Experiences of adversity can generate positive psychological effects alongside negative impacts. Little research to date has evaluated predictors of post-traumatic growth in mental or community healthcare workers during the COVID-19 pandemic. Following a survey of 854 community and mental healthcare staff in the United Kingdom in July to September 2020, multiple linear regression was used to determine the association between hypothesised risk and protective factors  and total scores on the Post-traumatic Growth Inventory–Short Version. Positive self-reflection activities, black and minority ethnic status, developing new healthcare knowledge and skills, connecting with friends and family, feeling supported by senior management, feeling supported by the UK people, and anxiety about the personal and work-related consequences of COVID-19 each significantly independently predicted greater post-traumatic growth. Working in a clinical role and in mental healthcare or community physical healthcare predicted lower post-traumatic growth. Our research supports the value of taking an organisational growth-focused approach to occupational health during times of adversity, by supporting staff to embrace opportunities for personal growth. Valuing staff’s cultural and religious identity and encouraging self-reflective activities, such as mindfulness and meditation, may help to promote post-traumatic growth. It is widely acknowledged that the coronavirus disease COVID-19) pandemic has placed healthcare staff under unprecedented stress 9 pandemi.Stressful life experiences are also known to have the potential to generate positive psychological effects . HealthcThere is a dearth of research on post-traumatic growth in the workplace, and on organisational conditions enabling this . The unpHealthcare organisations, as well as government health policy actors, have a responsibility to protect their staff from burnout and stress and enable them to achieve personal growth in times of adversity . The preHypotheses. No hypotheses were derived regarding sociodemographic characteristics; these were analysed in an exploratory manner. Staff working in inpatient settings may experience lower post-traumatic growth due to being more significantly affected by personal safety considerations and concerns for their patients ,31. ConvHypotheses. In a number of studies, greater subjective or objective stress exposure predicts greater post-traumatic growth, through allowing opportunities for changes in mindset, attitude, self-perception and coping behaviours . We hypoHypotheses. Evidence suggests that social support promotes post-traumatic growth, particularly when mutual experiences of both stress and growth can be shared ,35,36,37Hypotheses. Self-care, i.e., taking care of one’s own holistic wellbeing, is core to the delivery of effective professional mental healthcare, and can prevent burnout ,39. PracHypotheses. Gaining new knowledge and learning new skills opens up people’s minds to new ways of seeing the world and to a new appreciation of their own abilities . We hypoHypotheses. Occupational support, based in supportive work relationships and enabled by supportive organizational cultures, can play a critical role in helping workers cope with work-related crises and has been shown to promote post-traumatic growth ,45. We hHypotheses. In line with previous research, we hypothesise that staff with greater trait psychological resilience will experience greater post-traumatic growth ,48,49,50Hypotheses. In line with previous research, we hypothesise that depression and anxiety will be negatively associated with post-traumatic growth ,52.Cross-sectional analysis of predictors of post-traumatic growth, using data from the first round of a cohort study.The study was approved by the United Kingdom Health Research Authority on 7 July 2020 (ref. 20/HRA/2982). All participants gave written informed consent for participation via a tick-box on the Qualtrics internet-based survey platform.The study was conducted across four National Health Service (NHS) Trusts in England: two Trusts specialised in mental health care, whilst two specialised in both mental health and community care. The two mental health care Trusts were in semi-rural localities whilst the two mental health and community care Trusts were based in urban inner London localities. The present analysis uses data collected between 16 July 2020 and 30 September 2020. At the start of the survey, coronavirus cases were falling across the country . RestricAny member of staff working in any role in one of the participating trusts was eligible to participate. Both clinical and non-clinical staff were included.Research and development personnel in participating NHS trusts sent invitations to participate in the survey to all staff in their trusts, via targeted emails and via inclusion in staff news bulletins, between 16 July 2020 and 30 September 2020. Interested staff were provided with a link to view the participant information sheet, hosted on Qualtrics survey software, and were provided with the research team’s contact details in case they wanted to ask any further questions before deciding whether to participate. Interested staff then completed the consent form and survey online, using Qualtrics. The survey was designed by the authorship team using the measures below.Demographic and professional characteristics, including gender identity, age, ethnicity, British citizenship, healthcare sector, work location, profession, and NHS Trusts, were collected using a standardised pro forma developed by the research team.Personal, environmental and organisational risk/protective factors were derived from available academic literature and were collected using a standardised pro forma developed by the research team. These included the following items rated on a binary yes/no scale: self, family or friends becoming seriously ill or hospitalised with COVID-19; frequent workplace exposure to COVID-19; serious illness of local or wider colleagues from COVID-19; self or family classified as clinically extremely vulnerable. A measure of anxiety about the personal and professional effects of COVID-19 was derived from mean scores on the following items, rated on a Likert scale from Not at all (1), A little bit (2), Somewhat (3) to A lot (4): Worry about yourself or loved ones becoming seriously ill or dying from COVID-19; Worry about colleagues becoming seriously ill or dying from COVID-19; Worry about service-users becoming seriously ill or dying from COVID-19; Worry about your service-users becoming seriously ill or dying from other serious mental or physical health conditions; Feeling less able to deliver adequate and safe mental health care; Feeling less able to deliver adequate and safe physical health care (α = 0.78). These items were based on contemporary academic and professional body publications outlining the specific concerns of healthcare and mental healthcare workers ,21,22,23Psychological resilience was measured using the Connor–Davidson Resilience Scale—10 item Version ,  ,  ,  were entered simultaneously. In a final step, variables that were non-significant in the full multiple regression model were removed and the Akaike and Bayesian information criteria used to establish whether this improved the fit of the model to the data.Linear regression in STATA version 14.2 was used to determine the association between individual predictors and total scores on the Post-traumatic Growth Inventory—Short Version. To adjust for multiple testing, the Holm–Bonferroni correction was calculated in Excel to produce adjusted p-values . SubsequA total of 854 staff took part, from a total potential sample of 24,800 staff members across participating NHS Trusts (data provided by Trust Research and Development departments). Thus, the survey response rate was 3%.The mean age of participants was 46.68 years (11.24). The majority were female (81.7%) and White British (73.4%). The majority of the participants worked in mental health (88.2%), with 7.8% working in community physical health and 4% working in primary care. Half of the sample worked in a community setting  (51.1%), 13.6% worked in inpatient services, 10.9% worked both in community and inpatient, and 24.4% worked at administration offices. Participants’ professions varied and included administration (17.2%), consultant/SAS medical doctor (3.9%), allied health professional (12.8%), psychology/psychotherapy (18%), healthcare assistant/support worker (5.6%), nursing/midwifery (24.8%), social worker (3.2%), management (6.4%), other (5.3%), trainee doctor (0.7%), scientific and technical professions (0.5%), pharmacy (0.6%), and additional clinical services (1.1%). Participant mean age and gender distribution was similar across Trusts. The two urban London trusts had a substantially higher proportion of ethnic minority participants (43% and 51% respectively) compared to the semi-rural Trusts (9% and 14% respectively). The average total and item scores on the brief post-traumatic growth inventory were 20.35 (s.d. 10.92) and 2.03 (s.d. 1.09) respectively. Twenty-one percent of staff reported moderate to high levels of growth (PTGI item mean score ≥3) .Findings from the linear regression models of individual predictors of post-traumatic growth are shown in Higher post-traumatic growth was significantly associated with Asian or Black ethnicity, working in a non-clinical role and/or in administrative offices and/or in primary care, and working for a particular NHS Trust (located in London). Contrary to the hypothesis, working in an inpatient setting was not linked to lower post-traumatic growth, whereas working in a community setting was. Contrary to the hypothesis, allied health professionals, nursing staff and psychology staff reported less post-traumatic growth than non-clinical staff. The variable with the highest explanatory power was ethnicity, explaining 9% of the variance in post-traumatic growth. Age and British citizenship were not related to post-traumatic growth.The average score on our COVID-19 anxiety measure was 2.60 (s.d. 0.57), suggesting that on average participants were “somewhat worried” about the personal and work-related consequences of the COVID-19 pandemic. As hypothesised, greater personal/familial exposure to or risk from COVID-19 and increased anxiety about COVID-19 were each linked to greater post-traumatic growth. Workplace exposure to COVID-19 was not related to post-traumatic growth.As per the hypothesis, more time spent connecting with others was associated with greater post-traumatic growth.As per the hypothesis, more time spent on self-care  was generally associated with greater post-traumatic growth, with time spent on positive self-reflection a particularly strong predictor. Time spent away from work, time not thinking about work, and adequate sleep were not significantly related to growth. As per the hypothesis, greater professional development at work was linked to greater post-traumatic growth.As hypothesised, feeling supported at work was consistently associated with greater post-traumatic growth. Whilst feeling supported by one’s immediate team was linked to greater growth, this was not the strongest predictor, with feeling support from senior management, the UK government and the people of the UK being most highly predictive. Contrary to hypothesis, practical support at work in the form of infection control and access to PPE was not linked with growth.Contrary to the hypothesis, psychological resilience was not associated with post-traumatic growth.Contrary to the hypothesis, depression and anxiety were not associated with post-traumatic growth.2 = 0.09). Time spent on positive self-reflection was added first due to its strong conceptual relationship with post-traumatic growth (Model 1). The addition of ethnicity led to a significant increase in the explanatory power of the model, almost doubling the R2 to 0.17 (Model 2), indicating that ethnicity has a substantial association with post-traumatic growth that is largely independent of the effect of positive self-reflection. In subsequent models , the addition of variables related to professional skills development, connecting with others, feeling supported at work, professional characteristics, and exposure to or risk of COVID-19 each led to a significant increase in the explanatory power of the model, with the full model holding a total adjusted R2 of 0.31. An exception was the addition of variables related to other self-care , which did not add significant additional explanatory power to the model (Model 5). In a final model (Model 9), variables that were non-significant in earlier multiple regression models were dropped. This did not lead to any drop in explanatory power, explaining 31% of the variance in post-traumatic growth, and yielded superior Akaike and Bayesian information criteria over the full model, indicating it offered the best balance of explanatory power versus parsimony and hence provided the best fit to the data. The final model is shown in Time spent on positive self-reflection and ethnicity jointly explained the most variance in single regression models , and to see religion as a strong marker of their identity . ReligioAs much as the pandemic brought challenges for safe and effective healthcare, it also necessitated healthcare staff learning new skills, including the use of video technologies for delivering remote assessment and training, enhanced infection control competencies, and, in some cases, redeployment into a new area ,22,92. WConnecting with friends and family and feeling supported by senior management and the people of the UK each independently predicted greater post-traumatic growth. According to Calhoun and Tedeschi , cognitiContrary to the hypothesis, but congruent with research on Dutch peacekeepers , feelingFurther, our survey took place when public attitudes to pandemic healthcare workers were resoundingly positive, with the weekly public “Clap for carers” initiative having recently ended, and NHS rainbow artwork still festooning many residential and commercial windows . Whilst Staff scores on our COVID-19 anxiety measure represent a moderate level of anxiety about themselves, loved ones, colleagues, and their service-users becoming seriously ill or dying from COVID-19, as well as worry about service-users becoming more unwell for other reasons whilst staff feel less able to deliver an adequate level of care. In the UK and elsewhere, mental health and community workers were tasked with preventing the spread of infection amongst patients and staff, with inadequate training and less access to PPE provision than other staff groups ,22,23,24Contrary to the hypothesis and some international studies of healthcare workers during the pandemic ,49, psycThis was, to our knowledge, the first published evaluation of post-traumatic growth amongst UK healthcare personnel during the COVID-19 pandemic, and the first international evaluation of post-traumatic growth specifically amongst mental health and community staff. Strengths include sampling via NHS trusts rather than through social media, arguably resulting in less selection bias , and theLimitations include our low response rate (3%). Healthcare workers busy dealing with the pandemic and all of its associated stresses may have missed the recruitment emails or may have been put off by the advertised survey completion time (15 to 20 min including a reflection activity not described here). Thus, potentially, the staff who did respond may be a sample that were particularly motivated to reflect on positive and negative pandemic effects. However, low response rates have been found to exert only minimal effects on statistical associations between variables in surveys , which iFurther research should explore why black and minority ethnic identity may help to promote growth, including an investigation of how a sense of community belonging and religious identity may be beneficial, but also drawing on qualitative data to better understand the complexity of black and minority healthcare staff’s experiences of the pandemic. Similarly, drawing on healthcare staff’s qualitative accounts of their experiences of the pandemic could better elucidate what specific management behaviours were beneficial in promoting growth. Finally, further potential predictors of post-traumatic growth, such as religiosity, coping skills and post-traumatic stress, should be tested in order to explain additional variance. Future research should assess the course of post-traumatic growth over the pandemic as the findings identified here reflect post-traumatic growth at the peak of the pandemic, where healthcare staff were experiencing both the highest levels of stress and equally the greatest prospects for growth through adaptation to new circumstances. Evaluating prospective predictors and consequences of post-traumatic growth would better elucidate the directionality of associations and enable a better understanding of whether post-traumatic growth exerts a protective influence on future mental health.A resilient organization “builds and uses its capability endowments to interact with the environment in a way that positively adjusts and maintains functioning prior to, during, and following adversity”  (p. 742)


Perceived discrimination and work impairment are commonly observed in COVID-19 survivors, but their relationship has not been well understood. We aimed to evaluate the role of discrimination in the development of psychological distress and work impairment in COVID-19 survivors. From April 2020 to November 2021, 309 patients were recruited at two designated COVID-19 hospitals in Japan. Participants completed a standardized questionnaire including COVID-19 sequelae, psychological distress, impairments in work performance and perceived discrimination. The majority of participants (62.5%) experienced one or more COVID-19 sequelae. Psychological distress was observed in 36.9% and work impairment in 37.9%. In multivariate logistic regression analyses, COVID-19 sequelae and discrimination were associated with both psychological distress and work impairment. Mediation analysis demonstrated that the direct effect of sequelae on work impairment was non-significant after accounting for psychological distress, suggesting that the effect of sequelae on work impairment was mainly mediated through psychological distress. These findings were replicated in a subgroup analysis limited to patients with mild COVID-19. We conclude that discrimination plays an important role in the development of psychological distress and work impairment, and that both discrimination and psychological distress should be targets of intervention in COVID-19 survivors. Some individuals may experience persistent neuropsychiatric symptoms such as cognitive dysfunction, depression, anxiety, reduced sleep quality, and post-traumatic stress7. In addition, a considerable proportion of COVID-19 patients, even those with mild cases, experience functional impairment in their work, social, and home life after recovery from the acute phase9. Some studies have shed light on the relationship between mental health and functional impairment in COVID-19 patients, demonstrating that COVID-19–related stress is associated with worsening anxiety, depression, and functional impairment11. Those with persistent symptoms after COVID-19 may have an increased utilization of healthcare resources and more functional impairment12.Acute coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and has led to a global pandemic. COVID-19 was initially considered to be a time-limited disease, albeit one with severe symptoms and dire outcomes such as high mortality. However, grave concerns have recently been raised about the long-term effects of COVID-19. Mounting evidence suggests that symptoms such as fatigue, shortness of breath, headaches, and anosmia/dysgeusia may persist for months, resulting in a substantial burden on COVID-19 survivors14. Anti-Asian discrimination was widespread, particularly in Western countries17, and it negatively affected their mental and physical health and well-being20. Discrimination influenced their health behaviors as well, leading to low compliance with social-distancing recommendations22.COVID-19–related discrimination has been another major concern. As COVID-19 spread worldwide, fear of contagion and limited knowledge promoted negative attitudes or even discrimination towards people of Asian descent, due to the presumed origin of the virus, as well as towards those suspected to have or diagnosed with COVID-1924, and was shown to be associated with mental health problems such as psychological distress25, anxiety26, depression, difficulty sleeping27, and PTSD symptoms28. Hence, it is possible that discrimination against COVID-19 survivors adversely influences their mental health, which in turn impairs their social life. However, no studies have examined the relation between discrimination and functional impairment in this population.Discrimination also posed a serious threat to COVID-19 survivorsIt is imperative to understand the mechanisms underlying discrimination, mental health and associated functional impairment in COVID-19 in order to devise appropriate interventions to prevent or reduce the long-term adverse effects of the disease. This study aimed to elucidate the relationship between discrimination and COVID-19 sequelae, psychological distress, and work impairment in COVID-19 survivors in Hiroshima, Japan. We hypothesized that both COVID-19 sequelae and COVID-19–related discrimination would be risk factors for psychological distress and work impairment after COVID-19. We also hypothesized that psychological distress would mediate the relationship between COVID-19 sequelae and work impairment, i.e., the long-term effects of COVID-19 on work function would at least partially be explained by its mental effects. We additionally assessed whether discrimination moderated the indirect effect of sequelae on work impairment through psychological distress.29. Hospital A is a designated medical institution for Class 2 infectious diseases and a regional hub medical center for mild and moderate COVID-19 in its catchment area. Hospital B is a designated key medical institution for COVID-19 patients in Hiroshima Prefecture. Patients who were diagnosed with COVID-19 based on polymerase chain reaction (PCR) testing and admitted to or visited the outpatient consultation clinics of these hospitals for COVID-19 were eligible. Patients who were admitted to Hospital A during April 14, 2020 and November 30, 2021 and visited its outpatient consultation clinic thereafter were recruited by their physicians. Patients who visited Hospital B between April 11, 2020, and May 1, 2020 were sent a letter requesting participation in the study in August 2020. Informed consent was obtained from all participants. A set of self-reported questionnaires was sent by mail to those who provided written consent to participate in the study after recovery from COVID-19.This cross-sectional study analyzed data collected in collaboration with two major COVID-19 hospitals  in Hiroshima Prefecture, JapanStandardized questionnaires were used to obtain the following information: age (years), gender, smoking history , medical history, and COVID-19 sequelae . COVID-19-related experiences of discrimination were assessed by a multiple-choice question  supplemented by an open-ended question.30. The Wfun questionnaire was developed to evaluate a worker’s health-related ability to complete their work tasks, and was demonstrated to be linearly associated with work productivity32. The scale comprises seven screening questions for measuring impaired work function, and responses are made on a 5-point scale from 1 to 5 . A cutoff point of 14/15 was employed to indicate possible deficits in work performance30. Work impairment is graded by Wfun scores as follows: 14–20, mild; 21–27, moderate; and 28–35, severe.The Work Functioning Impairment Scale (WFun) was used to screen for impairments in work performance33. The Japanese version of the K6 Scale was demonstrated to have excellent discriminatory ability for mood and anxiety disorders34, and consists of six questions that are each scored from 0 to 4 . Total scores of 0–4 are categorized as no distress, while those equal to or higher than 5 reflect possible mood or anxiety disorders35. The severity of these disorders corresponds to K6 scores as follows: 5–9, mild; 10–14, moderate; and 15–24, severe35.The six-item Kessler Psychological Distress Scale (K6) was employed to assess the severity of psychological distress36. For each patient, COVID-19 severity and the date of COVID-19 onset were obtained from medical records.The United States National Institutes of Health defines four levels of COVID-19 severity based on the need for respiratory support during hospitalization, as follows: no supplemental oxygen, require supplemental oxygen, require oxygen through non-invasive mechanical ventilation (non-IMV), and require IMV or ECMO The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. This study was conducted under the approval of the Ethical Committee for Epidemiology of Hiroshima University .37. The characteristics of participants with and without COVID-19 sequelae were compared before and after March 1, 2021. The chi-square and Cochran–Armitage trend tests were used for categorical and ordered categorical variables, respectively, and the t-test was used for continuous variables (or the Wilcoxon rank-sum test if the distribution was skewed).Participant characteristics were summarized overall and according to the time of COVID-19 diagnosis and the presence or absence of COVID-19 sequelae. The distribution of SARS-CoV-2 variants in Hiroshima dramatically changed in March 2021, since the Alpha variant (B.1.1.7) became predominant after this timeMultivariate logistic regression analysis was employed to identify factors associated with post–Covid-19 work impairment (defined as a Wfun score ≥ 14) and psychological distress (defined as K6 score ≥ 5). The independent variables were gender , age , time period , time from diagnosis to survey, and whether they received any support after diagnosis, presence or absence of the following: COVID-19 sequelae and COVID-19–related experience of discrimination.38. The analysis was performed with bias-corrected confidence intervals using 5000 bootstrapping iterations. The sequential ignorability assumption was examined by a sensitivity analysis with various values for the correlation between mediator residuals and outcome regressions39. We also conducted a moderated mediation analysis to test the moderating effect of discrimination on the indirect effect of sequelae on work impairment through psychological distress by introducing the interaction terms with respect to sequelae and psychological distress to the logistic regression models.Causal mediation analysis was performed to assess how COVID-19 sequelae influenced work impairment through psychological distress as a mediating factorSubgroup analyses limiting the analytic sample to participants with mild COVID-19 were conducted to examine the long-term effects of mild disease on work impairment and psychological distress.All analyses were conducted using R version 4.1.12, and a p value less than 0.05 was considered statistically significant.During the study period, 1177 patients were admitted to Hospital A and 329 (28.0%) agreed to participate in the study. Forty-three patients were sent a letter for participation and 22 (51.2%) responded to the survey. A total of 351 patients participated in this study and answered the survey. Those lacking information on COVID-19 severity (n = 10) or who did not fully complete the K6 (n = 7) or Wfun (n = 25) questionnaire were excluded from the analysis, resulting in an analytic sample of 309 participants.Table A total of 101 participants (32.7%) experienced COVID-19-related discrimination. The most common type of discrimination was “treated as infectious after recovery” (57.4%), followed by “work disadvantages caused by harmful rumors” (32.7%), “suffer from slander” (20.8%), and “trouble securing opportunities to train or study” (14.9%).p = 0.003) and to experience psychological distress and work impairment (both p < 0.001), but these differences were not statistically significant between March 2021 and November 2021.Between April 2020 and March 2021, participants with COVID-19 sequelae were significantly more likely to be older . The bootstrapped indirect effect (unstandardized coefficient) was 0.09 with a 95% confidence interval between 0.02 and 0.15, suggesting that the indirect effect was statistically significant. The direct effect of sequelae on the likelihood of work impairment became non-significant in mediation analysis after accounting for psychological distress . In moderated mediation analysis to test the moderating effect of discrimination on the indirect effect of sequelae on work impairment through psychological distress, the indirect effect did not significantly differ between participants with and without discrimination (p = 0.93).Mediation analysis demonstrated that the effect of sequelae on the likelihood of work impairment was at least partially mediated through psychological distress. The effects of sequelae on psychological distress and of psychological distress on work impairment were both statistically significant , 158 (62.2%) reported COVID-19 sequelae; of these, 96 (37.8%) and 99 (39.0%) experienced psychological distress and work impairment, respectively. All analyses were repeated in analytic samples limited to participants with mild COVID-19, and the results replicated those obtained in the overall sample .In the present study, perceived discrimination was prevalent among COVID-19 survivors, and it was associated with both psychological distress and work impairment. COVID-19 sequelae were significantly and independently associated with both problems in analyses that treated each as separate outcomes, but mediation analysis demonstrated that the effect of sequelae on work impairment was mostly explained by their effect on psychological distress. The indirect effect of sequelae, i.e., the effect of sequelae on work impairment via psychological distress, was not moderated by discrimination.3. A recent study in 63 hospitalized patients reported that the prevalence of sequelae was 76% at 14 days, 48% at 2 months, and 27% at 4 months after COVID-19 onset, results that were consistent with the prevalence of 62.5% in this study40.The prevalence of COVID-19 sequelae varies greatly depending on the geographic location of the study area and on patient background factors28. We also showed that COVID-19 sequelae and discrimination were associated with functional limitations; to our knowledge, this finding has not been previously reported. We conducted additional analyses to delineate these associations and found that the effect of sequelae on work impairment was largely mediated via psychological distress. This suggests that interventions to prevent or reduce work impairment in COVID survivors should target psychological distress after recovery from COVID-19. For those who require hospitalization, discharge preparation programs can prepare them to effectively cope with persistent COVID-19 symptoms. Outpatient psychological support programs may provide close follow-up to monitor persistent symptoms of COVID-19 and psychological distress, and provide necessary care for them after discharge as well as for those with mild COVID-19 symptoms and recuperate without hospitalization. The development of such programs is urgently needed considering that the cumulative number of COVID-19 cases has been increasing worldwide, and a significant proportion of these individuals may suffer from COVID-19 sequelae, psychological distress, and functional impairment. Our finding that COVID-19 sequelae and discrimination were associated with psychological distress corroborated a previous study in which risk factors associated with anxiety and depression included perceived discrimination and a greater total number of symptoms in COVID-19 survivors41. Our study found a higher prevalence of perceived discrimination and suggests that discrimination towards COVID-19 survivors may be more widespread, possibly due to the continuation of the COVID-19 pandemic. Infection spread between individuals in close proximity may arguably intensify the fear of contagion, which could contribute to discrimination42. In the meantime, more knowledge and treatment options have rapidly become available, which can alleviate the fear of COVID-19. Change in virulence from COVID-19 variants over time may also affect peoples’ fear of and attitudes to COVID-19. Additional research is needed to follow longitudinal changes of perception towards COVID-19 patients. Our study demonstrated that although discrimination did not moderate the relationship between COVID-19 sequelae and work impairment, it remains an important risk factor for both psychological distress and work impairment. It is essential to implement measures to reduce discrimination against COVID-19 patients. Our findings in the overall sample were replicated in a subgroup analysis of participants who had recovered from mild COVID-19, implying that COVID-19 survivors may require support programs regardless of disease severity.There is little information on the frequency of discrimination towards COVID-19 survivors in Japan. A small study in 27 patients showed that 23.1% of COVID-19 patients in Japan experienced discrimination or harassment after discharge43. Therefore, extrapolation of our findings to other societies with different cultural backgrounds should be carried out with caution. Second, the response rates at two hospitals were relatively low in this study though they are comparable to similar studies conducted during the COVID-19 outbreaks. It may introduce selection bias. Third, the results should be interpreted with much caution due to the relatively short duration between COVID-19 and data collection (median 25 days). Since many symptoms experienced 4 weeks after recovery from COVID-19 may become persistent for longer periods of time44 and functional impairment may be observed several months after COVID-199, long-term effects of sequela on psychological distress and work impairment should be investigated in future research. The current study focuses on short-term impacts of COVID-19, which may provide insight into the development of psychological distress and work impairment after the acute phase of COVID-19 and help design interventions for early recognition and treatment. Fourth, the study design was cross-sectional and did not allow us to infer a causal relationship. The assumption of the mediation analysis was that the cause of work impairment was sequela and psychological distress was the mediator of their relationship. We have made this assumption based on previous studies reporting the association between persistent COVID-19 symptoms, stress and functional impairment12 and the presumed chronological order in which sequela develop first, psychological distress ensues, and returning to work after a certain quarantine period occurs at the end. However, it may be still possible that work impairment could cause increased psychological distress. The associations observed in this study should be replicated in future research using a longitudinal design. Fifth, discrimination was assessed using an unvalidated question since there was no specific scale to measure discrimination towards COVID-19 survivors. Finally, information on some important participant characteristics, such as a history of mental health disorders, was not available and could not be adjusted for.The study had several limitations. First, the study participants were recruited at two COVID-19 hospitals in Hiroshima, and our findings should be interpreted in the context of Japanese society and culture. When considering pandemics such as COVID-19, we must take into account cultural perceptions and ways they may affect symptom recognition, access to care, treatment provided, and fear of stigmatizationDiscrimination affects approximately one-third of COVID-19 survivors and plays an important role in the development of psychological distress and work impairment. COVID-19 sequelae are also a risk factor for both problems. However, sequelae exert their effect on work impairment mainly via psychological distress, implying the importance of psychological monitoring and support after discharge. Future research with experimental design should be conducted to develop effective intervention programs to prevent or lessen psychological distress and work impairment in COVID-19 survivors.Supplementary Information.


The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide among individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. These guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. The ultimate judgement regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. On the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set out in the guidelines when, in the reasonable judgement of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to the publication of the guidelines. The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognised that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.− decay to stable hafnium-177 with a half-life of 6.647 days Lu-DOTA-TATE (Lutathera®) was approved for the treatment of progressive, well-differentiated somatostatin receptor-positive gastroenteropancreatic NETs following the results of phase 3 NETTER-1 trial. The trial randomly assigned 229 patients with well-differentiated metastatic midgut NETs to receive either [177Lu]Lu-DOTA-TATE  plus long-acting somatostatin analogues or long-acting somatostatin analogues alone. Twenty-month projected progression-free survival (PFS) was 65.2 vs. 10.8% in the treatment and the control arm, respectively (p < 0.0001). The [177Lu]Lu-DOTA-TATE treatment produced only transient haematological toxicity, with grade 3/4 neutropenia, thrombocytopenia, and lymphopenia occurring in 1%, 2%, and 9% of patients, respectively Lu-SSRT and [177Lu]Lu-PSMA are administered intravenously, the blood elements are the first to be exposed to radiation. The major determinant of radiation exposure of the haematopoietic stem cells is radiopharmaceutical circulation within the bone marrow. However, specific targeting mechanisms to more differentiated blood cell progenitors may also contribute. For instance, SSRs are overexpressed on activated leucocyte subtypes, such as lymphocytes and monocytes . Additio7LuLu-SSRWeak but significant correlations between image-based estimates of the red-marrow absorbed dose and haematological toxicity have been demonstrated –40. MoreAbdominal organs are irradiated in [177Lu]Lu-SSRT and [177Lu]Lu-PSMA therapies due to radiopharmaceutical-specific uptake or their physiological excretory functions. The kidney is generally considered the dose-limiting organ in therapy with [177Lu]Lu-SSRT, owing to unspecific uptake mechanisms by proximal tubular cells . Acute rThe liver is generally not considered an organ at risk for [177Lu]Lu-SSRT or [177Lu]Lu-PSMA therapies, and the liver function has been shown to improve after [177Lu]Lu-SSRT therapy . HoweverThe major salivary glands comprise three pairs of glands, the parotid, submandibular, and sublingual glands. Recently, a fourth pair of salivary glands were identified after analysing [68Ga]Ga-PSMA PET imaging, the tubarial glands in the nasopharynx region . RadiatiThe lacrimal glands are paired exocrine glands in the upper lateral region of the two eye orbits. [177Lu]Lu-PSMA exhibits accumulation in the lacrimal glands , which hThe pituitary gland, or hypophysis, is located at the base of the brain in a skeletal hollow termed sella turcica (“Turkish saddle”). It has a high expression of SSRs and is thus targeted by [177Lu]Lu-SSRT. Radiation exposure may affect the hypothalamic-pituitary axis, a key regulator of endocrine function. Different hormone-secreting cell types have different radiosensitivity, with somatotropic and thyrotropic cells being the most and least radiosensitive pituitary cells, respectively. In EBRT, an absorbed dose limit of 20 Gy is recommended to avoid growth hormone (GH) deficiency. The absorbed dose limit for panhypopituitarism is 45 Gy . ComplexIn [177Lu]Lu-SSRT therapy of NETs current evidence points at the existence of relationships between the absorbed dose and response, although data are yet limited and the target absorbed dose for an effective treatment is to be defined. A tumour-volume reduction was observed in the therapy of mixed NETs using 86Y-based dosimetry for [90Y]Y-DOTA-TOC therapy . For 17, 73. ForFollowing the medical internal radiation dose (MIRD) formalism –78, the The mentclass2pt{minimIt is noted that From Eqs.  density , 82, 84.to unity . This obEquation resented , 87.For source regions with high activity accumulation and retention, located in a surrounding with modest activity, the self-absorbed dose is generally the dominant contributor for 177Lu. The self-absorbed dose is, in turn, dominated by the electron emissions, since: (i) y organs . The appentclass1pt{minimaentclass1pt{minimasoftware . Table 2As noted, for the kidney and spleen, the product mass × mentclass2pt{minimAs noted, the self-absorbed energy from Olinda v.1, Olinda v.2.2, and IDAC-Dose 2.1 are consistent, and for target regions with a mass between 2 and 300 g, the values agree to within 2%. The values for Olinda v.2.1 are for unknown reasons lower and inconsistent with Olinda v.1 and v.2.2. While the importance of the photon contribution increases as the dimensions of the source/target region increase, there is for smaller regions an increasing escape of electron energy. Both effects cause a difference with respect to the LED value. However, for source/target regions with comparably convex shapes and mass between approximately 2 and 300 g , the self-absorbed dose calculated by LED is within 1–2% from that using In principle, the MIRD formalism is not limited to a specific geometry. When the source is located in a point in a uniform medium and the deposited energy scored in symmetric shells around the source, the el (DPK) . Likewises (VSV) , 90. Foroperties . For 177ribution . From EqWhen a voxel-wise map of the mass density Equation Different activity uptakes and excretion rates can produce the same absorbed dose, although the absorbed dose rates differ. In EBRT and brachytherapy, the absorbed dose rate is known as a modifying factor for the radiobiological effects, owing to cellular repair during radiation exposure. [177Lu]Lu-SSRT or [177Lu]Lu-PSMA therapies are characterised by low absorbed dose rates in comparison to most other radiotherapy techniques. Fractionation is another factor associated with cellular repair and tissue recovery, especially for late-responding tissues. This is considered in therapies with [177Lu]Lu-SSRT or [177Lu]Lu-PSMA, which are generally given in repeated cycles (or fractions), with a pre-defined cycle interval. An additional modifying factor is nonuniform radiation exposure, which, owing to the short electron range of 177Lu, is characteristic for these therapies.The biologically effective dose  , 109. ChThe PVE is relevant in most cases of 177Lu dosimetry. It is essentially a result of the limited spatial resolution of SPECT systems, which produces a blurred version of the underlying activity distribution. Assessment of PVEs can be made by phantom studies of a set of inserts covering a range of clinically relevant volumes. The same parameters for image acquisition and reconstruction as used in patient studies are applied. The recovery coefficient It is recommended to use the same SPECT/CT system for the entirety of the dosimetry study. Medium energy collimators are recommended for 177Lu imaging for most systems. Although 177Lu has two photo peaks (113 and 208 keV), commonly only the 208 keV photopeak is used for quantitative imaging with NaI-based gamma cameras, as this peak contains considerably less scatter than the 113 keV window . For sysunt rate , 106. AsQuantification of the activity A robust and consistent segmentation strategy needs to be maintained for VOI delineation. Furthermore, the segmentation method needs to be applicable for all imaging time points and across patients. The practical implementation of SPECT image segmentation depends partly on the image data available. For hybrid SPECT/CT systems, VOI delineation for organs is preferably made using CT information. Due to organ motion between the CT and SPECT acquisitions, the VOI positions may require adjustment to the SPECT data set. For tumours, VOI delineation on a low-contrast CT is often challenging, and a co-registered contrast-enhanced CT or the SPECT image may then be useful. Techniques used for SPECT image segmentation include manual operator delineation, fixed-percentage thresholds , adaptivThe absorbed dose can be reported for whole organs, tumours, or parts of these, although the limitations associated with spatial resolution and noise need to be respected. Segmentation of parts of large organs, such as the liver, may be useful to assess regional differences in absorbed dose if there are pronounced clusters with different activity concentrations.Although planar imaging is known to suffer from superposition of activity in tissues that lie above or below the source region to be analysed, there are still applications within 177Lu dosimetry. These include estimation of the total-body TAC for tissues where the cross-absorbed dose from the photons emitted by 177Lu is important, as may be the case for bone-marrow. Other applications include dosimetry for salivary, lacrimal and pituitary glands. Planar image-based activity quantification has been described in MIRD Pamphlet 16 , and theEarlier methods for planar image-based activity quantification were based on patient acquisition early after administration before the patient had voided. A conversion factor was calculated from the image counts over the whole body divided by the administered activity. This conversion factor was then assumed to take all physical effects into account, i.e. both the system sensitivity and effects of photon attenuation and scattering, thus neglecting the variation in these phenomena across the patient body.A preferable method is to determine the calibration factor separately and then apply corrections for attenuation and scatter. The planar calibration factor, activity , 124. ToRegarding the collimator and energy window settings, the same recommendations apply for planar as for SPECT image acquisition. The matrix size is often 1024 × 256, covering the patient’s length. The couch velocity is adjusted to the expected count rate at patient imaging and may vary for the different time points after administration.-1 Lu-PSMA and [177Lu]Lu-SSRT, particularly focusing on the pharmacokinetics of the kidney. Characterisation of the early-phase kinetics of [177Lu]Lu-DOTA-TATE was achieved by dynamic scintigraphy for the first 60 min post-administration . It was The accuracy of the TIA estimate will depend on the characterisation of the TAC. Figure For trapezoidal integration, in Figure Random and systematic errors will also affect the accuracy of the TIA estimate. Trapezoid methods will be more influenced by these errors. The fitting of analytical functions to the data will be less influenced by random errors, which can be further reduced by increasing the number of data points acquired. Advanced techniques for deriving the appropriate TAC function include statistical tests  and pharIt is generally not recommended to routinely perform absorbed dose calculations based on a single time point. However, as shown in recent publications on [177Lu]Lu-SSRT and [177Lu]Lu-PSMA therapies –142, it 3 filled with 7.4 GBq: without clearance, this would lead to an absorbed dose in the order of 1400 Gy. However, neither for [177Lu]Lu-SSRT Lu-SSRT –146 nor ]Lu-SSRT , 148 any]Lu-SSRT –146. Abs]Lu-SSRT , 150. Th]Lu-SSRT .Extravasation monitoring is often made by whole-body planar imaging. However, the risk of false negatives should be considered in cases where the patient’s arm is on the border of the camera FOV. A gamma-probe can be used to measure the count rate at the injection site, enabling relative measurements and an accurate determination of the rate of washout. In case of extravasation, SPECT imaging is advisable to determine the volume of the infiltrated tissue and to quantify the activity. Typically, two or three imaging time points at 2, 4, and 24 h are sufficient to estimate the TAC. Alternatively, one SPECT image at an early time-point can be used in conjunction with probe measurements at the injection site. The estimated absorbed doses will in most cases be uncertain due to difficulties of determining the exact volume of the infiltrated tissue. A relevant range of volumes can be applied to assess the uncertainty in the estimated absorbed dose.The kidney is probably the most well-examined organ in terms of dosimetry for 177Lu therapy. For both [177Lu]Lu-SSRT and [177Lu]Lu-PSMA therapies, there is renal transit, and especially for [177Lu]Lu-SSRT also renal accumulation, making the kidneys a treatment-limiting organ. Dosimetry-guided treatments have been applied that tailor the number of therapy cycles and/or the administered activity per cycle with respect to the renal absorbed dose. The intent is then to achieve the maximum possible absorbed dose to tumour while respecting constraints for the kidneys.The kidney absorbed dose levels in therapies with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA are of a similar magnitude. Mean absorbed doses range between 0.54 and 1.00 Gy/GBq for [177Lu]Lu-SSRT , 151 andThe ranges of the reported values can be associated with different patient characteristics such as renal function and tumour burden, the use of different amino-acid solutions for renal protection, and methodological aspects, such as the selection of imaging time points and methods used for activity quantification and dosimetry. The variability due to patient-specific factors is reflected by the reported absorbed dose ranges from single centres. For [177Lu]Lu-PSMA, the minimum and maximum absorbed doses vary with up to a factor three , 21, 23 There is also an intra-patient variability in the absorbed doses across therapy cycles with [177Lu]Lu-SSRT , 154–157Owing to the inter- and intra-patient variability in the absorbed dose per unit of administered activity, administering a fixed amount of activity across a fixed number of therapy cycles results in a highly variable cumulative kidney absorbed dose.Kidney dosimetry based on planar imaging has been shown to overestimate or result in less precise absorbed dose estimates compared to dosimetry based on quantitative SPECT/CT , 159. St3 Lu-SSRT with a median value across all studies of 50 mGy/GBq (range: 2–150 mGy/GBq) , 171–173The total-body TAC for [177Lu]Lu-SSRT is generally biphasic, with effective half-lives of 1.3 (0.9–1.5 h) and 50 h (45–57 h) , althougThe blood TAC for [177Lu]Lu-PSMA also follows a biphasic pattern, with reported effective half-lives of 0.16 ± 0.09 and 10.8 ± 2.5 h . The expThe red-marrow absorbed dose can either be indirectly estimated from image-based methods, or from blood-based measurements . The meamentclasspt{minimaue Table . The facdy scans , 38, hybdy scans , or SPECdy scans . With seThe absorbed dose to blood has been used to investigate correlations to the expression of biomarkers for DNA damage . The meaThe entclass1pt{minimaor 177Lu , 45.Specific uptake in the skeleton is of concern for patients with bone metastases, which is generally observed in end-stage prostate cancer . In such ICRP 89 . Table 4ICRP 133 , where tMeasurement of the activity concentration in the blood remains the most common method for red-marrow dosimetry. Sampling time points should be chosen to capture both the early TAC peak and the slower washout phase. An example sampling schedule is directly after administration, 10 min, 30 min, 60 min, 90 min, 120 min, 360 min, 24 h, and one later time-point. Image-based estimation of the red-marrow TAC can also be made using sequential planar or SPECT/CT whole-body imaging , 178. TyAbsorbed doses to salivary and lacrimal glands following [177Lu]Lu-PSMA therapy are summarised in Appendix 1, Table The pituitary gland has a high expression of SSRs Fig. . AbsorbeFor the three pairs of salivary glands, the parotids have typical dimensions smaller than 5 cm in all directions, submandibular and sublingual glands have typical dimensions smaller than 4 cm and 2 cm, respectively . The tot3 for individuals aged 50 years or more [Individual mass estimation of salivary glands for [177Lu]Lu-PSMA dosimetry is generally only made for the parotid and submandibular glands. Reported ranges are 31–43 g for both sets of glands . Another or more .Activity quantification for salivary, lacrimal, and pituitary glands during [177Lu]Lu-PSMA or [177Lu]Lu-SSRT therapies was mostly based on planar imaging , 188. InAlthough the use of planar-based activity quantification is recognised to suffer from the superposition of activity located in different tissues, for salivary and lacrimal glands the count contribution from overlapping tissues can be expected to be modest at later time points. However, at early time points (<3 h) activity in larger blood vessels may interfere with the activity estimate. Due to the small dimensions of these glands (<30 mL), the PVEs are large. In one study based on 3 SPECT/CT images, VOIs that included a 1- to 2-cm margin were applied to quantify activity in salivary and lacrimal glands . Given tTACs of [177Lu]Lu-PSMA within the salivary and lacrimal glands exhibit an increase up to approximately 24 h post-administration and a constant rate of washout beyond this point . ConcernMost of the reported absorbed dose values have been calculated based on using CT , 23, or using CT  correspousing CT . LacrimaThe ICRP 110 reference computer models include the salivary glands , and \doOpenDose , IDAC-DoOpenDose , as wellAs noted, the differences between the values in Table culation . For absLacrimal glands are not included in the ICRP110 phantom, and precomputed  earlier , which c earlier , 189.The pituitary gland is included as a target region in OpenDose, which is thus the recommended Dosimetry for salivary, lacrimal, and pituitary glands presents new and challenging tasks for physicists and physicians involved in [177Lu]Lu-SSRT and [177Lu]Lu-PSMA therapies. The challenge is mostly related to the small volume of these glands, which makes the patient-specific mass estimation difficult. For lacrimal and pituitary glands, dosimetry can be made assuming a standard mass that should preferably be varied across a realistic range to obtain an estimate of the uncertainty introduced by the mass assumption. Another challenge is the lack of studies that include sequential SPECT/CT over these glands. Thus, to date, there is no standardised approach for dosimetry for these glands. However, SPECT/CT-based dosimetry is encouraged as it is expected to provide important dosimetry data and a better understanding of the levels of the absorbed doses delivered.Dosimetry results for tumours in 177Lu]Lu-SSRT therapy are summarised in Appendix 2, Table 7LuLu-SSRTable Whilst early studies used planar-based activity quantification of [177Lu]Lu-SSRT, there is a general transition towards sequential SPECT/CT or hybrid planar-SPECT/CT protocols. For [177Lu]Lu-PSMA, planar image-based activity quantification is still employed, possibly due to the large imaging FOV required to cover the entire extent of disease. For [177Lu]Lu-SSRT, a comparative study of different methods for activity quantification in the same cohort of patients reported tumour absorbed doses of 2.6 ± 1.5 Gy/GBq when using SPECT/CT only, 3.1 ± 2.2 Gy/GBq using a hybrid planar-SPECT/CT approach, and 5.3 ± 6.3 Gy/GBq using planar quantification . Median Between three and five image acquisitions have generally been included, where the timing of the last acquisition has varied between 72 (3 d) and 168 h (7 d). To our knowledge, an explicit comparison of the impact of a late acquisition time has not been made for tumour dosimetry. However, the long biological half-life for tumours warrants a late time point. Most studies used Tumour dosimetry requires SPECT/CT for activity quantification, preferably using sequential SPECT/CT, or otherwise a hybrid planar-SPECT/CT approach. For the latter, only tumours that are not overlapped with other tissues with a pronounced activity accumulation can be included . ApplicaNotable advances have been made in the field of radionuclide therapy with the introduction of new targeting molecules, radionuclides, equipment, technology, and methods for activity quantification and dosimetry. In parallel, theranostic approaches are expanding and the evidence of dose-effect correlations increasing , 196–198The absorbed dose tolerance of radiosensitive organs and the tumour absorbed doses required for treatment efficacy are not yet established. Organs at risk for therapy with [177Lu]Lu-SSRT are considered to be the kidneys, bone marrow, and possibly the pituitary gland. For [177Lu]Lu-PSMA therapy, the primary organs at risk are the parotid and lacrimal glands and bone marrow. The radiobiological reactions of the bone marrow and parotid glands are manifested both early and late, while kidneys and pituitary gland are generally regarded as late-responding tissues. Several studies have addressed dose-effect investigations for therapies with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA. Relationships between tumour diameter or volume reduction and the absorbed dose evaluated at the time of best response were observed in [177Lu]Lu-SSRT therapy of NET , 73. ForLarge intra- and inter-patient variabilities in absorbed doses delivered during therapies with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA have been demonstrated in several studies, both regarding tumours and normal organs , 140. ThThe practical implementation of dosimetry requires imaging at several time points after administration. For most of the tissues of dosimetry interest in therapy with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA, we find that three acquisitions, well separated in time, are sufficient to capture the pharmacokinetics. Generally, the last image should be acquired at a time beyond the effective half-life for the particular tissue, and especially for tumours, this extends to many days after administration. For tissues where the typical pharmacokinetics is well known from previous patient cohorts, proposals have been made of using a lower number or even a single acquisition time point for dosimetry –141. TheTherapies with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA are to be envisaged in an overall framework of precision medicine, involving imaging, clinical data, genetics, dosimetry, and radiobiology. As with other biomarkers, dosimetry data do not represent the only predictive parameter, but it is regarded as one among others that need to be taken into account. 177Lu is well suited for imaging and dosimetry-guided treatment schedules and can achieve the prerequisites for multicentre comparability. In addition, from a radiation protection point of view, there are legislative obligations of performing dosimetry for therapeutic nuclear medicine .There is a growing body of data on absorbed doses to organs and tumours in treatments with [177Lu]Lu-SSRT and [177Lu]Lu-PSMA. Together, such data provide an improved understanding of these therapies and may, in the long run, lead to the development of dosimetry-guided treatment protocols. The methods outlined in this report are not prescriptive but aim to harmonise data collection between centres in order to obtain comparable data. The methods should be within reach for all cancer centres that offer therapy with 177Lu-labelled compounds.


Approximately 80% of breast cancers are estrogen receptor-positive (ER+), and 68–80% of those occur in premenopausal or perimenopausal women. Since the introduction of tamoxifen for adjuvant endocrine therapy in women with non-metastatic ER+ breast cancer, subsequent trials have demonstrated an oncologic benefit with the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy. Subsequently, therapies to either suppress or ablate ovarian function may be included in the treatment plan for patients that remain premenopausal or perimenopausal after upfront or adjuvant chemotherapy and primary surgery. One strategy for OFS, bilateral salpingo-oophorectomy (BSO), has lasting implications, and the routine recommendation for this strategy warrants a critical analysis in this population. The following is a narrative review of the utility of ovarian suppression or ablation  in the context of adjuvant endocrine therapy, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The long-term sequelae of bilateral oophorectomy include cardiovascular and bone density morbidity along with sexual dysfunction, negatively impacting overall quality of life. As gynecologists are the providers consulted to perform bilateral oophorectomies in this population, careful consideration of each patient’s oncologic prognosis, cardiovascular risk, and psychosocial factors should be included in the preoperative assessment to assist in shared decision-making and prevent the lifelong adverse effects that may result from overtreatment. Approximately eighty percent of breast cancers diagnosed in premenopausal women are estrogen receptor-positive (ER+) ,2,3. ThePremenopausal breast cancer is associated with distinctive risk factors, tumor characteristics, and clinical outcomes that oftentimes warrant additional therapy . There ip = 0.009). However, women deemed “low-risk” and thus not requiring adjuvant chemotherapy in this trial still did extremely well on tamoxifen alone, with an overall survival of 98.8% [A 2007 meta-analysis demonstrated a reduction in recurrence in women with ER+ breast cancer when an ovarian function suppressor (OFS) was combined with tamoxifen . A more The publication of this and subsequent trials demonstrating the benefit of OFS when added to adjuvant endocrine therapy has led to the addition of suppression or ablation of ovarian function for most women with premenopausal breast cancer. As such, medical oncologists may refer these patients to gynecologists for consideration of BSO, a single operation, instead of monthly or tri-monthly injections of a GnRH agonist to achieve suppression, especially in cases of continued menstruation after primary treatment .BSO is associated with long-term adverse effects in both premenopausal and postmenopausal populations. These risks include cardiovascular disease, stroke, accelerated bone density loss, and mood disorders ,12,13,14Long-term survival continues to improve with the addition of adjuvant CDK 4/6 inhibitors to high-risk premenopausal patients with ER+ breast cancer; however, long-term sequelae of permanent ovarian ablation will vary from patient to patient . As a reAn electronic search was conducted to identify relevant publications in PubMed since the year 2000. The following (MESH) terms were used and combined: oophorectomy, salpingo-oophorectomy, breast cancer, breast neoplasms, endocrine therapy, premenopausal breast cancer, adverse effects, quality of life, cardiovascular effects, and bone density. Eligibility was assessed by FK and PJ, and discrepancies were resolved through discussion. Publications evaluating cancer-related outcomes of BSO after a diagnosis of ER+ premenopausal breast cancer and publications evaluating long-term effects of BSO regardless of cancer history were included. Specifically, we searched studies that provided a comparison of overall survival (OS) or disease-free survival (DFS) between individuals who received BSO and those in a control group. Regarding long-term effects, we focused on studies that provided adequate measurements of risk in individuals who received BSO compared to those in a control group. We also sought data examining cost and quality of life. Publications were considered for review if they were randomized controlled trials (RCTs), cohort studies, retrospective studies, reviews, and cost analyses. Publications were excluded if they: (1) were not in English; (2) evaluated BSO surgical technique only; (3) did not use BSO as the primary independent variable; (4) were case reports; (5) were non-clinical ; or (6) included only women undergoing prophylactic surgery for HBOC syndrome.Our initial search yielded 446 publications, 417 of which were excluded after full-text screening, leaving 30 for inclusion in this review . The incAdditional studies report similar or slightly improved outcomes with the addition of OFS to endocrine therapy, alongside high rates of adverse effects.Tamoxifen, a SERM, is an integral component of the adjuvant treatment of premenopausal ER+ breast cancer treatment, and is recommended by the NCCN Clinical Guidelines in Oncology and the 2014 American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines based on level 1 evidence ,20,21. Sp = 0.56) or OS  [The Adjuvant Breast Cancer (ABC) Ovarian Ablation or Suppression Trial included 2144 participants with perimenopausal or premenopausal breast cancer, all of whom received tamoxifen with or without chemotherapy and who were randomized to receive either OFS with tamoxifen or tamoxifen alone. At 5.9 years, there was no significant difference in the OFS vs. non-OFS arms in relapse-free survival  .p = 0.0003 and p = 0.0002, respectively) [In a sample of 709 premenopausal women with breast cancer, a 2008 phase III randomized trial found that seven-year DFS and OS were significantly improved after receipt of BSO plus tamoxifen compared to those of the control group (ctively) . Notablyp = 0.004) [The 2014 phase III Eastern Cooperative Oncology Group (ECOG 3193) trial randomized 345 women with node-negative ER+ breast cancer to either tamoxifen alone or tamoxifen and OFS, where none of the enrolled patients received chemotherapy. There was no significant difference in the 5-year rates of DFS or OS between the arms. Notably, grade 3 toxicities were twice as high in patients who received OFS  .p = 0.009) [The combined analysis of the randomized Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT) sought to determine the benefit of the addition of OFS to either tamoxifen or exemestane, an aromatase inhibitor, in premenopausal women with early-stage ER+ breast cancer. The 8-year results from SOFT found a disease-free survival (DFS) of 78.9% with tamoxifen alone, 83.2% with tamoxifen plus OFS, and 85.9% with exemestane plus OFS (p = 0.033) [The 2020 ASTRRA trial was a randomized phase III study allocating 1483 premenopausal women with ER+ breast cancer to either five years of tamoxifen alone or five years of tamoxifen with OFS for two years. Most patients received OFS through a monthly injection of a gonadotropin-releasing hormone (GnRH) agonist. The five-year DFS was significantly greater in the group that received an additional two years of OFS  . However= 0.033) . There wOverall, the addition of OFS confers a greater DFS and OS in many of these studies. While these studies did not directly compare BSO to non-surgical methods of OFS, the statistically significant differences in DFS in these studies were achieved largely by non-surgical methods of OFS. Therefore, the irreversibility of BSO and its associated risks may not afford an additional oncologic benefit, especially in high-risk women who are likely to receive chemotherapy or CDK 4/6 inhibitors in the neoadjuvant or adjuvant setting ,27.Many scholarly reviews also offer perspectives regarding the value added by OFS. In a review of OFS combined with various adjuvant endocrine therapy modalities, Jain et al. determined that the benefits of OFS plus tamoxifen are best achieved among higher-risk populations, defined as women under 40 years with higher grade and stage, lymph-node-positive disease, among other factors . Citing While OFS shows gains in DFS when added to tamoxifen in younger patients with more advanced disease who may not be candidates for chemotherapy, the benefits of surgical OFS in average-risk women in resource-rich settings are less likely, and need to be evaluated on a case-by-case basis.Aromatase inhibitors (AIs) have become a standard of care for the adjuvant endocrine treatment of most postmenopausal women with early-stage ER+ breast cancer. Although the use of aromatase inhibitors alone is generally contraindicated in premenopausal women due to the stimulation of estrogen production in functioning ovaries, the combination of OFS with an AI in premenopausal women is a potential strategy for adjuvant therapy for high-risk women.There are very few studies that directly compare OFS and ovarian ablation through surgery or radiation when combined with an aromatase inhibitor. In the landmark MONARCH-E trial, high-risk patients with ER+/Her2- breast cancer were randomized to receive either adjuvant endocrine therapy alone or adjuvant endocrine therapy with the CDK 4/6 inhibitor abemaciclib. “High-risk” was defined as having four or more positive axillary lymph nodes on surgical pathology or one to three positive nodes with any of the following: tumor size ≥ 5 cm, grade 3, or high ki-67 (>20%). Endocrine therapy included AI+/-OFS and tamoxifen +/-OFS, depending on the patient’s menopausal status. Approximately 45% of the patients were premenopausal, but only half received OFS. The addition of the CDK 4/6 inhibitor abemaciclib to endocrine therapy resulted in a 25% reduction in the risk of an invasive event over a median follow-up period of 15.5 months. This risk reduction was even greater (37%) in patients who were premenopausal at the time of randomization. Comparative DFS analyses between therapy strategies, such as tamoxifen alone vs. endocrine therapy with OFS, in the premenopausal subgroup have not been reported.However, any benefit to one strategy over another is tempered by the benefit afforded with the addition of the CDK 4/6 inhibitor . As suchp = 0.245). Most patients in both arms achieved a clinical response after six months, and there was a significantly higher proportion of patients in the BSO group compared to the GnRH group  [In a retrospective analysis of 66 premenopausal women with recurrent or metastatic breast cancer, BSO plus AI treatment did not result in a significantly higher progression-free survival when compared to patients who received OFS with a GnRH antagonist plus an AI  . Interesp < 0.001) [Several studies have noted an association between early BSO and an increased risk of cardiovascular death, which is the leading cause of death in women living in the United States ,31,32. I< 0.001) ,34. Thou< 0.001) ,35,36. T< 0.001) . A revieGiven that estrogens and androgens inhibit bone resorption, the decline in estrogen from natural menopause or BSO has significant implications for bone health. A phase II randomized controlled trial of 80 women with breast cancer not on aromatase inhibitors but with a history of BSO demonstrated a mean reduction in bone mineral density of 8.5% in the lumbar spine and 5.7% in the hips over 18 months, which translates to an increased risk of fracture .Additionally, a prospective study of 270 Asian women previously treated with BSO for premenopausal breast cancer found a reduction in bone mineral density of 4.7% in the lumbar spine . Taken tp < 0.05, two-sided) [The effects of BSO have the potential to impact overall quality of life in several aspects, including vasomotor symptoms. BSO is an independent predictor of vasomotor symptoms in postmenopausal women treated for breast cancer , and was the most prominent quality-of-life symptom reported among women under the age of 35 years in the TEXT/SOFT trials . In a coo-sided) . BSO, asIn the Nurses’ Health Study, an ongoing prospective cohort study of over 15,000 women, BSO at any age for any indication was associated with an increased risk of death from all causes  . This elWhile our analysis illustrates either modest or no improvement in survival associated with OFS in patients with ER+ premenopausal breast cancer, additional retrospective analyses are necessary to elucidate the prognosis and sequelae associated with BSO exclusively. There is an ongoing clinical trial (NCT02440230) that aims to assess the safety of OFS with anastrozole compared to that of OFS with exemestane in Chinese premenopausal breast cancer patients. However, there is no treatment arm that does not receive OFS, and like in SOFT/TEXT trials, the method of OFS includes a mix of goserelin, a LHRH agonist, ovarian irradiation, and BSO.A 2016 review by Love et al. concluded that BSO with tamoxifen is an effective therapy for ER+ premenopausal breast cancer, particularly in resource-limited settings, as one-third of annual new cases of breast cancer globally are now hormone receptor-positive tumors in premenopausal women from low- and middle-income countries . As suchAdditionally, BSO is associated with an increased risk of cardiovascular death, especially amongst women with a family history of CVD. Furthermore, BSO increases the risk of osteoporotic fracture and impacts sexual function. Thus, the role of BSO for adjuvant permanent ovarian ablation in premenopausal women with ER+ breast cancer, considering the long-term sequelae, should involve a thoughtful multidisciplinary discussion between providers along with patient-shared decision-making.The value added to endocrine therapy by BSO has also been examined under an economic lens. In a cost–benefit simulation model, tamoxifen alone was associated with the highest life expectancy gain (18 years) at the lowest cost (USD 1566) . Adding The challenge in determining the isolated potential benefit from BSO as an OFS strategy is that in large landmark trials that provide rich data, BSO and medical OFS are often analyzed together, making it difficult to ascertain differences between these subsets of OFS. Furthermore, only a handful of studies have directly examined ovarian suppression or ablation against BSO in the context of breast neoplasms, as both methods have been shown to be effective in suppressing ovarian function ,52. TherA recurring theme in many of the studies included in this review is the conclusion that BSO is best reserved for individuals with high-risk disease. However, “high-risk” can be a subjective determination based on the variety of different criteria used in these studies, including node status, grade and stage, and the age of the patient. Additionally, the conclusions made in the landmark trials we have discussed are based on relatively small samples of participants. In SOFT, only 8% of the patients undergoing OFS received BSO, making the results of this trial difficult to generalize when considering BSO specifically.Premenopausal women diagnosed with ER+ breast cancer represent a cohort with unique challenges apart from coping with the stress of a diagnosis. Long-term survival in women living with breast cancer is steadily increasing due to improvements in early diagnosis and advances in cancer treatments and surveillance . Despite


Introduction: Coronavirus disease 2019 (COVID-19) generates a cytokine storm that predisposes patients to systemic complications including arterial thrombosis (AT) and acute limb ischaemia (ALI). This study reviews our understanding of the incidence and outcomes of patients with COVID-19 who develop AT.Methods: The case notes of all emergency patients with COVID-19 referred to the vascular services between March 2020 and March 2021 were reviewed. The study was undertaken to measure 30-day outcomes. Additionally, a literature search was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following search terms: acute limb ischaemia OR arterial thrombosis OR thrombectomy OR embolectomy AND COVID-19.Results: During March 2020 and March 2021, 60,000 people tested positive for COVID-19 in Norfolk. A total of 33 patients were referred to the vascular services, of which 15 had AT (estimated incidence of 0.03%). Of AT patients, 93% had ALI. Fourteen locations of AT were identified. Of ATs, 36% were infrainguinal. The 30-day mortality was 60%. Three patients underwent surgery: two embolectomies (one requiring subsequent below-knee amputation (BKA) and the other died) and one primary BKA requiring subsequent above-knee amputation. The 30-day amputation-free survival (AFS) rate was 29%. The literature search identified 361 studies prior to a thorough full-text review. Nine case series were included with more than 10 participants each. The incidence of AT was reported as high as 15%. In-hospital mortality was 40%, with a significant proportion undergoing amputation or palliative care. Approximately a third of patients undergoing revascularisation subsequently re-occluded. AFS remained as low as 25%.Conclusion: The incidence of AT within the vascular surgery territory in COVID-19 patients is low; however, it is associated with poor 30-day AFS. A computed tomography angiography protocol including the entire major vessels may be indicated in COVID-19 patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral illness, which has the tendency to predispose patients to vascular emergencies including arterial thrombosis (AT) and acute limb ischaemia (ALI). ALI affects around 14/10,000 individuals per year and composes 16% of the vascular workload, with AT being the most challenging subtype to treat [Respiratory symptoms and complications dominate the presentation of coronavirus disease 2019 (COVID-19); however, recent studies have shown the pathogenesis of the disease is more of a hypersensitivity pneumonitis as opposed to viral pneumonia. It is now more widely understood as a systemic disease. The exact mechanism of ALI in patients with COVID-19 is not yet well understood, but several theories have been proposed. It is thought that a cytokine storm activates coagulation factors and inhibits fibrinolysis, causing a hypercoagulable state. In addition to this, COVID-19 invades human cells through angiotensin-converting enzyme 2 (ACE2) receptors, leading to endothelial damage from inflammation and, subsequently, coagulation . HospitaCoronaviridae family as COVID-19, showed 11 episodes of deep vein thrombosis (DVT) and seven episodes of proven or suspected pulmonary embolism (PE) in the cohort [Thrombotic events including venous thromboembolism (VTE) and AT following alternative viral infections are uncommon, yet not unheard of. A retrospective study of 46 critically ill patients with the severe acute respiratory syndrome (SARS), a virus which belongs to the same e cohort . More reRecognising the presence of AT in patients with COVID-19 is important as it prevents mortality and amputation rates through early intervention. Current guidelines recommend anticoagulation with heparin as the management of choice in patients with AT as it has shown to decrease mortality . HoweverThere is currently limited published data regarding the vascular complications of COVID-19. This study reviews our understanding of the incidence, management, and outcomes of patients with COVID-19 who develop thrombotic complications, to reduce direct mortality.Case seriesA retrospective case series was performed at the Norfolk and Norwich University Hospital Foundation Trust, a tertiary referral centre. The case notes of all emergency patients diagnosed with COVID-19 who were referred to the vascular services between March 2020 and March 2021 were extracted from hospital medical records and reviewed. This includes hospitalised patients. All cases of COVID-19 were tested with a polymerase chain reaction (PCR) swab and diagnosed as per hospital policies. The study was undertaken to measure 30-day outcomes.The recorded variables included demographic characteristics, past medical history, date of admission, the reason for admission, date of a positive COVID-19 test result, presence of symptoms, arterial imaging findings, management, and mortality. Previous computed tomography angiography (CTA) imaging was used for evaluation. The indication for admission was categorised into COVID-19 and ALI (including upper and lower limb disease); patients who were admitted with stroke or coronary thrombosis were excluded. Management was categorised into anticoagulation, embolectomy, amputation, and palliation. Postoperative complications, as well as the cause of death, were recorded in relevant patients.Systematic reviewA systematic review of case series investigating the incidence and outcomes of COVID-19 and AT was undertaken using PubMed. The following search terms were used: acute limb ischaemia OR arterial thrombosis OR thrombectomy OR embolectomy AND COVID-19. Abstracts of all articles identified were reviewed, as well as articles were reviewed for additional citations. Only studies reporting solely on COVID-19-positive patients were included, with evidence of AT or ALI. Case reports were excluded, as were case series of less than 10 participants. Further studies were excluded following a full-text review.All duplicate studies, articles reviewing coronary or intracranial thrombosis, and studies involving less than 10 participants were excluded. During the screening, data for publication date, demographic characteristics, interventions, outcomes  with mortality rate), and loss to follow up were recorded by two independent reviewers (IS and PS). This was undertaken independently with discrepancies discussed with WAJ. Data extracted included the number of participants, the number undergoing revascularisation, the reintervention rate, and the number of amputations. In addition, the mortality and AFS were recorded.Quality assessmentThere was no risk of bias assessment possible; however, the studies were assessed for quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case series . This coStatistical analysisThe systematic review and data from the case series were analysed using Microsoft Excel  and presented as percentages. There were no comparative data; therefore, no statistical analyses were undertaken.Case seriesA total of 33 COVID-19-positive patients were referred to vascular services between March 2020 and March 2021. Fifteen patients had acute AT (46%), which was significantly higher than any other vascular complication  . Out of Baseline characteristics are presented in Table The 30-day mortality rate for patients with COVID-19 and AT was 60%. The direct primary cause of death was COVID-19 in 67% of these patients. Eight patients were managed conservatively with anticoagulation (53%) and five patients were palliated (33%). Of the remaining three patients, one underwent primary below-knee amputation (BKA), and two patients (13%) underwent embolectomies (one required subsequent BKA and the other died). The 30-day AFS rate was 29%  flow diagram presented in Figure In the selected case series, each had a sample size of 12 to 30 patients, totalling 147. The incidence of AT differed between studies ranging from 12.3% to 76.2% depending on the study population. The incidence of AT in the intensive care unit (ICU) was reported as high as 12%.In-hospital mortality was reported in up to 40% of cases with COVID-19 and ALI, with a mean mortality rate of 31.9%. The palliation rate among the sample reached 13 patients (8.84%). A total of 80 revascularisations took place with 13 reinterventions, predominately occurring due to re-occlusion of the artery. This led to a calculated reintervention rate of 16.3% across seven studies . Furthermore, a significant proportion of patients underwent amputation (17%), with an average AFS rate of 47.1%. This includes both primary and secondary amputations.Quality assessmentAmong the case series, four studies received a perfect score (10/10) and one study had the lowest score (6/10), with an overall mean score of 8.78 Table . Having This case series and systematic review demonstrate the substandard 30-day outcomes for patients who develop AT as a complication of COVID-19. The case series illustrates a high 30-day mortality rate (57%), accompanied by a low AFS rate (29%). These results are consistent with the systematic review, as similar outcomes were identified. The systematic review demonstrates a high mortality rate (40%), alongside a poor AFS rate (44.1%).Comparing the 30-day outcomes of COVID-19 ALI to surrounding literature on non-COVID-19 ALI emphasises the severity of the prognosis. A 10-year prospective study conducted by Howard et al. found a 30-day mortality of 24.7% in non-COVID-19 patients, which was significantly more favourable than the high mortality rate concluded in our case series of COVID-19 patients (57%) . These rThe case series ascertained that the location of AT differed in patients with COVID-19 as the majority of our sample developed thromboses involving more systemic, proximal, and thoracoabdominal vessels. This series reported that 21% of patients had a thrombus in their great vessels, 7% in the superior mesenteric artery, 36% in the proximal limbs, and 36% in the distal limbs. Cases affecting the major vessels including the aortic arch, descending thoracic aorta, mesenteric, splenic, and renal arteries have been associated with a poor prognosis . SurrounWhen assessing the baseline characteristics of each patient, the series reported as high as 73% of patients were hospitalised due to severe infection. This indicates that severe COVID-19 is a significant risk factor for developing thromboembolic complications, which may be attributed to the aggressive nature of severe COVID-19, leading to the development of a cytokine storm and consequently, hypercoagulability [Veyre et al. reported the presence of ALI in a healthy 24-year-old with non-severe COVID-19 and no other predisposing conditions . IncidenCurrent guidelines recommend anticoagulation with heparin as the management of choice in patients with AT as it has shown to decrease mortality . This stThere are several limitations to this study. There was no standardised care protocol for COVID-19 patients referred to the vascular services. Consequently, a small number of our cohort was not evaluated using CTA imaging prior to management due to poor health; therefore, it is only possible to comment on the thrombus location in nine patients, lowering the internal validity of these results. It is likely that not every patient with AT was referred to the vascular services. During the first wave of the pandemic, in particular, staff were reluctant to operate on comorbid individuals, and due to the unprecedented stressors on the healthcare system, the management of severe COVID-19 was prioritised over the treatment of other comorbidities. As a result, some individuals may have been referred straight to ICU with severe COVID-19, rather than via vascular services and appropriately managed or palliated by the intensive care teams. In addition, this study was conducted during the first year of the pandemic prior to the availability and offering of the COVID-19 vaccination programme and the emergence of subsequent variants of the coronavirus. Hence, the study results may not be applicable to the current dominant variants, e.g., Omicron. The systematic review includes only small studies, with no large dataset for patients with COVID-19 and AT. There is a lack of data on patients' vaccination status and its impact on AT outcomes. There are also no randomised or non-randomised data regarding treatment options for AT.The hospital experience of COVID-19 and the review of surrounding literature gave similar results. The incidence of ALI still remains relatively low; however, the 30-day outcomes are poor. COVID-19 plays a vital role in viral-induced hypercoagulability and correlates with the severity of infection, as the majority of our patients were hospitalised. The data from our systematic review showed that COVID-19 was associated with a high incidence of amputation as well as a four-fold increase in mortality compared to non-COVID patients with ALI. Additionally, the majority of patients had more proximal locations of AT and therefore a more widespread CTA may be indicated.