoid fluid overload in the body. Personalized fluid consumption goals and education can improve the patient compliance with dietary restrictions.26Although studies are small- several support the idea that plant-based diets can delay the progression of CKD- provide endothelial protection- control high blood pressure- and decrease proteinuria. These days-our dialysis patients seldom die secondary to high potassium or uremia.34Researchers recommended to promote plant-based diet for ESRD as well as all types CKD patients- which can provide nutrients that not only assists in ESRD but also can provide an edge of protection against diet cost-reduce inter-related co-morbidities or complications (diabetes and hypertension).35A consulting clinical dietician at Gig HarbourWashington- USA reported although the studies are small in size- several evidence support the idea that plant-based diets can delay even the progression of CKD- provide endothelial protection- control high blood pressure- and decrease proteinuria. These days- dialysis patients seldom die secondary to high potassium or uremia.36 It is still a “Thorny” issue since the influence of most dietary interventions has been examined in small studies in patients with CKD. A careful renal diet management could be considered until a plant-based diet will be examined through large randomized controlled trials in patients with CKD.Michael Greger reported that the researcher at Harvard University followed thousands of women- their diet and their kidney for more than a decade that concluded animal protein was the culprit in declining kidney function. Studies reported that kidney appeared to handle plant protein very differently from animal protein and plant protein was found to help preserve function in ailing kidneys. Animal protein tends to have a higher level of sulfur-containing amino (methionine)- which produces sulfuric acid when metabolized in the body. Worst offenders: fish (including tuna), pork, poultry, cheese. An equivalent amount of plant protein causes no noticeable stress on kidneys. In contrary- fruit and vegetables are generally base forming- which helps neutralise acids in our kidneys and eating normal whole foods can return dopamine sensitivity to normal levels.An effective strategy to enhance the dietary management is inevitable by adhering to dietary restriction but through a proper diet therapy without causing malnutrition means assuring the daily calorie-vitamin- minerals and protein in-take- adequate energy.Thus- it is vitally important for the ESRD patients to know about the importance of dietician's role since they could benefit tremendously by visiting dietician for a proper dietary counselling and nutritional management.


ObjectiveRates of anxiety have increased during the coronavirus disease 2019 (COVID-19) pandemic, partially attributable to the experience of COVID-19 related concerns. It remains pivotal to determine the implications of such concerns on the severity of anxiety as they may represent opportune targets for public health preventative or therapeutic efforts. The current study evaluated COVID-19 related concerns as predictors of anxiety symptom severity. It also assessed the relative risk associated with sub-types of COVID-19 concerns, the role of age, sex, and minority status as potential moderators; and the unique contribution of COVID-19 concerns beyond sociodemographics, perceived stress, and self-reported general mental health.MethodsThe data source was obtained from the publicly available ”Crowdsourcing: Impacts of COVID-19 on Canadians-Your Mental Health survey” conducted by Statistics Canada. Participants were Canadians aged 15 and older living in ten provinces or three territories. Only participants that completed the self-reported sociodemographics, COVID-19 concerns, and general anxiety symptoms measures were included (n = 44549). Multivariate linear regression was used to evaluate continuous reports of anxiety symptoms, and the relative risk of meeting anxiety cut-off levels was determined using chi-square non-parametric testing.Results2 = 0.205, p < 0.001), distal , and proximal concerns  were found to predict the severity of anxiety experiences, which was determined to be robust to statistical control for sociodemographics, perceived stress and self-reported general mental health . Minority status and sex were significant moderating variables, although the interaction accounted for less than 0.1% of the observed variance. Family stress from confinement, support during and after the crisis and personal health concerns significantly predicted more than a 200% increase in the risk of meeting anxiety cut-off levels.Within the sample, 29.1% met cut-off levels of anxiety. Levels of coping and security (RConclusionThe current study represents a novel examination of COVID-19-related concerns as risk factors for the experience of anxiety amongst a sizeable Canadian cohort. Coping and security-related concerns represented robust predictors of anxiety symptom experiences. Participants who experienced concerns relating to their proximal social groups were two times more at risk for meeting cut-off anxiety levels than individuals without such concerns. Longitudinal and evidence synthesis remains essential for identifying therapeutic targets and developing pandemic-related public health prevention and care. Coronavirus disease 2019 (COVID-19) and the associated public health response, economic challenges, and uncertainty have had deteriorating impacts on mental health, including increases in the incidence of anxiety . A natioDespite the increased risk of developing or worsening anxiety symptoms during the pandemic, there is a dearth of research identifying variables linked to the intensity of anxiety within a Canadian context. Analysis of these risk factors can further public health understanding of pandemic-related anxiety and guide the development of treatment strategies. The present study set out to address the link between COVID-19 related concerns and the incidence and intensity of anxiety symptoms. Of particular interest was exploring the moderating role of sociodemographics in the link between COVID-19 related concerns and anxiety.Data source Data were obtained from the following web-only data longitudinal collection series from Statistics Canada ‘Crowdsourcing: Impacts of COVID-19 on Canadians’, SE = 0.00477, t = 97.35789, p < 0.001) and males  were determined to experience anxiety symptoms as a function of COVID-19-related concerns, however females experienced greater levels of anxiety than males when considering high levels of COVID-19-related concerns  and non-visible minority  groups were determined to experience an association between COVID-19-related concerns and anxiety symptoms, higher levels of COVID-19 concerns were more greatly linked to anxiety experiences for the non-minority group  and distal concerns . In addition, perceived stress accounted for 21.1% of the variance in perceived mental health  and 15.8% of perceptions of change when comparing mental health during pre-and-post social distancing . Perceived mental health was highly correlated with anxiety experiences, accounting for 36.2% of the observed variation in anxiety reports . Modelling controlling for sociodemographics and inclusive of perceived mental health, stress and COVID-19 related concerns accounted for 55.51% of the explained variance in anxiety, of which 6.25% was uniquely attributed to COVID-19 related concerns  = 2061.937, p < 0.001). Within this model, coping and security was found to uniquely account for 3.17% of anxiety experiences , followed by proximal concerns , and distal COVID-19 related concerns . Although perceived stress and COVID-19 related concerns were found to synergistically interact, the moderation of perceived stress on the association between COVID-19 related concerns and anxiety symptoms was determined to account for less than 0.6% of the variance in anxiety experiences  = 484.273, p < 0.001).Perceived stress was determined to predict 34.8% of the variance associated with anxiety symptoms  and Acceptance and Commitment Therapy . The feaWithin the current sample, concerns relating to proximal social groups  and vulnerable individuals were associated with greater anxiety symptoms when compared to concerns about distal populations such as Canadian or international population health. Furthermore, all pandemic-related concerns about social networks and personal health doubled the relative risk of meeting general anxiety symptoms cut-off levels, demonstrating a clear link between perceived proximal social hindrance and anxiety outcomes. The current evidence demonstrates that worries relating to one's social support network represent a key target to consider for the mitigation of COVID-19-related anxiety experiences. Social support has been a vastly accepted resource for coping with a stressor, serving a critical role in secondary stress appraisal . PerceivAlthough higher reports of distal COVID-19 concerns predicted greater anxiety symptoms, the observed effect size for this concern was low compared to coping, personal, and proximal health concerns. Future public health communication relating to COVID-19 concerns can benefit from such findings. The results from the current study point toward potential benefits from the provision of information on mitigation strategies specific to coping and the health of proximal social groups, as opposed to emphasizing global or distal information. In addition, there have been various lines of evidence demonstrating benefits from tailored health communication approaches .The associations between COVID-19-related concerns and anxiety experiences were not found to be influenced by age. However, the association between COVID-19-related concerns and anxiety was greater in females and individuals identifying as not part of a visible minority in the circumstance the COVID-19-related concerns were severe. These findings align with previous Canadian evidence examining the role of minority status  and gendThe current evidence further demonstrates that perceived stress and self-reports of mental health are major risk factors for the experience of anxiety during the pandemic. However, COVID-19-related concerns were determined to account for anxiety symptoms beyond the current sample's perceptions of stress and general mental health. The implications of COVID-19 may thus operate to some degree outside the implications of psychopathology through the modulation of perceptions of well-being.Higher COVID-19-related concerns might uniquely increase anxiety in a few ways, including increases in maladaptive thinking and decision making , as wellLimitationsThe current study is highly powered due to the analyses of a large sample, allowing the precision necessary to detect potential minor effects relating to specific concern types. Furthermore, the current study included participants from all territories and provinces in Canada. However, the study includes several limitations to consider when interpreting the current findings. First and foremost, data analyses were cross-sectional and thus did not account for temporal factors; participants with high anxiety may have had high anxiety prior to the COVID-19 outbreak. In addition, although the current sample was derived from the entire Canadian landscape, it does not entail national representativeness. Although the GAD-7 has been repeatedly demonstrated to be reliable and valid, the assessment tool for COVID-19-related concerns has not undergone rigorous validity assessments as it was created for the intent of this data collection. Assessments of participant perceptions of stress and general mental health were limited due to a single item assessment of these experiences. Regarding ethnic differences, the current study only had access to a dichotomized visible minority status. However, evidence has demonstrated that anxiety experiences differ within ethnic minorities; for instance, South Asians have reported lower anxiety symptoms than African Canadians . SimilarThe current study represents a novel examination of COVID-19-related concerns as risk factors for the experience of anxiety in the context of both dichotomized cut-off and continuous symptom severity amongst a sizeable Canadian cohort. The results indicate that COVID-19 related concerns represent robust predictors of anxiety experiences during the COVID-19 pandemic. The experience of coping and security-related concerns were found to be stronger predictors than distal social concerns. In addition, participants who reported experiencing concerns relating to their proximal social groups had twice the risk of meeting anxiety cut-off levels when compared to individuals without such concerns. Although it is vastly accepted that worry derived from experiences of concerns serves as a predisposing factor for anxiety experiences, future studies examining longitudinal associations between these factors within a Canadian context remain unaddressed. Given that COVID-19 restrictions and policy vary from one province or territory to another, further examination of a representative sample for each province and territory may provide data to compare COVID-19 restriction implications on the association between COVID-19 concerns and anxiety outcomes. Further, developing a psychometrically validated tool to examine pandemic-related implications is primordial for optimizing the validity of data collection in the context of future pandemics. One potential solution may be achieved through the psychometric development of a non-specific general pandemic questionnaire that can be administered within a vast spectrum of communicable outbreaks.With the increased inoculation for SARS-CoV-2 infection, the window for data collection relating to the pandemic may be closing. Hence, longitudinal and evidence synthesis remains essential for identifying therapeutic targets and developing pandemic-related public health prevention and care.


Our world is facing recurrent waves of coronavirus disease 2019 (COVID-19) with the emergence of more infectious strains of the novel coronavirus, SARS-CoV-2. Multiple studies have established that heart failure (HF) patients are at high risk of severe disease and poor outcomes with COVID-19. Management of COVID-19 in patients with HF, heart transplant, and those supported with durable left ventricular assist devices present an arduous challenge due to underlying complex health conditions and overlap of symptoms. Based on available data, this review outlines the management of this vulnerable patient population who either present with COVID-19 with preexisting HF or with de novo HF from COVID-19. Since December 2019, when SARS-CoV-2 was first identified in Wuhan, China, over 250 million cases have been reported worldwide. As of this writing, we are in the midst of the fourth surge with the highly infectious and transmissible Delta variant and the new Omicron variant starting to emerge. This pandemic has tested the capacity of healthcare delivery worldwide while also affecting the global economy.Journal of the American College of Cardiology, Driggin et al. highlighted a number of studies, including two large population-based studies, suggesting an association between cardiovascular (CV) risk factors and underlying CV conditions in the COVID-19 cohorts. The authors found that increased case fatality rates and intensive care admissions were more likely in patients who have a higher comorbidity burden for cardiovascular risk factors than those who do not. For instance, although the overall case-fatality rate among 44,672 confirmed COVD-19 patients in Wuhan was 2.3%, it was higher in those with cardiovascular disease (10.5%), diabetes (7.3%), and hypertension (6.0%).1 Several studies have shown that myocardial injury in COVID-19 can be direct or indirect, but regardless of the underlying mechanism, troponin elevation in COVID-19 carries prognostic value in predicting both clinical severity and mortality.2 Additionally, the risk appears to be continuous, with higher elevations predicting worse outcomes.3The elderly and people with underlying chronic conditions such as asthma, cardiovascular disease, and immune system disorders are at particular risk for poor health outcomes. In a state-of-the-art review published in the Figure 1). SARS-CoV-2 infection is triggered by the binding of the S protein to its functional receptor angiotensin-converting enzyme 2 (ACE2) on the surface of host cells, typically via a type II pneumocyte. This viral complex is incorporated into the cytoplasm either by direct fusion with the cell membrane or via endocytosis. This leads to ACE2 down regulation, which activates the de novo renin angiotensin aldosterone system (RAAS) and causes an intense inflammatory response, increased pulmonary vascular permeability, and pulmonary edema.To understand the impact of COVID-19 in heart failure (HF), it is important to understand how the virus acts and its mechanisms of injury  and angiotensin receptor blockers (ARBs) might prevent widespread endothelial dysfunction and varying degrees of multiorgan damage resulting from the RAAS activation. In patients with HF, the process of reverse remodeling via neurohormonal modulation exploits the wide expressivity of ACE2 on cardiac myocytes, fibroblasts, and coronary endothelium to block RAAS, promote cardioprotective vasodilating properties, and decrease myocardial hypertrophy and fibrosis. This interaction between the S protein and ACE2 has also offered a therapeutic target for this syndrome.This mechanism prompted earlier preclinical studies to suggest that RAAS inhibitors (commonly used drugs in HF) might increase susceptibility to infection and patients should discontinue their use. However, it has been reported that the serum level of angiotensin II is significantly elevated in COVID-19 patients and correlates directly with viral load and lung injury.Multiple pathophysiological pathways are implicated in the diverse cardiovascular manifestations of COVID-19. Infection with SARS-CoV-2 results in intense cytokine storm and a proinflammatory state with hypercoagulability, increased sympathetic stimulation with vasoconstriction, hypoxic injury, sepsis, and, in severe cases, acute respiratory distress syndrome (ARDS) and multiorgan failure. These various insults lead to myocardial injury, HF, acute coronary syndromes (ACS), arrythmias, and thromboembolism. However, evidence of direct myocardial injury remains sparse.5 Myocarditis has been reported in a limited series from China, where 7% of deaths were attributed to myocardial damage but without a clear, definite diagnosis of myocarditis. Similarly, other reports have described fulminant myocarditis in the setting of high viral load with autopsy findings of inflammatory mononuclear infiltrate in myocardial tissue, but without histologic evidence of direct COVID-19 infection in the myocardial cells.8 Thus, increases in cardiac troponin indicative of myocardial injury are common and prognostic in COVID-19,9 albeit they represent multiple etiological mechanisms of cardiac injury that must be correlated with a clinical picture and other diagnostic modalities. Evidence to date suggests that direct myocardial injury is plausible but largely attributable to indirect effects of severe systemic inflammation. Direct cellular injury of myocyte is reported in autopsy findings by Bailey et al., who examined four autopsies and demonstrated cardiac myocyte infection by identifying intracellular viral particles budding on electron microscopy with associated macrophage infiltration and cell death. Figure 1 outlines interfaces of various mechanisms of injury in HF and COVID-19.10Cardiac myocytes are a potential target for SARS-CoV-2 due to the virus’ cell entry mechanism.9 reported an HF prevalence of 4% in a cohort of patients hospitalized with COVID-19 at a single center in Wuhan, with similar percentages for cardiomyopathy among hospitalized COVID-19 patients in a study by Guo et al.,11 whereas other studies from Wuhan reported HF incidence in up to a quarter of studied patients and up to 50% of those who died.13 Older age and a high burden of comorbid conditions, especially in patients with HF with preserved ejection fraction, predispose patients to a decompensated state in the setting of sepsis, heightened inflammatory response, and impaired renal axis.Studies to date have reported a variable prevalence of HF in patients with COVID-19. Moreover, it is difficult to elucidate the prevalence of a decompensated state of chronic HF from COVID-19 versus incidence of acute de novo HF from the viral syndrome. Shi et al.14 Regardless of underlying pathophysiological response, decompensated HF worsens underlying pulmonary edema associated with ARDS and, in severe cases, leads to other multiorgan impairment due to elevated filling pressures with or without hypoperfusion.Acute HF may complicate the clinical course of severely ill COVID-19 patients. Prolonged and worsening hypoxemia can lead to hypoperfusion, multiorgan failure, and worsening hemodynamics. The interplay of several mechanisms in COVID-19 with acute HF can exacerbate clinical worsening, possibly leading to acute myocardial ischemia from type 1 or type 2 myocardial infarction or myocarditis, ARDS, acute kidney injury, stress-induced cardiomyopathy, and tachyarrhythmias. A profound systemic cytokine storm characteristic of COVID-19 also contributes to acute HF or exacerbates chronic HF in COVID-19. Patients who present with ACS due to type 1 or type 2 myocardial infarction in the setting of COVID-19 are susceptible to a decline in contractile function and decompensation of underlying disease. Furthermore, a prolonged hospital stay for severely ill COVID-19 patients with advanced sepsis, cytokine storm, and immune response to infection makes them susceptible to developing stress-induced cardiomyopathy.Patients with underlying HF are at increased risk of severe COVID-19 illness, and a high index of suspicion for viral testing should be maintained for this vulnerable population. Telemedicine should be considered whenever possible to provide medical advice and follow-up of stable HF patients to avoid exposure, and vaccination should be encouraged and reinforced.Table 1 outlines effective patient management steps to enhance safety and mitigate risk.Since patients with HF are at much greater risk of morbidity and mortality with COVID-19, it is imperative that appropriate measures are taken by healthcare professionals to ensure safety while providing high-quality care for these patients. Low-risk ambulatory patients, especially immunocompromised patients, should be encouraged to get vaccinated and observe appropriate masking in healthcare settings to prevent exposure. All healthcare personnel should maintain proper personal protective equipment and undergo surveillance testing according to institutional protocols. Virtual encounters are encouraged to help determine if an in-person clinic visit is required and also to reassure and educate patients to reduce their anxiety and ensure that they seek health care when necessary. In-person visits should be completed for high-risk patients, and those who fail COVID-19 screening should be seen virtually.15 Elevated jugular venous pressure, rales, and edema are more suggestive of HF, which in itself can exacerbate underlying pulmonary edema. Most patients with severe COVID-19 develop hypoxia 5 to 10 days after onset of infection, which can then rapidly progress to ARDS and aggravate preexisting organ dysfunction leading to multiorgan failure.17It is extremely important to obtain a thorough history and physical examination because COVID-19 and HF can present with overlapping symptoms and signs related to the cardiopulmonary involvement. In the face of recurrent surges and emergence of highly infectious strains, physicians must keep a high index of suspicion that COVID-19 is the cause of HF decompensation. Similarly, patients who have underlying cardiovascular disease and its risk factors are at greater risk for worsening COVID-19 syndrome and poor outcomes. History suggestive of exposure to COVID-19, fever, upper and/or lower respiratory tract infection symptoms, loss of taste and smell, and fatigue are all signs of COVID-19 infection, although fever is observed in less than half of patients.18 Similarly, in a multicenter international registry, 14% of hospitalized COVID-19 patients developed QT prolongation by 7 days after admission.19 Underlying cardiac injury, proarrhythmic potential of medications used in management of COVID-19, and electrolyte abnormalities all require close monitoring. Computed tomography provides high sensitivity and specificity to diagnose COVID-19–associated lung disease20 and pulmonary embolism, and it can provide information on the extent of complications like superimposed infections, effusions, and edema.Electrocardiogram abnormalities are highly prevalent in hospitalized COVID-19 patients, mostly as nonspecific ST-T changes. In a study of 138 patients with COVID-19 admitted to a hospital in Wuhan, 16.7% had arrythmia.21 Brain-type natriuretic peptide (BNP) is elevated in many patients with COVID-19 and HF; however, a low level of BNP has a very high negative predictive value for excluding cardiac dysfunction. As discussed, troponin elevation  is common among hospitalized patients with COVID-19 (incidence ranging from 14–44% across 18 studies), with higher levels correlated with worse outcomes.2 Increases in markers of inflammation and thrombogenicity such as C-reactive protein, erythrocyte sedimentation rate, ferritin, interleukin-6, lactate dehydrogenase, fibrinogen, and D-dimer are associated with higher mortality.22Multiple laboratory abnormalities are seen in patients with COVID-19. Numerous reports indicate that severity of COVID-19 is inversely correlated with low lymphocyte count, with repletion linked to recovery. Extracorporeal membrane oxygenation (ECMO) can exacerbate lymphocyte depletion.23 Endomyocardial biopsy should be considered for patients presenting with de novo HF and/or myocarditis.Figure 2 outlines assessment of patients with HF and COVID-19.Transthoracic echocardiography (TTE) is an important screening and diagnostic tool and must be considered in all patients with HF, heart transplant (HT), or left ventricular assist devices (LVADs) with suspected or confirmed COVID-19. TTE provides assessment of biventricular cardiac function and filling pressures, allows noninvasive hemodynamics evaluation, and helps distinguish concomitant causes of HF, either preexisting  or COVID-19–related  complications. Patients who present with rising troponin may need coronary angiography. Invasive hemodynamics may need to be assessed in patients presenting with shock. When available, cardiac magnetic resonance imaging should be used when myocarditis is suspected.24 Appropriate consultants  should be involved early to manage other organ systems, immunosuppression, and drug interactions. Palliative consultation should be obtained for very sick patients with low likelihood of recovery.Recurrent surges in the COVID-19 pandemic have led to hospital bed and staff shortages, necessitating the use of telemedicine to monitor stable patients at home. HF patients, including those with HT or LVAD, remain at high risk of complications and mortality when infected by SARS-Cov-2.Medications. Hospitalized HF patients should be continued on guideline-directed medical therapy (GDMT) as much as possible depending on their clinical stability, underlying renal function, and pulmonary status. Some maintenance of diuretics is helpful for pulmonary decongestion, even when patients appear to be euvolumic. Patients should be closely monitored for signs of hypoperfusion, and medications should be withdrawn as needed. ACEIs, ARBs, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid antagonists (MRAs) should be continued unless clinically contraindicated due to hypotension, acute kidney injury, or hyperkalemia. Several large series have confirmed that ongoing treatment with ACEIs/ARBs does not increase the severity of the clinical course of infection25 and may actually confer protection from severe COVID-19–related illness.26 A randomized clinical trial (RCT) in Brazil enrolled 659 HF patients hospitalized with mild-to-moderate COVID-19 who were taking ACEIs or ARBs before hospital admission and found no significant difference in the mean number of days alive and out of the hospital for those who discontinued versus continued these medications.27 These findings do not support routinely discontinuing ACEIs or ARBs unless clinically contraindicated. Beta blockers should also be continued unless the patient is in a low-output state. They can be helpful in sinus and atrial tachyarrhythmias. Treatment with intravenous metoprolol tartrate was observed to improve respiratory status in a small randomized trial of patients with COVID-19 and ARDS requiring mechanical ventilation.28 Some antiviral medications used in the treatment of COVID-19 may cause bradycardia, necessitating dose reduction or withdrawal. Ivabradine can be helpful to control heart rate when beta blockers cannot be used because it does not affect inotropy.20Extracorporeal membrane oxygenation. Patients with worsening hypoxemia and/or circulatory shock unresponsive to standard management should be assessed for candidacy for veno-venous (V-V) or veno-arterial (V-A) ECMO. COVID-19 patients whose clinical course is complicated by refractory ARDS necessitating ECMO usually stabilize with V-V cannulation unless they have a high vasopressor requirement. Less commonly, patients with myocarditis, stress-induced cardiomyopathy, or ACS may require V-A ECMO. ECMO duration may be longer in patients with COVID-19 than in those without, but published data shows similar mortality between the two groups.29Anticoagulation. Both HF and COVID-19 syndrome are hypercoagulable states. Long-term anticoagulation should be continued in less sick patients but switched to low-molecular-weight heparin in sicker patients due to drug interactions with novel anticoagulants. All hospitalized patients with COVID-19 should receive pharmacologic thromboprophylaxis unless the risk of bleeding outweighs the risk of thrombosis. In the setting of heparin-induced thrombocytopenia, fondaparinux is recommended. Therapeutic and intermediate-dose anticoagulation are being studied to reduce mortality and/or severity of COVID-19 in multiple RCTs. However, given the variability in interventions and primary outcome measures, it remains uncertain whether higher-intensity anticoagulation offers benefit over standard thromboprophylaxis in patients hospitalized for COVID-19, particularly in moderately ill patients.31 Recently published data from a large RCT sponsored by the National Institutes of Health showed that, in critically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin was no more effective than usual-care pharmacologic thromboprophylaxis in improving survival to hospital discharge or the number of days free of cardiovascular or respiratory organ support.32Figure 3 presents a suggested algorithm for managing patients with HF and COVID-19.33Patients on long-term mechanical circulatory support (MCS) have an inherently higher risk of infections, mainly due to hardware, drive line exit site, and functionally impaired immunity. Moreover, warfarin, which is notorious for interactions, is the only approved anticoagulant for this patient population. Therefore, extensive preventive measures should be employed against COVID-19 for this cohort of patients. The Trans-CoV-VAD registry, a multicenter registry of LVAD and cardiac transplant patients with confirmed COVID-19 in the United States, includes data on 40 patients and is the largest LVAD series reported to date. They report no significant differences in the racial or gender breakdown of COVID-19 cases compared with the total population receiving LVADs in the last 21 months at participating sites (N = 955). Of the 40 COVID-19–positive patients, 60% were hospitalized, 25% developed critical illness, and 1 patient had a suspected LVAD thrombosis that was medically managed. Overall, the case fatality rate was high at 20%, with death occurring at a median of 22 days after admission.Advanced HF patients who need an LVAD implant are particularly vulnerable in their perioperative period. These patients might face longer recovery times due to limited available rehabilitation options.34 Multicenter data from northern Italy show a doubling of COVID-19 prevalence and related mortality (30%) for patients with HT. However, this increased mortality may be related to the speed at which the pandemic spread in northern Italy, straining the healthcare system.35 A study from a large transplant center in New York City captured a similar case-fatality rate.36Patients with HT may be at increased risk of mortality from COVID-19 due to comorbidities and immunosuppression. Precautionary measures of social distancing, masking, sterility, and balancing the need for patient visits against risk of infection are fundamental to limit COVID-19 illness among HT recipients. In a multicenter prospective study in Spain, demographics, clinical features, management, and outcomes in solid organ transplant recipients diagnosed with COVID-19 were compared before (first wave) or after (second wave) July 13, 2020. Of these, 149 (9%) were HT recipients; they had a case-fatality rate of 19.7% in the first wave and 14.5% In the second.37A recently published study including 99 HT patients with COVID-19 from 11 centers reported observations regarding the clinical course, immunosuppression, and outcomes. The median time from transplant to infection was 5.6 years. Age ≥ 60 years was associated with a higher risk of death, and use of a combination of calcineurin inhibitor, antimetabolites, and prednisone was associated with more severe disease compared with the combination of calcineurin inhibitor and antimetabolite alone . Tachypnea, oxygen requirement, elevated creatinine, and inflammatory markers were predictive of a severe course. Interestingly, 43% of patients had no fever, but gastrointestinal symptoms were common, occurring in 46% of patients. Moreover, the investigators found a high case-fatality rate of 24% among hospitalized patients and 16% among symptomatic patients.38 Though practices vary, most transplant centers routinely deintensify immunosuppression in the face of active infection.Guidance from the International Society for Heart & Lung Transplantation (ISHLT) released in February 2021 states management for HT patients with COVID-19 should generally be the same as that for the general population, with some special considerations. For instance, patients with VADs may be proned, but care should be taken to avoid tugging the driveline, and driveline dressings can be changed when the patient is not prone. The ISHLT also advises that providers consider holding mycophenolate mofetil, mTOR inhibitors, or azathioprine in HT patients admitted with moderate-to-severe COVID-19 illness.39 Although it is preferred that patients would complete the vaccine series 2 weeks or more prior to transplantation, transplantation should not be routinely delayed. Updated recommendations suggest that transplant recipients should wait at least 1 month after transplant surgery to receive the COVID-19 vaccine. However, COVID-19 vaccination should be postponed for at least 3 months following T-cell or B-cell–depleting therapies , whether given for induction immunosuppression or as treatment for rejection.40Both the American Society of Transplantation and the ISHLT recommend vaccination of patients with HF and HT recipients and support a third dose for those who received an mRNA vaccine.43 While the detectable serological response is only about 50% in fully vaccinated solid organ transplant recipients (SOTRs), early clinical effectiveness data suggests that < 1% of fully vaccinated SOTRs experience breakthrough infections.45Observational data has established that the COVID-19 vaccine is effective at reducing symptomatic disease, hospitalization, and death from COVID-19.The COVID-19 pandemic represents a daily challenge for healthcare systems. Patients with HF, HT, and LVAD represent a high-risk cohort for developing COVID-19 and experiencing worse outcomes. Strict preventive measures and vaccinations are crucial to reduce the spread. Clinicians must be vigilant and maintain a high degree of suspicion in ruling out COVID-19 in hospitalized patients with HF, HT, and LVAD. GDMT should be continued in chronic HF patients whenever hemodynamic conditions and other organ function permit and considering drug interaction with COVID-19–related therapies and side-effect profiles. It is important to emphasize that as the pandemic evolves, so too does our understanding of the disease; therefore, the aforementioned recommendations may change as updated information is published.The COVID-19 pandemic with recurrent surges has tested the capacity of healthcare delivery worldwide. Numerous databases have established that the elderly and people with underlying chronic conditions, including cardiovascular disease, are at particular risk for poor health outcomes.Patients with heart failure (HF), including those with heart transplant and left ventricular assist devices, are at much greater risk of morbidity and mortality when infected with COVID-19. It is imperative that healthcare providers take appropriate preventive measures to ensure safety while providing high-quality care for these patients.As in the general population, the decompensated state of chronic HF from COVID-19 is a more common presentation than acute de novo HF. However, it remains challenging to tease out the true incidence of either manifestation. Based on available data, this review outlines the management of this vulnerable patient population who present with either COVID-19 with preexisting HF or with de novo HF from COVID-19.


As of December 31, 2021, CoV-RDB encompassed 257 publications including 91 (35%) containing 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 neutralizing CP susceptibility results, and 178 (69%) containing 33,540 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a GitHub repository in a documented machine-readable format.As novel SARS-CoV-2 variants with different patterns of spike protein mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB;  Beginning in late 2020, several SARS-CoV-2 variants sharing multiple spike mutations were reported from different parts of the world. These variants have been classified according to their phylogenetic lineage and component mutations. Variants that spread widely and displayed evidence for being more transmissible, causing more severe disease and/or reducing neutralization by antibodies generated during previous infection or vaccination have been classified as variants of concern (VOCs) by the World Health Organization and U.S. Centers for Disease Control and Prevention (reviewed in ). VarianAs novel SARS-CoV-2 variants have emerged, numerous investigations assessed the susceptibility of individual and combination spike mutations to neutralization by monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). The susceptibility of SARS-CoV-2 variants to mAbs is obviously relevant for preventing and treating SARS-CoV-2 infections with mAb regimens. The susceptibility of SARS-CoV-2 variants to CP provides insight into the likelihood that a variant will infect and cause illness in a person previously infected with and recovered from a different variant. The susceptibility of SARS-CoV-2 variants to VP provides insight into the risk that a variant will infect and cause illness in a previously vaccinated person. Ultimately, however, the risks of re-infection and vaccine breakthrough, and the nature of the ensuing illness must be assessed in epidemiological studies.The SARS-CoV-2 spike protein is a 1,273-amino acid trimeric glycoprotein responsible for entry into host cells. Each spike monomer has a largely exposed S1 attachment domain (residues 1–686) and a partially buried S2 fusion domain  , 5. Apprin vitro, animal model, and clinical trial data intended to promote uniform reporting of experimental results, to facilitate comparisons between candidate antiviral compounds, and to objectively synthesize published antiviral research [n vitro passage of SARS-CoV-2 in the presence of mAbs and in vivo emergence in persons receiving mAbs for treatment. The CoV-RDB website enables users to query its database and the associated GitHub repository enables users to download the entire database. The CoV-RDB website also contains a companion sequence analysis program that annotates SARS-CoV-2 user-submitted sequences using CoV-RDB data.In April 2020, we created a relational database that we called the Stanford Coronavirus Antiviral Research Database containing research . With thin vitro mAb selection experiments, 91 (35%) with 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 with CP susceptibility results, and178 (69%) with 33,540 neutralizing VP results. As publications often contain more than one type of experiment, the sum of the percentages is greater than 100%. The complete database schema is available at https://github.com/hivdb/covid-drdb/blob/master/schema.dbml.The CoV-RDB data model is made up of four major entities: published references, viral mutations and variants, antibodies , and experimental results. As of December 2021, the database contains 257 publications: 19 (7%) with 427 results from in vitro and in vivo, and neutralizing susceptibility data for individual spike mutations or combinations of spike mutations, such as those present in SARS-CoV-2 variants to mAbs, CP, and VP. As of December 31, 2021, 57 (22.2%) of 257 references were preprints including 13 (5.1%) published online during the first six months of 2021 and 44 (17.1%) during the last six months of 2021. Studies initially published as preprints are re-reviewed following peer-review publication. Studies that remain unpublished for more than one year will be evaluated for continued inclusion in the database.Published references included in the CoV-RDB are obtained weekly from three literature sources: i) PubMed using the search term “SARS-CoV-2”; ii) BioRxiv/MedRxiv COVID-19 SARS-CoV-2 preprint servers; and iii) the Research Square SARS-CoV-2/COVID-19 preprint server. Publication titles and abstracts are reviewed manually to identify studies containing data on SARS-CoV-2 spike mutations and humoral immunity. Studies that pass initial review are downloaded to a Zotero reference database and full texts are reviewed manually to extract specific data on the selection of spike mutations https://github.com/hivdb/covid-drdb-payload). Data are then imported into a PostgreSQL database where they are validated for completeness and consistency. The data in the PostgreSQL database are then exported as a single SQLite database file that is both available for download under the CC BY-SA 4.0 open-source license and used as the source for regularly updated datasets and queries on the CoV-RDB website. The entire workflow is summarized in For each publication, data are first entered into linked comma-separated files (CSVs) contained in a Github repository  replication-competent primary SARS-CoV-2 isolates [In the CoV-RDB data model, the virus entity represents individual spike mutations, combinations of spike mutations, and virus variants for which the full set of spike and genomic mutations is known including VOCs and VOIs. Published isolates ; (ii) reisolates ; (iii) risolates ; (iv) noisolates –14; and isolates –17.in vitro selection experiments have been performed using chimeric VSVs containing SARS-CoV-2 spike proteins as these viral constructs can undergo multiple rounds of replication in cell culture.For primary SARS-CoV-2 isolates, the virus is also characterized by mutations in other viral proteins that may influence viral replication kinetics but not neutralization susceptibility. For pseudotyped, chimeric, and recombinant viruses, the virus can be characterized entirely by its spike mutations. For surrogate neutralization assays, the virus is generally characterized only by the virus’s RBD mutations. Most in vitro selection and neutralization susceptibility data [in vitro passage, and mutations that reduce mAb binding and/or susceptibility.In CoV-RDB, mAbs are characterized according to their stage of clinical development; spike target; and specific epitope, i.e., the list of amino acids within 4.5 angstroms of the mAb paratope, according to structural data obtained from the Protein DataBank (PDB). ity data . CoV-RDBity data . For 64 In CoV-RDB, CP are characterized by the sequence of the infecting variant, severity of illness, and time since infection. The time since infection was available for all CP sample results including 16,846 samples obtained within six months of infection and 1,055 samples obtained beyond six months. The severity of illness was described for 4,613 (27%) CP samples with 2,754 samples from persons with mild-to-moderate disease and 1,859 samples from persons with severe disease. Although the sequence of the infecting virus was rarely known, the vast majority were obtained prior to the emergence of VOCs and VOIs. Nonetheless, 8%, 3%, 1%, and 2% were obtained from persons known to be infected with the Alpha, Beta, Gamma, and Delta variants, respectively.In CoV-RDB, VP are characterized according to the vaccine received, number of vaccinations, time since vaccination, and whether the VP was obtained from a person who was also previously infected with SARS-CoV-2. −6 for all comparisons). A similar fold-reduction in neutralizing susceptibility against a given VOC is likely to be more consequential for those vaccines that elicit lower titers of neutralizing antibodies.The CoV-RDB website contains four main features: (i) searchable tables containing SARS-CoV-2 variants, mAbs, vaccines, and references; (ii) regularly updated data summaries such as the data shown in in vitro selection data for mAbs. If the “Plasma / mAbs” dropdown option is selected, users must select either a specific mAb, CP from a person infected with a specific variant, or VP from persons who received a specific vaccine. If the “Variants / Mutations” dropdown option is selected, users must select a particular VOC, VOI, other variant, individual spike mutation, or combination of spike mutations. Selecting items from multiple dropdown boxes restricts the output to the data specified by the combination of dropdown items. The query interface allows users to search the database using one or more of the following three criteria: (i) published reference; (ii) antibody preparation ; and (iii) SARS-CoV-2 variant or spike mutation(s). If the “References” dropdown option is selected, then all the data associated with that reference is displayed in separate tables containing neutralization susceptibility data for mAbs, CP, and VP and/or 50 in ng/ml; and fold-reduced susceptibility compared with a control virus . If the individual measurements are available, they can be viewed by clicking on the spreadsheet icon in the “Data Availability” column. This will create a pop-up table containing the data, which can then be copied to the user’s clipboard. The “Download CSV” tab at the top of each table allows users to download all rows for analysis.Each table can be considered to have multiple dimensions represented by the table’s column headers. For example, The CoV-RDB website contains a SARS-CoV-2 sequence analysis program that leverages the code base written for the widely used Stanford HIV Drug Resistance Database interpretation program , 21. TheIf one or more spike mutations is submitted, the CoV-RDB sequence analysis program reports information on specific mutations and generates summary tables containing the susceptibility of viruses with these mutations to mAbs, CP, and VP . If a FABecause SARS-CoV-2 is a rapidly evolving RNA virus infecting millions of people worldwide, new variants will continue to emerge and influence regional and global pandemic trajectories. Ongoing epidemiological and clinical studies are needed to understand the risk of re-infection and vaccine failure posed by different variants. However, because the spectrum of SARS-CoV-2 variants is expanding and shifting faster than epidemiological studies can be conducted, laboratory-based markers will increasingly be used to identify those variants that could predispose to re-infection and vaccine failure. SARS-CoV-2 neutralizing antibody titers are correlates of immune protection and are likely to be useful as an endpoint in vaccine trials and to determine the need for vaccine boosters and immunogen updates.CoV-RDB is the only database to comprehensively curate published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to mAbs, CP, and VP. Although non-neutralizing Abs and cellular immune responses also contribute to protection from infection, the presence of neutralizing antibodies targeting the spike protein has correlated most strongly with protection from infection in animal models and in previously infected and vaccinated persons –25, NeutCoV-RDB can be downloaded in its entirety without restrictions. This is accomplished using a dual database pipeline that combines the full-fledged PostgreSQL database system to enforce relational data integrity and the simplicity of the SQLite database system to enable users to download and query the database without the overhead of accessing a host server. By making the database fully available to all users, we aim to encourage data sharing and the editing of the underlying CSV files by the authors of published studies.CoV-RDB neutralizing susceptibility query output can be considered multidimensional tables in which the rightmost columns contain numerical results  while the leftmost columns contain experimental conditions. The experimental conditions are explanatory variables that either directly influence neutralizing susceptibility  or have a more subtle effect on susceptibility . The CoV-RDB query interface enables users to explore the query results at different levels of granularity by filtering or aggregating them according to one or more experimental conditions without making additional calls to the web server.The sequence analysis program shares many features with the Sierra HIV Drug Resistance Database sequence analysis program. For the analysis of NGS data, both programs use Minimap2  to alignNeutralizing susceptibility data are highly heterogeneous occasionally resulting in discordant results across studies , 17, 27.in vitro neutralizing data. For example, vaccine efficacy data depends not just on the vaccine, the variant, and the time since vaccination but also on the study design and the age and immune status of the study population. Moreover, in many vaccine-efficacy studies, the proportion of individuals infected with different variants is not known.Data on the clinical significance of SARS-CoV-2 neutralizing susceptibility is continually evolving , 30–34. 50 (for mAbs) or a plasma dilution [Although the CoV-RDB is centered around just four main entities , differences among the types of viruses, types of antibody preparations, and types of experiments has necessitated a sophisticated database design. Nonetheless, as new types of experiments are being published, database schema will require continued updating. For example, the use of an international external standard for calibration such as the one developed by the WHO will increase concordance across different assays and will be reported using international units rather than as an ICdilution , 35.in vivo. Although binding data have been reported for many other mAbs using enzyme linked immunoassays, surface plasmon resonance, and biolayer interferometry, we have not curated these data as they have not been as comprehensive as the deep mutational scanning data.We have also added the comprehensive deep mutational scanning data published by the Bloom laboratory to the database –41. The Commercial total binding assays do not differentiate between binding and neutralizing antibodies. They also do not measure binding or neutralization of multiple variants but rather assess binding to pre-variant spike proteins. However, total binding assays often display moderately strong correlations with neutralizing assays , 42, 43 in vitro neutralizing data in CoV-RDB.Although CoV-RDB contains neutralizing susceptibility data obtained using the plasma from infected animal experiments , we have not included data from animal model challenge studies as such studies would require extensive modifications to our current database schema. Therefore, we will continue to monitor these studies and consider adding top-line data from these studies to alert database users to the existence of these studies without rigorously representing study details. Finally, a similar approach will be considered for studies of vaccine efficacy. We are therefore exploring the possibility of adding the top-line data of these studies so that the findings of these studies can be correlated with the S1 Table(XLSX)Click here for additional data file.S1 Fighttps://github.com/hivdb/covid-drdb-payload). Extracted data are then imported into a PostgreSQL database where the data are validated for completeness and consistency before being exported as a single SQLite database file that serves as the back end for the CoV-RDB website and is available to users for download.Weekly incremental searches of PubMed and preprint servers (BioRxiv/MedRxiv and Research Square) are performed. Publications that appear to have data pertinent to SARS-CoV-2 variants and their susceptibility to mAbs, convalescent plasma (CP), and vaccinee plasma (VP) are downloaded to a Zotero reference database folder to enable full-text review and data curation. Extracted data are exported into a set of linked CSV files in an open-source GitHub repository ((TIF)Click here for additional data file.S2 FigFASTQ files are aligned to the consensus Wuhan-Hu-1 reference sequence using the Minimap2 alignment program. The resulting BAM/SAM files are then processed by a library SAM2CodFreq that we wrote to generate a codon frequency (CodFreq) file containing seven columns as shown on the right. The table here shows the results from three codons (spike positions 500 to 502). The observation that many codons shown in this (and other parts of the same file which are not shown) are present at levels between 0.2% and about 2% suggests that codons present at these low proportions likely represent sequencing or experimental artifacts . However, as the mutation N501Y occurs at a considerably higher proportion (34.3%), it is likely to be present in the infecting virus population.(TIF)Click here for additional data file.S3 FigThe program supports three types of input: a list of spike mutations; one or more consensus FASTA sequences containing any part of the SARS-CoV-2 genome; and one or more FASTQ sequences. However, because a FASTQ sequence can take several minutes to analyze, users are advised to first convert them to a codon frequency (CodFreq) file through an auxiliary program. If a list of spike mutations is submitted, the program returns comments about notable mutations and summary tables reporting the susceptibility of viruses with these mutations to mAbs, CP, and VP. If a FASTA sequence is submitted, the program returns the preceding information plus a list of the SARS-CoV-2 genes, the amino acid mutations in the sequence, and the sequence’s PANGO lineage. If a FASTQ sequence or codon frequency table is submitted, the program provides the preceding information and the read coverage for each position along the genome. It also provides users with the options to select read depth and mutation-detection thresholds below which mutations will not be reported.(TIF)Click here for additional data file.


The goal for laypersons after training in basic life support (BLS) is to act effectively in an out-of-hospital cardiac arrest situation. However, it is still unclear whether BLS training targeting laypersons at workplaces is optimal or whether other effective learning activities are possible.The primary aim was to evaluate whether there were other modes of BLS training that improved learning outcome as compared with a control group, i.e. standard BLS training, six months after training, and secondarily directly after training.n = 2623) from workplaces were cluster randomised into 16 different BLS interventions, of which one, instructor-led and film-based BLS training, was classified as control and standard, with which the other 15 were compared. The learning outcome was the total score for practical skills in BLS calculated using the modified Cardiff Test.In this multi-arm trial, lay participants . The highest score was for the BLS intervention including a preparatory web-based education, instructor-led training, film-based instructions, reflective questions and a chest compression feedback device (95% CI for difference 0.9–5.0), 6 months after training.BLS training adding several different combinations of a preparatory web-based education, reflective questions and chest compression feedback to instructor-led training and film-based instructions obtained higher modified Cardiff Test total scores 6 months after training compared with standard BLS training alone. The differences were small in magnitude and the clinical relevance of our findings needs to be further explored.ClinicalTrials.gov Identifier: NCT03618888. Registered August 07, 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03618888The online version contains supplementary material available at 10.1007/s40670-020-01160-3. Learning activities in basic life support (BLS) for laypersons must bridge the reality of an out-of-hospital cardiac arrest (OHCA) situation. It is urgent to alert the emergency medical service (EMS) and initiate high-quality cardiopulmonary resuscitation (CPR) and automated external defibrillation (AED) –5. MedicThe learning outcome for training in BLS includes sufficient practical skills and theoretical knowledge. Experiential learning might be appropriate in order to understand the process of learning BLS. According to Kolb’s experiential learning theory, learning is individual and comprises four stages: (1) concrete experience, (2) reflective observation, (3) abstract conceptualisation and (4) active experimentation . DiffereInstructor-directed training compared with self-directed training and video-based instructions has been shown to be as good as instructions from the instructor alone , 9–13. PGlobally, cardiovascular disease (CVD) is a major public health issue and an increased level of educated community members may increase cardiovascular health . WorkplaThere are scientific gaps in relation to educational interventions in BLS, including OHCA, CVD and the effectiveness of digital strategies , 17, 26.This study was an educational, multi-factorial intervention in BLS, CPR and AED for laypersons at workplaces in Sweden in 2014 to 2016. The design was a 16-arm parallel-group, experimental, cluster randomised, controlled trial (RCT) according to Reporting of Multi-Arm Parallel-Group Randomized Trials Extension of the CONSORT 2010 Statement  and checrandomizer.org [ClinicalTrials.gov (ID: NCT03618888).Allocated laypersons were cluster randomised to one of 16 BLS training interventions using blocks of 25 individuals in 112 clusters calculated by the izer.org . The genizer.org , the invn = 2623) was recruited from 84 workplaces in the community outside hospitals, in the south of Sweden. The criteria for inclusion were laypersons with no BLS training at all  or without prior BLS training within 5 years or longer  and 18 years of age or older. The criteria for exclusion were that potential candidates for participation were either healthcare professionals or participants who had not performed the retention test. The participants and workplaces were given both oral and written information and written informed consent was obtained from all the participants.The study population  guidelines , 36. SevOne or two instructors from the workplaces facilitated the instructor-led interventions. In total, 16 instructors, accredited by the Swedish resuscitation council, with about 10 years of experience were updated to 2010 ERC guidelines.Data were collected directly after the training and 6 months after the training through individual questionnaires , adjusted for multiple comparisons using Dunnett’s method. Standardised effect size (Cohen’s d) is also given for each comparison with group 9 regarding Cardiff Test total score.Least square means with corresponding standard errors are presented for each intervention group, together with 95% confidence intervals and p values below 0.05 were considered statistically significant. SAS for Windows version 9.4 was used for all the performed analyses.All tests are two-sided and The Regional Ethical Review Board in Gothenburg approved the ethical application on 23 March 2014 (2014/134-14).n = 2480) or directly (n = 2425) after training. The characteristics of the participants are presented in Table This multi-arm parallel cluster RCT enrolled 2623 laypersons recruited from workplaces in a BLS educational project from 2014 to 2016, of which 2529 were eligible for analysis either at 6 months , i.e. BLS instructor-led practical training with film-based instructions Table . The staA description of individual items in the Cardiff Test score Table  and sepaSeparate variables, variables for quality of practical skills for cardiopulmonary resuscitation (CPR) and automated external defibrillation (AED), 6 months after training in basic life support (BLS)Data was collected from the Resusci Anne Manikin connected to the PC Skill Reporting system  and from direct observation. All results are crude, i.e. not adjusted for clustering or imbalances in participants’ characteristics. All available data was usedFor secondary outcome, i.e. BLS skills directly after training, intervention numbers 16, 12 and 14, all including a preparatory web-based interactive education, instructor-led training and film-based instructions, obtained a significantly higher modified Cardiff Test total score compared with the control group, when adjustment was made for imbalances in participants’ characteristics Table .Table 5TTheoretical knowledge on first action if stroke or AMI and OHCA, i.e. call 112, general symptoms of stroke and AMI and healthy lifestyle factors, self-assessed theoretical knowledge and practical skills, confidence and willingness to act in a real-life OHCA situation, directly and 6 months after training are described in Supplementary file The main results in this cluster RCT showed that a preparatory interactive web-based education on CVD, a feedback device on the quality of compressions and reflective essential questions, in addition to instructor-led and film-based training, appear to provide potential benefits for practical skills in BLS when compared with the standard, 6 months after training. However, the clinical impact and the way these three additional learning activities could be combined in an optimal way have been investigated but it is still unclear and further studies are required to explore this issue.Yet, all three learning activities have previously been reported to be beneficial for learning. Firstly, E-learning has been reported to be as good as lectures and teaching before training , 37–39, Moreover, the results in this study indicate that an instructor who facilitated the interventions appeared to be favourable for learning. This is in line with a systematic review by Chen et al., who presented interventions that improved high-quality CPR by laypersons and the result showed that an instructor or dispatcher was engaged in most of the studies which improved efficacy , even ifFurthermore, compression-only CPR, real-time feedback and mobile devices with CPR instructions are factors which appear to improve efficacy . MoreoveIn addition to the main result, two of the learning activities, numbers 16 and 14, resulted in improvement both directly after training and 6 months after training. Six months can be regarded as long-term retention as practical skills deteriorate after 3 to 6 months , 6, but,In this study and according to the national guidelines in BLS, the instructor gave verbal feedback and helped the participants visually to achieve the learning objective and the participants self-assessed their practical skills with the manikin. Self-assessment is possible in both instructor-directed and self-directed training, but, if the assessment of the participants was performed in communication with the instructor and using technological feedback, we might have another result. Assessment is recommended for long-term retention with mastery learning , 6. UnprAdditionally, when comparing interventions numbers 10, 11, 14 and 16 with the control group 9, several individual items in the Cardiff Test and separate variables obtained higher scores.Consequently, the preparatory interactive web-based education in addition to the instructor-led and film-based training was involved when improvement compared with standard was found at primary outcome 6 months after training. Adding theoretical knowledge on CVD as stroke, AMI and OHCA, and BLS, CPR and AED and healthy lifestyle factors may provide motivation for learning practical skills, but this is unclear. For further implementation, the web-based education could also include some synchronous brief practical self-retraining with a simple manikin, with feedback and encouragement to collaborate at the workplace and be spaced over the year. This might increase the level of re-qualified potential bystanders, as well as being easy to update, and it may reduce the financial costs and organisational affordances . The eduWith this third study, we conclude that the learning activities of a preparatory interactive web-based education on stroke, AMI, OHCA, CPR, AED and healthy lifestyle factors, an instructor present, film-based instructions, reflective questions and chest compressions feedback may have benefits for learning in BLS compared with instructor-led and film-based instructions alone.The cluster randomised design targeted at a study population at workplaces was a strength as was the large sample size. Limitations include, in spite of the randomisation design, imbalances between the intervention groups regarding baseline characteristics. In addition, since we have no exact data on the actual time spent on each intervention, we could not adjust for this factor, which is a limitation. Thus, we cannot exclude the possibility that some of the differences that were found between groups may have been explained by a different duration of the training. The duration of the self-learning training was not exactly defined and that is a limitation of the study design. Furthermore, it might be argued whether the statistically significant differences are of clinical relevance since the effect size was small to moderate.BLS practical training, adding different combinations of a preparatory web-based interactive education, reflective questions and chest compression feedback to instructor-led training and film-based instructions, obtained higher modified Cardiff Test total scores 6 months after training compared with instructor-led and film-based BLS training alone. The differences were small in magnitude and the clinical relevance of our findings needs to be further explored.ESM 1(DOCX 36 kb)ESM 2(DOCX 21 kb)ESM 3(DOCX 62 kb)ESM 4(DOCX 61 kb)ESM 5(DOCX 21.6 kb)