We conducted a prospective, randomized, unblinded superiority trial of the safety and efficacy of modified reporting of positive urine cultures to improve the appropriateness of treatment for asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) in long-term care facilities (LTCFs).Consecutive positive urine cultures collected from LTCF patients were randomized between standard (identification and susceptibility) or modified (without identification and susceptibility) laboratory reports. Exclusion criteria were current antibiotic treatment, neutropenia, or transfer to acute care. The diagnosis of UTI or ASB was made prospectively.P = 0.33). Untreated ASB was higher in the modified report arm: 13/32 (41%) versus 8/30 (27%) . There were two deaths  and 15 adverse events in the modified arm. There were no deaths (P = 0.16) and 11 adverse events (P = 0.43) in the standard arm. Three patients with untreated UTI survived.One hundred and sixty-nine urine cultures were considered, 100 were randomized and included in ITT analysis, and 96 were included in PP analysis. Sixty-two out of 100 (62%) patients had ASB [41/62 (66%) treated] and 38/100 (38%) had UTI [35/38 (92%) treated]. The lab was called to report the identification and susceptibility in 31/51 (61%) modified reports. The rate of appropriate treatment was higher in the modified report arm: 31/51 (61%) versus 25/49 (51%) (+10%, Modified reporting of urine culture improved the appropriateness of treatment by reducing treatment of ASB, but not significantly. Many LTCF prescribers requested standard urine culture reports. Modified reporting may not be suitable for LTCF implementation. If the reason for collection of urine culture is unknown to the prescriber interpreting the positive culture, antibiotics may be given inappropriately for ASB. Traditional antimicrobial stewardship interventions in LTCFs, including education, clinical practice guidelines and prospective audit and feedback, do not directly address the provider’s decision to prescribe in response to the positive urine culture. Modification of the wording of the positive urine culture report may change the interpretation of the result and the consequent patient management/treatment decisions.5 Modified reporting of urine cultures was first described in an observational study.6 We performed two randomized trials previously to evaluate modified reporting of positive urine cultures in acute care, demonstrating improvement in treatment appropriateness in the modified reporting arm.8 Appropriate treatment was defined as both treatment for UTI and lack of treatment for ASB, since the intervention is designed to reduce treatment of ASB without reducing treatment of UTI. The aim of this study was to apply this same modified reporting intervention in LTCFs, to determine if modified reporting improved the appropriateness of ASB/UTI treatment decisions.Laboratory-based antimicrobial stewardship interventions may improve antimicrobial treatment decisions.The study was a prospective, randomized, parallel, unblinded superiority trial comparing two different methods of reporting for positive urine cultures. There were no changes to the trial design during the study.Between 5 November 2018 and 29 June 29 2019, urine specimens received for urine culture testing were inoculated onto blood and MacConkey agar plates, incubated overnight and interpreted according to the standard laboratory procedures at the Public Health Microbiology Laboratory, Division of Laboratory Medicine, Eastern Health, in St. John’s, NL, Canada. This laboratory performs all microbiology testing in the city. Urine specimens submitted from any of the eight LTCFs in the city were assessed prospectively for eligibility using clinical electronic medical records (EMR). The inclusion criteria were urine cultures demonstrating significant growth, collected by midstream or in-and-out catheterization from adult patients (aged ≥18 years) admitted to LTCFs. The exclusion criteria were urine cultures collected from an indwelling catheter, patients not residing in a LTCF (transferred to acute care), pregnancy, initiation of antibiotic treatment at the time of collection, or neutropenia.Physicians in LTCFs were notified about the trial before initiation. Eligible urine cultures were randomized to standard reporting (SR) or modified reporting (MR), prior to reporting in the EMR system. The SR included bacterial count, identification, and antimicrobial susceptibility. The MR withheld this information and stated: ‘This POSITIVE urine culture may represent asymptomatic bacteriuria or urinary tract infection. If urinary tract infection is suspected clinically, please call the microbiology laboratory at (phone number) between 09:00 and 23:00, or the microbiology technologist on-call at (phone number) at night, for identification and susceptibility results’. If a provider contacted the laboratory and requested the SR, the SR was released immediately by telephone and updated in the EMR system. Participants were followed for 30 days after reporting to monitor adverse events and safety outcomes, using the EMR system and paper charts.2 UTI was defined as one or more of: fever (>38.0°C), suprapubic tenderness, costovertebral angle pain or tenderness, increase in urine frequency, increase in urinary urgency, and dysuria. ASB was defined as positive urine culture in the absence of any of these signs or symptoms. Participants were reassessed at 7 days and 30 days by a geriatrician to collect treatment data and study outcomes. There was no communication between study investigators and attending physicians. If participants were discharged during the 30 day follow-up period, health records were reviewed, and the primary care physician was contacted.After culture reporting, the clinical diagnosis of UTI or ASB was determined at 72 h by a geriatrician investigator, using the EMR and completing an assessment using published criteria.3, altered mental status, significant oedema, and hyperglycaemia in the absence of diabetes), or any other new symptom or unscheduled healthcare visit recorded in the medical record.The primary efficacy outcome was the proportion of appropriate antibiotic treatment, defined as treated UTI and untreated ASB. The secondary efficacy outcome was the proportion of requests for SR in the MR arm. A request for SR after receiving MR represents a failure of the MR report to inform the provider’s treatment decision alone, so a request for SR in the MR arm was considered a failure of the MR intervention. Safety was reported as mortality or bacteraemia or other adverse event rate over 30 days. Adverse events were defined using the systemic inflammatory response syndrome (SIRS) criteria  in the SR to 44/55 (80.0%) in the MR.A randomization sequence was generated without blocking or stratification, using Microsoft Excel, Version 1903, by an investigator not involved in enrolling participants. Allocation concealment was maintained by placing the reporting assignments into serially numbered, sealed and opaque envelopes to be opened by investigators at the time of recruitment.The attending physicians and investigators were not able to be blinded to the intervention because the laboratory report revealed the intervention arm. The investigators performed the analysis.All specimens randomized and reported were analysed using ITT analysis. Inappropriately included specimens were excluded from a PP analysis. The proportion of appropriate treatment and subgroup analyses were compared between arms using a two-sided Pearson chi-squared test .The research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. The protocol was approved by the Provincial Health Research Ethics Board on 16 July 2018 (file 2018.121). The requirement for patient consent was waived because physicians were the research subjects. The requirement for physician consent was waived because the intervention posed minimal risk to participants, and awareness of the study may have influenced therapy decisions. Serious adverse events were reported to the ethics committee within 24 h.One hundred and seventy consecutive positive urine culture specimens (participants) were assessed and 70/170 (41.2%) were excluded, see Figure The trial ended when the sample size was recruited.The two groups were comparable, see Table The rate of appropriate treatment was non-significantly higher in the MR arm compared with the SR arm (31/51 (60.8%) versus 25/49 (51.0%), absolute difference = 9.8%, relative risk (RR) = 1.19, 95% CI (0.83–1.69), see Table Among 16/51 31.4%) participants randomized to the MR arm, healthcare workers called the laboratory requesting SR. Among participants who crossed over to the SR arm, appropriateness of treatment worsened non-significantly , see Table 1.4% partP = 0.048), see Table MR had a significantly stronger impact on appropriate treatment among patients with ASB compared with patients with UTI  patients (two deaths during follow-up). There were no deaths in the SR arm. There were two deaths in the MR arm (one untreated ASB and one treated ASB). Both deaths were not considered related to the study intervention, see Table There was one bacteraemia in the SR arm and no bacteraemia in the MR arm. The bacteraemia occurred on Day 22 of the follow-up period. Because the patient received treatment for ASB, the bacteraemia was not considered related to the study intervention.P = 0.45 at 72 h; SR 27/61 (44.2%), MR 34/61 (55.7%), P = 0.20 at 30 days], see Tables P = 0.20]. None of the safety outcomes demonstrated a significant difference between study arms.At 72 h and at 30 days, SIRS occurred more frequently in the MR arm [SR 6/14 (42.8%), MR 8/14 (57.1%), There were three cases of untreated UTI in the MR arm, but these did not result in adverse events or mortality over 30 days.7 if LTCF providers’ beliefs strongly favour treatment of ASB compared with acute care providers. Our study was powered based on the improvement observed using the same intervention in acute care hospitals, but the observed impact in LTCFs was less. Treatment decisions made by LTCF providers were not as strongly influenced by the MR. Despite the lack of statistically significant difference, we have produced evidence to inform sample size calculations for future interventions. Our intervention is a simple and feasible laboratory intervention, which does not require ongoing effort.We hypothesized that MR would improve the appropriateness of treatment in LTCFs. We demonstrated that MR was associated with a non-significant increase in the appropriateness of treatment, without a significant reduction in safety. Although we failed to achieve a significant difference, we measured indicators for future quality improvement. The intention of MR is to influence the interpretation of the positive urine culture away from a decision to treat. The MR does not change the provider’s beliefs about the significance of the urine culture result. For this reason, MR may have less impact in influencing treatment decisions in LTCFs compared with acute care, where we previously reported a significant difference,Sixty-two out of 100 (62%) positive urine cultures in our LTCF study represented ASB. Urine culture should not be collected from patients who do not meet UTI diagnostic criteria. The inappropriate collection of urine cultures promotes treatment of ASB and further intervention may reduce this behaviour.6 MR had a more positive influence on appropriate treatment of patients with ASB compared with UTI, indicating that ASB treatment decision is based on responding to a culture result, as opposed to clinical assessment.In 31/51 (60.8%) of MR reports, healthcare workers called the lab to request the SR, causing significant crossover of these participants from the MR arm into the SR arm. This rate of requests for SR was higher compared with the rate of requests for SR in our previous study in acute care (33.3%).MR did not cause increased death or bacteraemia among LTCF patients; however, a non-significantly higher rate of adverse events and three cases of untreated UTI were observed. The LTCF population has a high rate of mortality and acute illness. We cannot conclude that MR is safe in LTCFs based on our data.We relied on EMRs and clinical data provided by LTCF nursing and physician staff to make the diagnosis of ASB or UTI and collect safety data. If medical records were incomplete, our diagnosis may have been biased towards ASB. Given the randomization, this bias would have a balanced impact in both groups. It was not possible to blind the investigators because investigators accessed final urine culture reports while assessing outcome. This lack of blinding did not influence treatment decisions, because investigators were not involved in treatment decisions; however, awareness of assignment may have influenced outcome assessment.9Our inclusion criteria represented a large proportion of all urine cultures collected from LTCFs, suggesting that our findings may be generalizable to other LTCFs. We excluded urine collected from indwelling catheters because indwelling catheters are associated with a significant increase in risk of UTI.10 Urine culture restriction interventions may be more suitable in LTCFs.11 Access to urine culture could be restricted to specific clinical criteria indicating UTI (‘pre-authorization’). Furthermore, it may be helpful to explore provider attitudes towards UTI diagnosis and treatment in LTCFs.It may be worthwhile to repeat this study in LTCFs; however, we observed a high rate of requests for SR, suggesting that the MR intervention may not be accepted by LTCF providers. In LTCFs, interventions such as education and algorithms have not proven to be effective in improving urine culture ordering or rate of appropriate antimicrobial use.Treatment of ASB is common in LTCFs. Modified reporting reduced treatment of ASB, but not significantly. Many prescribers requested the SR, causing crossover of patients from the MR arm to the SR arm. Modified reporting may not be suitable for LTCF implementation without further study.


Research into the quality of cancer screening programs often lacks the perspective of clinicians, missing insights into the performance of individual hospitals. This retrospective cohort study aimed to identify guideline deviation  related to the cervical cancer screening program in Dutch hospitals by deterministically linking nationwide insurance data with pathology data for cervical intraepithelial neoplasia (CIN). We then constructed quality indicators using the Dutch CIN guideline and National Health Care Institute recommendations to assess compliance with CIN management, treatment outcomes, and follow-up, using an empirical Bayes shrinkage model to correct for case-mix variation and hospitals with few observations. Data were linked for 115,899 of 125,751 (92%) eligible women. Overtreatment was observed in the see-and-treat approach (immediate treatment) for women with low-grade referral cytology , CIN ≤ 1 treatment specimens , and follow-up cervix cytology ≥2 months before the guideline recommendation after treatment for CIN 2  or CIN 3 . By contrast, undertreatment was observed for treatment within 3 months after a CIN 3 biopsy result  and follow-up ≥2 months beyond the guideline recommendation after treatments for CIN 2  and CIN 3 . In conclusion, we found evidence of CIN overtreatment and undertreatment in all measured domains at the hospital level. Guideline adherence could be improved by implementing the developed indicators in an audit and feedback instrument for use by healthcare professionals in routine practice. InvasivIn 2017, the Netherlands changed its cytology-based screening program to an hrHPV-based program that refers women with hrHPV-positive cervical cytology showing atypical squamous cells of undetermined significance or worse for colposcopy . CIN lesResearchers in other countries have shown the utility of national database linkage between health insurance claims data and cancer registries when analyzing practice variation in cervical cancer screening . A simil22.1We conducted a retrospective, cross-sectional, data linkage study in the Netherlands that included all women referred to the gynecologist for abnormal cervix cytology between January 1st, 2018 and December 31st, 2019. Women were identified by Diagnosis Treatment Combination code G19  and were included irrespective of the indication for the abnormal cervix cytology. This could either be through the national screening program or due to specific complaints .Zorgverzekeraars Nederland, the umbrella organization of all health insurance companies in the Netherlands. Its database provides information on healthcare costs related to the Dutch Health Insurance Act  and treatment decision after CIN 2 biopsy (indicator 4), we performed sub-analyses by age group (<40 years and ≥40 years) as a proxy for having completed childbearing. We opted to perform sub-analyses here, rather than altering the definition of indicators, because the guideline advises more restraint when offering treatments to women who might want to become pregnant in the future.2.3Appendix B shows all steps in the deterministic linkage of PALGA and Vektis datasets that used pre-defined rules to classify whether records from different datasets referred to the same woman . Before Data security was guaranteed with a privacy sending module for all data transfers between PALGA, Vektis, Zorg TTP, and our research group. The participating university required data analysis on an offline computer with storage in a secure offline archive after completion. Although we could only publish anonymous information per hospital, individual healthcare professionals could gain preliminary insights using the audit results and feedback for their own hospital. To ensure data security and privacy, pseudonymized audit and feedback information reports were generated and published on the secure website of the Dutch Society of Obstetricians and Gynaecologists. Hospitals could request Zorg TTP access codes to gain insights about their own report. National outcome data were not published.2.4SAS  was used for data storage and analysis. We calculated the hospital-specific crude rate for each indicator and the case-mix adjusted rate (AR) for indicators of the CIN management strategy, and we present risk estimates as average, minimum, and maximum rates. Funnel plots were constructed using SAS to examine the variation between Dutch institutions for each of the 12 indicators, maximizing reliability by excluding institutions that treated <500 women with CIN between 2018 and 2019. To account for differences in observations between hospitals, we used a Bayes shrinkage model for management indicators because a treatment decision for a few women could significantly affect the outcomes of indicators for hospitals with relatively few cases (i.e. slightly more than 20 cases). We estimated these models using random effects logistic regression, drawing the hospital effects from a (random) normal distribution. Outcomes were estimated with and without adjustment for the covariates age and hrHPV status, allowing case-mix correction for indicators of the CIN management strategy. The hospital predicted value was based solely on an intercept and a hospital random effect. This intercept was chosen to ensure that the mean of the predicted means per hospital was mean preserving.Sensitivity analyses were performed to compare the groups included and excluded during data linkage. Data for both groups were only available in the Vektis dataset, allowing comparison by age, colposcopies, and treatments. Furthermore, analyses on see-and-treat low grade referral cytology (indicator 1), treatment decision after biopsy CIN 1 (indicator 3) and treatment specimen (indicator 6) were stratified by age group <40 years and ≥40 years.33.1We could deterministically link 92%  of the women seen by a gynecologist with abnormal cervical cytology during the study period. Appendix B presents the number excluded per step in the data linkage procedure, which resulted in the further exclusion of 3,019 women treated in 23 hospitals serving <500 women during our study period . At the hospital level, 4%–10% of women could not be linked, though for one outlier, linkage was not possible for 31% of women. Concerning the risk of registration bias, exclusions due to intervention type (LEEP or biopsy) did not correspond between the datasets involving 13%  of the observations in the Vektis dataset and 15%  in the PALGA dataset. 3.2Appendix C provides the funnel plots for all indicators and Appendix D shows the empirical Bayes shrinkage models for indicators 1–5 and the crude results of all indicators per hospital, including the sub-analyses by age group.Wide variation existed in the management strategies of women with low- and high-grade referral cytology. 3.3Of the 112,880 included women, 19,873 (18%) received 20,617 treatments according to both datasets. Of these, 20,110 (98%) and 507 (2%) received LEEP and cold knife conization, respectively. The contribution of cold knife conization to CIN treatment (including adenocarcinoma in situ) was 0%–15% per hospital. 3.4In total, 29,314 women underwent colposcopy with or without a biopsy showing CIN 1 histology and received no treatment. During follow-up, 35%  underwent cervical cytology testing within the correct timeframe of 10–14 months, while 38%  did so within 10 months and 27%  did so after 14 months. Another 4,175 women received no treatment after colposcopy for a CIN 2 biopsy result, with 15%  having follow-up within the correct timeframe of 10–14 months, 65%  doing so within 10 months, and 21%  doing so after 14 months. Of the 5,637 women treated for CIN 2, 77%  had follow-up cervical cytology within the correct timeframe of 4–8 months, while 2%  and 21%  had follow-up within 4 months and after 8 months, respectively. Finally, of the 9,328 women treated for CIN 3, 75%  had follow-up within the correct timeframe of 4–8 months, while 5%  had follow-up before 4 months and 20%  had follow-up after 8 months.3.5The Vektis and PALGA datasets could not link 9,852 (8%) women. Although the linked and unlinked groups did not differ by age (39 vs 40 years), they did differ by colposcopies (0.51 vs 0.70) and LEEPs (0.16 vs 0.23) performed per person, with fewer procedures when datasets could be linked. Appendix D shows outcomes of indicator 2,3 and 6 stratified by age.4Despite a long tradition of guideline implementation in the Netherlands, our results indicate areas of deviation for the management of CIN across 12 quality indicators covering CIN management, treatment outcomes, and follow-up. After correction for hospital case mix, our data reveal areas where the care quality can be improved. Most hospitals treated women with low-grade referral cytology by the two-step approach, performing colposcopy and biopsy before treatment (97%), but we also identified several hospitals (6%) that used a see-and-treat approach for more than 20% of women. Although the see-and-treat approach is known to produce overtreatment , we founPhysician and patient factors each have the potential to cause treatment variation. On the one hand, some physicians may perform more treatments due to perceived pressure to accommodate patients, while others might have strong beliefs about the efficacy of a particular therapy. Differences in malpractice concerns or financial considerations could explain the variations between physicians . On the Audit cycles with healthcare professional feedback and input can reduce treatment variation by providing key information about clinical performance over a specific period . LiteratA desirable quality indicator should not produce a black or white outcome . Indeed,Our study has several strengths. First, using two nationwide databases and an effective deterministic linkage algorithm allowed us to provide a nearly complete dataset representative of the general population. PALGA could also provide data for all registered cytological and histological results, irrespective of the source, ensuring a complete dataset even if women switched between hospitals or the general practitioner took follow-up samples. Women could also change their health insurance company without affecting the dataset because Vektis covers all companies in the Netherlands. Second, our ability to track most referred women meant that the results had minimal insensitivity to sampling variability and chance findings. Although some hospitals produced few observations, we excluded those with <500 women and used empirical Bayes shrinkage models to correct for low numbers in each indicator category, thereby preventing chance findings from affecting the outcomes.An important limitation of our study is that we could not use social security numbers due to privacy concerns, meaning that we could not link 8% of the women in the Vektis dataset to the PALGA dataset. Although sensitivity analysis showed that the groups of excluded and included women did not differ by age, women in the excluded group received fewer treatments per person. This may be explained by a comparatively higher number of women undergoing treatment before the study period or by migration to another postal code. When that occurred, a return to their initial hospital with a follow-up CIN result could not be linked back if the woman did not inform the hospital of their updated postal code. Nevertheless, we believe these women received similar treatment and that their exclusion did not affect the representativeness of our outcomes. Finally, a new Dutch clinical guideline on CIN was published in September 2021. This introduced several changes that will necessitate minor adaptations to the quality indicators used in the present study, such as the integration of hrHPV status in the follow-up of CIN. Future studies should seek to align our quality indicators with the new guideline.5Women with CIN do not receive consistent treatment among Dutch hospitals, with examples of undertreatment and overtreatment evident throughout their management and follow-up. Linking data from routinely collected sources may facilitate audit and feedback loops that can improve the quality, efficiency, and equity of healthcare provision. Future research should analyze whether implementing audit and feedback in daily clinical practice will result in improved guideline adherence and care quality for women with CIN.MV and RB designed the study. AS, MH, FK, EH, and MV were involved in the compliance procedure to retrieve the data from PALGA and Vektis. GH analyzed the data and XK provided feedback to the statistical analyses performed. MV and GH drafted the manuscript. XK, EH, AS, KB, RB, and FK revised the manuscript. All authors reviewed and approved the final manuscript.https://zorgevaluatiegepastgebruik.nl. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was funded by Health Evaluation and Appropriate Use (no specific grant ID). The funder website URL is: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Supplemental Digital Content is available in the text Diffuse pigmented villonodular synovitis (PVNS) of knee is a rare benign disease that has a destructive clinical course. Synovectomy and adjuvant radiotherapy (RT) have been reported as treatment options but literatures reporting functional outcomes were sparse. This study aimed to evaluate the long-term functional outcomes and disease control among treatment modalities through the 22 years of experience.A single-center database was searched for patients who received synovectomy of knee with the pathologic diagnosis of PVNS. General data, treatment modalities, and recurrent status were retrospectively collected from medical records. Functional outcomes were evaluated by Western Ontario and McMaster Universities Osteoarthritis Index through phone interviews by an independent orthopedist.P = .038). Among those with preserved knee joints, there was no significant difference in the Western Ontario and McMaster Universities Osteoarthritis Index score and stiffness score between patients in the OP + RT and OP groups.From January 1995 to December 2017, 24 patients with diffuse PVNS of knee were identified, including 19 receiving open synovectomy (OP) and 5 undergoing arthroscopic surgery. Adjuvant RT was performed on 14 patients with a median dose of 35 Gy (range 20–40 Gy). After median follow up of 6 years, recurrences were recorded in 10 cases. The recurrence rate was significantly lower in the OP + RT group than the OP group (8.3% vs 57.1%, For patients with diffuse PVNS of knee, the addition of moderate-dose adjuvant RT following OP provided excellent local control while maintaining good joint function with limited treatment-related morbidity. Our study emphasized the importance of moderate dose RT in diffuse PVNS of knee joint. It is a rare sarcoma-like benign disease, and its incidence is about 1.8 cases per million people. Therefore, although classified as a benign disease, diffuse PVNS could cause severe disability at a relatively young age.There are 2 distinct types of PVNS: localized and diffuse. The 2 types are histologically similar, but differ in the extent of synovial involvement. Diffuse PVNS presents with more pronounced symptoms and is more destructive. It has a high tendency to invade extra-articular structures, such as muscles, tendons, bones, neurovascular structures, and skin. Complete tumor removal may be challenging in patients with diffuse PVNS. The recurrence rates after surgical resection ranged from 8% to 56%, depending on the extent of surgery.,2 Open or arthroscopic synovectomy have been reported as treatment options for diffuse PVNS. According to previous studies, the recurrence rate is higher for diffuse PVNS patients receiving arthroscopic synovectomy when compared to those who undergo open synovectomy (OP).–11 Furthermore, PVNS of different anatomical locations should be analyzed separately since it influences the choices of treatment and surgical techniques. Hence, surgical modalities and affected joints should be taken into consideration when comparing clinical outcomes of diffuse PVNS.Despite having a high recurrence rate and possible severe joint function decline, there is a lack of strong evidence for the optimal treatment for diffuse PVNS.–15 Most of them are retrospective cohort studies with small sample sizes or even case reports. The results might be affected by confounding factors, such as localized versus diffuse types, affected joints, surgical modalities (open or arthroscopic synovectomy) and approaches (anterior only or anterior combined posterior approach), if no proper stratification or analytical correction was done with limited case numbers.,15 Furthermore, the goals of PVNS treatment are not only preventing disease recurrence, but also relieving pain and stiffness, and preserving joint function. A recent cohort study reported the long-term functional outcomes for PVNS patients, but the result of stiffness was lacking. Therefore, the efficacy and long-term functional outcomes of adjuvant RT in treating diffuse PVNS of knee remained unclear.,15Adjuvant radiotherapy (RT) is also recognized as a treatment modality for diffuse PVNS. For the past decades, researches have focused on the disease control of diffuse PVNS with the addition of radiotherapy after synovectomy.The purpose of the present study was to evaluate the disease control and long-term functional outcomes in treatments of diffuse PVNS of knee in a single medical center. Arthroscopic and OP with or without subsequent external-beam RT were compared. We hypothesized that OP with subsequent external-beam RT in treating diffuse PVNS of knee would lead to the less disease recurrence rate but more stiffness in the knee joint.22.1After we received approval from the research ethics board, the pathology database of our institute was searched for patients who received synovectomy of knee with the pathologic diagnosis of PVNS. Those who had diffuse PVNS of knee joints were enrolled. PVNS originating from joints other than knee and localized PVNS were excluded. Clinical data were retrospectively collected from medical records, image studies, surgery notes, and radiotherapy charts. The data collected included the patient's age, sex, whether the disease was primary or recurrent, treatment modalities, radiation treatment technique and dose regimens, and current disease status.2.2Localized or diffuse PVNS was determined by pre-operative magnetic resonance imaging (MRI) or operative findings. The major features of the localized PVNS were localized nodules with a clear boundary and a single or no pedicle. In diffuse PVNS, the surface of the synovial membrane is villous, and there is an extensive involvement of the adjacent vessels and nerves.2.3The primary endpoint was functional outcomes and the secondary endpoints included local control and skin reaction. Functional outcomes were evaluated by the standardized questionnaire of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC score) through phone interviews by an independent orthopedist. The degree of hyperpigmentation, hypoalgesia, and any skin changes of the affected knee were scored by the RTOG (Radiation Therapy Oncology Group) scoring system. It is also easier to understand than the Toronto Extremity Salvage score and functional rating systems of the Musculoskeletal Tumor Society, especially in conversations through a phone interview. Therefore, the WOMAC score was used.The WOMAC score is widely used in the evaluation of hip and knee osteoarthritis and other hip and knee disabilities. It is a self-administered questionnaire consisting of 24 items that are divided into 3 subscales: pain, stiffness, and physical function. It is scored from 0 to 100, with higher the score denoting less perceived disability. The WOMAC score provides a more comprehensive assessment of patients’ subjective perception than the 4 functional categories assessments which was previously applied.Local control was defined as:1)the absence of clinical evidence of disease  for at least 2 years after treatment or2)stable disease in MRI imaging for at least 2 years after treatment.2.4Data were processed and analyzed using the Statistical Package for the Social Sciences . Considering the small sample size, nonparametric statistics with Fisher exact test was performed for categorical variable with a 95% confidence interval (CI). The mean WOMAC score of 90 was used to stratify the study cohort for analysis (WOMAC > 90 vs WOMAC < = 90). A mean stiffness score of 6 was used as a cut-off (stiffness score > 6 vs < = 6). The correlation between WOMAC score and RT dose as continuous variables was evaluated by logistic regression.33.1From 1995 to 2017, 40 consecutive histologically proven cases of PVNS were found. Seven cases were excluded due to localized PVNS, and 9 were excluded due to origins other than knee joint. Twenty-four patients with diffuse PVNS of knee were included, including 13 women and 11 men. The mean age was 40.4 years (range 19–65 years)  of the cases . When focusing on those receiving OP, the local control benefit of adjuvant RT was still apparent, with a local recurrence rate of 8.3% in the OP + RT group versus 57.1% in the OP group (P = .038) (Table After a median follow-up of 6 years (range 2–15 years), the overall local recurrence rate was 41.7% (10 of 24 patients), including 6 demonstrating progressive gross recurrent disease on post-treatment MRI and 5 pathologically proved recurrence with re-operation of the affected knee. Comparing the outcomes among treatment modalities, there was a significantly higher local control rate with OP and adjuvant RT  of the affected joints for progressive osteoarthritis. Three of the 4 patients were in the OP group and 1 was in the arthroscopic synovectomy group, all without adjuvant radiotherapy.There were 20 patients with preserved knee joints at recruitment. Nineteen of them completed the functional outcome measures through phone interviews while 1 refused the interview. After long-term follow-up, the mean WOMAC score was 88 range 48–100) Tables  and 4. A8–100 TabP = .226). When testing the effect of adjuvant RT, rates for good functional outcomes were 61.5% (8/13) for those receiving adjuvant RT, which was higher than 50% (3/6) for those without adjuvant RT, though no statistically significant difference found. Regression between the WOMAC score as continuous variable and the RT dose revealed no significant correlation (Table http://links.lww.com/MD/F435).To analyze the impact of adjuvant RT and disease recurrence on joint function, further analysis was performed, excluding those who received TKA. The proportion of patients with good functional outcomes (WOMAC score > 90) was higher among those without recurrent disease (8/12 without recurrent PVNS versus 3/7 for those with recurrent PVNS). However, the correlation between recurrence and poor WOMAC score was not statistically significant arthroscopic synovectomy resulted in a higher recurrence rate than OP;2)adjuvant RT might improve disease control, which was also found for those who underwent OP; and3)after long-term follow-up, adjuvant RT was not associated with worse stiffness or WOMAC functional outcomes, which is also a new contribution to current literatures. Blanco et al has reported that arthroscopic synovectomy alone was insufficient to eliminate all affected tissue. In another retrospective cohort study published in 2015, recurrence rate of 36% (35/97) in open, 58% (69/118) in arthroscopic, and 50% (5/10) in arthroscopically-assisted mini OP were reported, which was consistent with the finding in our study. These literatures support the necessity of evaluating the effects of different surgical modalities. However, limited studies had compared treatment outcomes with stratification by the surgical modalities.,11–15 Having such different recurrence rate, the surgical modalities should be taken into consideration when assessing other treatment options.In previous studies, arthroscopic synovectomy was linked with higher PVNS recurrence rate when comparing to OP. An observational study published in 2011 indicated that there was limited access to the affected joint during arthroscopic surgery in 52.9% (9/17 cases) of patients.,13 In the latest meta-analysis including 35 retrospective cohort studies, the addition of adjuvant RT following synovectomy significantly decreased the disease recurrence rate. The benefit was observed both in patients receiving open and arthroscopic synovectomy; . When focusing on diffuse PVNS of knee, our study also revealed a superior disease control with adjuvant RT, both in the overall study population and the OP subgroup.Adjuvant radiotherapy has long been recognized as an important treatment modality for PVNS to lower the rate of disease recurrence. All of them had their disease controlled without late complications after 29 months of follow up. Park et al reported that the effect of low-dose radiation therapy at 20 Gy was similar to that of a moderate dose about 35 Gy. Griffin et al used RT with a mean dose of 39.8 Gy (range 24–50 Gy in 13–25 fractions). After the mean follow up of 94 months, the mostly applied regimen of 35 Gy over 14 fractions led to an 88.5% local control, while the disease control rate being 82.0% for the whole study cohort. Therefore, it is believed that a low to moderate dose of adjuvant RT could achieve a satisfactory local control rate.Despite the well-recognized disease control advantage of adjuvant RT, there is no consensus on the radiation dose and regimen at present. Berger et al reported 7 patients who were treated with 30 to 50 Gy post-operatively. The local control rate was 94%. However, 4 out of the 14 patients who completed functional evaluation were rated as having poor joint function, leaving some concerns about late tissue reaction of RT. Long-term functional outcome was also reported in a meta-analysis with a mean follow up of 56 months. The proportion of patients experiencing stiffness of the affected knee was 3.3% for those receiving RT and was 8.0% for those without RT (P = .068).The goal of PVNS treatment is not only to prevent disease recurrence, but also to preserve joint function and quality of life. Griffin et al had assessed the efficacy and long-term functional outcomes with adjuvant RT in 50 diffuse PVNS cases, including 60% of which having multiple surgeries before receiving RT.P = 0 .226; Table Similarly, having 95% of those with preserved knee joints completing functional evaluation after the median follow up of 72 months, our cohort indicated that there was no significant difference in the rate of joint stiffness nor functional outcomes between patient with and without adjuvant RT. Furthermore, the results revealed a non-significant decrease in stiffness and poor activity with RT, which are contrary to previous understanding. This might be explained by the reduced recurrence rate and therefore preventing soft tissue scarring from multiple surgeries. Though no significant association observed between PVNS recurrence and lower WOMAC score , the local control advantage and the safety of adjuvant RT would still be reliable. Third, new treatment options such as monoclonal antibodies and tyrosine kinase inhibitors were not included in the treatment of our PVNS cohort since they were not covered by the national health insurance. Therefore, the validity of our result might be limited when extrapolating to patients receiving such target therapies. Further research with larger cohort and inclusion of more contemporary treatments is warrant.Comparing to previous literatures, our study focused on the functional outcomes of patients with diffuse PVNS of knee.5Focusing on diffuse PVNS of knee, the addition of moderate-dose adjuvant RT following OP provided excellent local control. There was no significant treatment-related morbidity and the functional outcomes were not negatively affected by radiotherapy.Conceptualization: Chun Yu Chen.Data curation: Chun Yu Chen, Wen Shan Liu, Shan Wei Yang.Supervision: Wen Shan Liu, Shan Wei Yang.Writing – original draft: Ju Chun Chien, Yi Ping Wei.Writing – review & editing: Wei Hsin Hsiang, Yuan You Wang, Wen Shan Liu, Shan Wei Yang.


Suillus granulatus (Sg), Pisolithus tinctorius (Pt), Pleotrichocladium opacum (Po), and Pseudopyrenochaeta sp. (Ps), isolated from the roots of Pinus tabulaeformis were investigated in vitro. Then, the effects of the fungi on the growth performance, nutrient uptake, and rhizosphere soil microbial community structure of P. tabulaeformis under different N addition conditions  were examined. The biomass and phytohormone contents of the Sg, Pt and Po strains increased with increasing N concentration, while those of the Ps strain first increased and then decreased. All four fungal strains could effectively colonize the plant roots and form a strain-dependent symbiosis with P. tabulaeformis. Although the effects depended on the fungal species, the growth and root development of inoculated seedlings were higher than those of uninoculated seedlings under N deficiency and normal N supply conditions. However, these positive effects disappeared and even became negative under high N supply conditions. The inoculation of the four fungal strains also showed significant positive effects on the shoot and root nutrient contents of P. tabulaeformis. Fungal inoculation significantly increased different microbial groups and the total soil microorganisms but decreased the microbial diversity under N deficiency stress. In summary, exogenous symbiotic fungal inoculations could increase the growth performance of P. tabulaeformis under N deficiency and normal N supply conditions, but the effects were negative under excessive N addition.Nitrogen (N) availability is significant in different ecosystems, but the response of forest plant-microbial symbionts to global N deposition remains largely unexplored. In this study, the effects of different N concentration levels on four types of fungi,  In recent years, atmospheric nitrogen (N) deposition has become one of the important phenomena of global climate change. Studies have shown that atmospheric N deposition has adverse effects on terrestrial ecosystems, and these effects are mainly related to soil N enrichment and increases in available N. In addition, N deposition can change the global carbon cycle and plant diversity, which will have a profound impact on the structure and function of terrestrial ecosystems . As an iPrevious studies showed that Pinaceae trees were obligate to ectomycorrhizal fungi, whereas recent research reported that dark septate endophytes were also the main root-associated fungi of pine , 2021. IDark septate endophytes have a wide ecosystem distribution and variable effects on the growth of host plants . Much rePinus tabulaeformis Carr., a coniferous evergreen tree of Pinaceae, is characterized by a well-developed root system, rapid growth, strong ecological adaptability and stress resistance and is a pioneer tree for vegetation restoration in a variety of stress environments  the growth performance under different N addition levels in pure cultures and (2) the effects of inoculation with these fungi on the performance of P. tabulaeformis plants and the soil microbial community in an inoculation experiment under different N supply conditions. Improving the growth of P. tabulaeformis will also be a better use of plant root-associated fungal resources, providing a theoretical basis for maintaining the stability of forest ecosystems. We expect that our results will help determine which inoculated fungi could adapt to the change in the N environment and reveal whether they have the potential for improving the stress tolerance and symbiotic performance of plants under N content variation.ronments . Researcaeformis . It has aeformis . In addi present . The ecoP. tabulaeformis in the Wuling Mountain Nature Reserve, Hebei Province  and were preserved in the Laboratory of Garden Plant Ecology, Hebei Agricultural University, China. These fungi were identified as two ectomycorrhizal fungi, Suillus granulatus (Sg) and Pisolithus tinctorius (Pt), and two dark septate endophytes, Pleotrichocladium opacum (Po) and Pseudopyrenochaeta sp. (Ps), by morphological characteristics and phylogenetic analyses of nuclear ribosomal DNA (nrDNA) internal transcribed spacer (ITS) sequences  at 25°C. During the incubation period, the seeds were rinsed with sterilized water twice a day. Seedlings with fully developed cotyledons were transferred to incubation plates containing autoclaved substrate and incubated in a greenhouse at room temperature. The seedlings were watered regularly to avoid water shortage.Mature seeds of 4NO3 was the only N source. The different N concentrations tested were 0 (N free), 0.0053 (low N), 0.053 (medium N) and 0.530 (high N) g l−1. Two disks of mycelium (5 mm) were cut from the edge of actively growing 21-day-old colonies of each isolate and inoculated into a 9-cm Petri dish containing 30 ml of MMN solid medium and into a 250-ml Erlenmeyer flask containing 100 ml of MMN liquid medium. Five replicates were performed per strain per N concentration. Then, the Petri dishes were placed in a thermostatic incubator and incubated on a shaker at 150 rpm at 27°C for 20 days in the dark. Upon harvest, the colony diameter on the solid medium was measured; the fungal mycelia in the liquid medium were filtered and washed with sterilized distilled water, and then the fungal mycelia were weighed after drying to a constant weight at 80°C to determine the biomass production. The filtrate was collected for the analysis of the hormone contents.The growth of the four isolates under different N addition conditions was tested in a preliminary experiment in liquid culture. The experiment was performed under sterile conditions, and the basal medium was a modification of modified Melin-Norkrans (MMN) medium (pH 5.5), in which NH3) was performed using high-performance liquid chromatography (HPLC). Briefly, after incubation for 20 days, 20 ml of filtrate of the liquid culture medium was collected and then purified and concentrated to 2.0 ml using a C18 solid-phase extraction column. HPLC was performed using a Thermo U3000 Syncronis C18 column  with deionized water and acetonitrile (volume ratio of 3:7) as the mobile phase. The flow rate, injection volume, detection wavelength, and column temperature were 1 ml min−1, 20 μl, 210 nm and 30°C, respectively.The analysis of hormone contents  containing 2 kg of autoclaved (90 min at 121°C) growth substrate, which consisted of a 1:1 (v/v) mixture of river sand and soil (< 2 mm). With respect to the fungal inoculation treatments, two 5-mm-diameter fungal mycelial discs cut from a 14-day-old PDA culture medium were inoculated within 1 cm of the roots of the P. tabulaeformis seedlings , Sg, Pt, Po and Ps) and N addition treatment  as the variables. Each treatment was replicated five times, totaling 75 experimental pots. Seedlings of eedlings . With re4NO3 as the only N source. Three N concentrations  were applied to the pots. During the experiment, 200 ml of nutrient solution was added once a week per pot. The positions of the pots were randomly rotated each week to minimize location effects. Finally, the plants were harvested after 6 months of treatment.Thirty days after inoculation, the mycorrhizal infection rate was detected by microscopic examination and the staining methods of Prior to harvest, the plant height and ground diameter in each pot were recorded. Plant shoots and roots were subsequently harvested separately. The roots were washed carefully with deionized water and scanned with a desktop scanner . Several morphological traits of roots  were determined using the WinRHIZO image analysis system  in each of the seedlings within each treatment. The percentage of root tips with distinct ectomycorrhizal structures was calculated by determining the number of mycorrhizal versus nonmycorrhizal root tips in each of the treatments . To evalP. tabulaeformis was calculated according to the following equations based on mean, then MGR (%) = 100 × (1 – NMmean/M), but if M < NMmean, then MGR (%) = 100 × (− 1 + M/NMmean), where M is the plant total dry weight in the given replicate of the fungal inoculation treatment and NMmean is the mean total dry weight in the corresponding noninoculated treatment. Positive values for MGR indicated that plant growth was promoted by fungi, and negative values indicated that plant growth was suppressed by fungi.The mycorrhizal growth response (MGR) of 2SO4 solution and heated for digestion until colorless and transparent. The cooled digestion solution was diluted to 100 ml by adding deionized water. The N concentrations of the plants were analyzed using the Kjeldahl method, the P concentrations were measured by the molybdenum-antimony colorimetric method, and the K concentrations were determined by atomic absorption spectrophotometry (Dried powder samples (approximately 0.1 g) of shoots and roots were immersed in Hotometry .The composition of the rhizosphere soil microbial community was determined by phospholipid fatty acid (PLFA) analysis . PLFA anH) based on the PLFA profiles using the following formula: H = –ΣiPlniP, where Pi refers to the ratio of the concentration of each PLFA to the total PLFA concentration in one soil sample and n is the number of PLFAs detected in each soil sample. Each PLFA was considered to be representative of one species  were performed with SPSS software . For the first experiment, two-way ANOVA was performed to analyze the effects of the fungal species (E) and N addition treatment (N) on the colony diameter, biomass and hormone content of the four fungi. For the second experiment, two-way ANOVA was performed to examine the effects of fungal inoculation (E), N addition treatment (N), and their interactions on the dry weight, root morphological traits, nutrient contents and soil microbial community structure. The effect of fungal inoculation on the soil microbial community composition consisting of all the PLFA markers was conducted by using principal coordinate analysis (PCoA) based on Bray–Curtis dissimilarity with R software . Permutational multivariate analysis of variance (PERMANOVA) was used to test the effects of fungal inoculation and N addition treatment on community dissimilarity . All datDifferent N concentrations had different effects on the colony diameters of the four fungi . The col3 of the Sg, Pt and Po strains increased with increasing nitrogen concentration and reached their highest values under the high N treatment. However, the IAA content of the Ps strain showed no significant difference under different nitrogen concentrations, and the GA3 content showed a trend of first increasing and then decreasing with increasing nitrogen concentration, with the GA3 content under the medium N treatment being significantly higher than those under the other nitrogen levels  and two dark septate endophyte strains (Po and Ps) secreted different concentrations of IAA and GA3 under different nitrogen concentrations, indicating that these fungi may have certain growth-promoting potential and produce plant hormones and then release them into the plant tissue.Under adverse conditions, mycelial biomass is one of the important indicators reflecting fungal resistance . Our resin vitro . Therefoin vitro . The C tin vitro . Therefoc stress . In thisP. tabulaeformis and improve the adaptability of host plants to different habitats through complex biological pathways  seedlings. Our study also provided direct evidence that dark septate endophytes may have a similar function to ectomycorrhizal fungi, forming a mutualistic symbiotic relationship with the host , Youth Natural Science Foundation of Hebei Province (C2020204169), and the starting Scientific Research Foundation for the introduced talents of Hebei Agricultural University (ZD201728).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fmicb.2022.1013023/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


The COVID-19 pandemic has required rapid and repetitive adjustment of radiotherapy practice, hospital-level and department-level organization and hygiene measures. To prospectively monitor and manage stress levels and health concerns, employees of a radiation oncology department were invited to participate in weekly online surveys during the first year of the pandemic.Starting March 31st, 2020, cross-sectional online surveys were distributed to all employees of the Department of Radiation Oncology, University Hospital Zurich. The survey included questions about the profession, the work setting, the global stress level as well as the health concerns during the past work week. Stress levels and health concerns were assessed on a 10-point scale. SurveyMonkey® was used to conduct the survey. Distribution was performed via email. Participation was anonymous and voluntary.Between March 2020 and February 2021, 50 weekly surveys were distributed to 127 employees on average and resulted in 1,877 individual responses. The average response rate was 30%. The mean global stress level varied significantly by profession, ranging from 2.7 (±2.5) points for administrative staff to 6.9 (±2.3) points for radiation therapy technicians (p < 0.001). The mean global stress level was highest with 4.8 (±2.9) points for in-hospital work with direct patient contact. Health concerns were highest regarding family and friends with 4.0 (±3.1) points on average. Changes of the stress level varied in correlation with infection waves.Weekly online surveys for prospective assessment of stress levels and health concerns were successfully conducted during the first year of the COVID-19 pandemic, indicating their feasibility and value to monitor profession and workplace specific stress patterns and to allowed for tailored interventions. The physical and mental health of frontline healthcare workers in radiation oncology should remain a top priority for departmental leadership beyond the COVID-19 pandemic. On March 11, 2020, COVID-19 was declared a pandemic by the World Health Organization (WHO) So far, there have been very few reports examining stress level and mental health problems in radiation oncology departments during the COVID-19 pandemic. Those studies focused on sub-groups of departmental staff such as radiation therapy technicians (RTTs) in Canada and Norway All employees of the Department of Radiation Oncology of the University Hospital Zurich (USZ) with an active contract between March 2020 and February 2021 were eligible for participation in this study. Professions surveyed included administrative staff, clinicians, medical physicists, nurses, nursing assistants, research staff, RTTs, and “other” professions. Participation in the study was voluntary, anonymous and unpaid. Completion of the questionnaire took place during working hours.Starting from March 31st, 2020, a survey was sent out to all department staff via their professional email address on a weekly basis. The email always included a link to the survey, an explanation about the context of the study, a reminder that participation in the survey was voluntary and anonymous, yet that participation was encouraged with the aim to improve employee well-being and satisfaction. The survey was designed by senior staff from different professions working in our department. The design of the survey was informed by other routine surveys conducted by the human resources (HR) department at the USZ as well as by a thorough review of the literature Descriptive statistics such as mean and standard deviation (SD) were calculated for all variables under study. The Kruskal-Wallis test was employed to assess statistically significant differences between groups. Statistical significance was set at p = 0.05. All statistical analyses were carried out using the software package STATA® (v.16.1). For visualization purposes, appropriate figures were created using the software Microsoft® Power BI Desktop® (v.2.9).Between March 31st, 2020 and February 17th, 2021, an average of n = 127 employees worked at our Department of Radiation Oncology. There were n = 28 (22%) RTTs, n = 22 (17%) clinicians, n = 22 (17%) research staff, n = 18 (14%) administrative staff, n = 15 (12%) medical physicists, n = 10 (8%) nurses, n = 7 (6%) nursing assistants, and n = 5 (4%) employees with other professions.Across the whole year starting March, 31st, 2020, a total of 50 online surveys were distributed, resulting in 1,877 responses. The overall average response rate across all professions was about 30%. Average response rates differed by profession and time point. Medical physicists had an average rate of 62%, while research staff and nursing assistants had average rates of 20% and 5%, respectively . The higThe average global stress level varied significantly between professions (p < 0.001). RTTs had the highest average global stress level with 6.9  points, followed by nursing assistants and medical physicists with 4.4  and 4.2  points, respectively. The lowest average global stress level was reported by research and administrative staff, with rates of 2.9  and 2.7 (2.5) points, respectively. When compared to all other professions, RTTs had the highest combination of point scores of global stress level and health concerns (p < 0.001). With respect to health concerns, all employees were most concerned about the health of family and friends, with an average of 4.0  points (p < 0.001). Concerns about the health of patients came second, with an average of 3.6  points, while the concern about one’s own health was scored lowest with 3.1  points on average. Sub-group analysis with respect to profession showed statistically significant differences (p < 0.001): RTTs had the greatest health concerns, followed by medical physicists and lowest values were observed for administrative and other staff. While RTTs were, on average, similarly concerned about the health of family and friends as well as patients with 7.2  points, they were, on average, less concerned about their own health . For all other professions, the concerns about health were strongest about family and friends and lower about their own health and the health of patients. An overview of health concerns by profession is given in Across all professions, the global stress level was highest for in-hospital work with patient contact with an average of 4.8  points, whereas the global stress level was slightly, but significantly different for in-hospital work without patient contact and home-office with 3.5  and 3.7 (2.6) points, respectively (p < 0.001). The same pattern was observed for the sub-categories of health concerns per work location, with differences also being highly statistically significant (p < 0.001). Health concerns were generally highest for the group of employees conducting in-hospital work with patient contact. In this work location, concerns about the health of family and friends were scored with 4.4  points on average, concerns about the health of patients and one’s own health with 4.2  and 3.6  points, respectively. For a detailed overview of global stress level and health concerns by work location, consult When analyzing the time trends of the global stress level and health concerns during the first year of the pandemic, average global stress level was 4.2  points in March/April 2020. It was lower during the summer months of 2020 and peaked again in November and December 2020 with an average of 4.7  and 4.8  points, respectively, before falling off to 4.3  points by March 2021. The health concern curves followed a similar pattern. While the average point score for concern about health of family and friends was higher than the global stress level in March/April 2020 , it fell below the global stress level in November and December 2020. These time trends are illustrated in Between March 2020 and February 2021, 50 surveys were distributed to 127 employees and resulted in 1,877 individual responses and a high response rate of 30% on average. The average global stress level varied significantly by profession, ranging from 2.7 points for administrative staff to 6.9 points for radiation therapy technicians. The average global stress level was highest for in-hospital work with direct patient contact with 4.8 points, whereas stress was similar for in-hospital work without patient contact and home-office with 3.5 and 3.7 points, respectively. Health concerns were highest regarding family and friends with 4.0 points on average compared to concerns about one’s own or patients’ health with an average of 3.1 and 3.6 points, respectively. Changes of response rates and the stress level varied with infection waves.Magill et al. (2020) conducted a rapid review on the mental health of frontline healthcare providers during pandemics. The authors assessed a total of 94 studies and found stress and anxiety to be the most common adverse psychological experiences, which decrease over time during pandemics. This rapid review also evaluated interventions to counter these adverse effects, concluding that more evidence-based measures are needed Busch et al. (2020) conducted a systematic review and meta-analysis of the epidemics and pandemics induced psychological burden for healthcare workers over the past two decades. This review of 86 studies, which assessed numerous different psychological and psychosomatic symptom clusters, revealed consistent evidence for significant and detrimental effects on the mental well-being of frontline healthcare workers. The authors close by recommending easy access to support structures for all staff involved in healthcare provision for the entire duration of the COVID-19 pandemic Cabarkapa et al. (2020) provided the most concise, detailed and well-planned rapid systematic review on the psychological impact of COVID-19 and other viral epidemics on frontline healthcare workers. Only studies with an established quantitative or qualitative methodology to assess psychological impact were included, totaling at 52 studies, which comprised various countries and staff during the SARS, Ebola, MERS and COVID-19 outbreaks. This review reported an increased risk for trauma, stress-related disorders, depression, and anxiety. Many examined studies stressed the need for increased offers for psychosocial support, and the need for a more transparent and clear communication strategy throughout viral outbreaks There is a wealth of literature documenting detrimental health effects on healthcare staff during the extreme conditions of a pandemic, which has been partially updated in light of the COVID-19 pandemic. Since the beginning of the COVID-19 pandemic in the spring 2020, an abundance of online surveys has been conducted examining people’s stress and anxiety levels, vaccination willingness, attitudes towards the national pandemic management and social behavior, among others Morassaei et al. (2021), in examining stress levels in RTTs in Canada and Norway, found high stress levels during the pandemic and identified similar stressors in both countries Vancappel et al. (2021) in surveying 1,010 healthcare workers at university hospitals in France from across different medical sub-specialties found a high prevalence of post-traumatic and burnout symptoms at the beginning of the COVID-19 pandemic In the pre-pandemic radiation oncology practice, almost all professions had regular patient contact. Yet while remote work in the home office setting was partially or fully implemented for some professions such as administrative staff, research staff, medical physicists or senior clinicians during the pandemic, due to the nature of their work as frontline healthcare workers, such arrangements were less likely to be implementable for nurses and RTTs. Consequently, these two professions had significantly higher average global stress levels and health concerns, with RTTs being most affected across all dimensions. In contrast to other international reports and policies, our department did not implement patient waiting times, deferral of radiotherapy treatment or changes of radiotherapy fractionation, and continued treatment of COVID-19 positive patients if their health status allowed so, which was obviously most difficult for RTTs and nurses In this context, it is important to highlight that these findings all originate from countries with largely publicly funded healthcare systems in high-income countries, raising the question whether similar findings would prevail when assessing countries with mostly privately funded or underfunded healthcare systems and/or more pronounced organizational hierarchies. Under such conditions, a lack of easily accessible informal support systems, institutionalized worker support such as labor unions, or even the recognition of the importance of staff wellbeing might influence stress levels and supportive interventions in systems with less favorable environments.While low global stress level and health concern scores for administrative and research staff may be influenced by the possibility to work from home, it is also important to point out that there does not seem to be a strong correlation between patient contact and employee stress level and health concerns. While clinicians in our department had regular patient contact during in-hospital work, their average global stress levels and health concerns were consistently lower than those of the non-patient facing professions. This finding is both encouraging and concerning at the same time: Encouraging, as it can be interpreted as evidence for empathetic and resilient character traits in the physician profession as well as the ability to immediately integrate new scientific evidence in light of an emerging disease into their day-to-day activities; but also concerning, as amongst physicians it is often expected that one’s own health and wellbeing comes last, as anecdotally exemplified in the self-reflections of a Canadian emergency physician suffering from mental illness Changes of the average global stress level and health concerns over the 50 surveyed weeks during the first year of the COVID-19 pandemic were graphically seemingly associated with the developments of COVID-19 in Switzerland. After the first wave in the winter 2020, average global stress level and health concerns dropped during the summer months, before rising to the all-time high during the first year of the COVID-19 pandemic at the height of the second wave in the winter 2021. We also observed that during the first and second infection waves, the weekly response rates increased, highlighting the healthcare worker’s heightened alertness, global stress levels and health concerns. The missing statistical evidence for a clear and statistically significant correlation between global stress levels and daily new COVID-19 cases results most likely from the comparatively high global stress levels during the first wave as well as the persistence of high global stress levels after the end of the second wave. Moreover, the effect, which is frequently described in the literature Skype for Business), and employees worked remotely from home whenever possible. In addition, all departmental-level standard operating procedures (SOP) were changed from a horizontal organization  to a vertical organization (clinicians responsible for certain workplaces and tasks), alongside with a fully paperless workflow, aiming to minimize “travelling” and contacts within the department; similarly, travelling between all workplaces was kept to a minimum and responsibilities adjusted in all other professions. Simultaneously, anti-stress interventions were designed and implemented in our department. For example, hospital leadership started sharing regular email updates regarding new health authority policies and explaining implications for all hospital staff. This included information on infection rates, hospital capacity and operations as well as effectiveness of personal protective equipment (PPE). Departmental leadership also circulated emails informing about latest developments, evolving new evidence, risk assessments and best practices to be followed. Moreover, during inter-professional departmental leadership meetings, the weekly survey results were analyzed and profession-specific interventions were developed and implemented. For instance, a meditation room was created for all staff and regularly used; voluntary virtual discussions were offered for each professional group; and a communication training for resident physicians was developed, where difficult situations were discussed and reflected upon with a professional coach. A hospital-wide telephone hotline for USZ employees was another resource, which was well received and regularly used by different professional groups, to lower global stress and levels and health concerns.These findings may become comprehensible when looking at the continuous interventions on a hospital- and departmental-level to order to address the COVID-19 pandemic and healthcare worker wellbeing: Hygienic and organizational adjustments of the USZ Department of Radiation Oncology allowed that all referred patients were treated without waiting times and without adjustment of our standard treatment concepts and fractionation. By March 20th, 2020, protective masks were mandatory for all staff, comprehensive social distancing was implemented, all meetings were shifted in a virtual environment  and the Bangerter-Rhyner Foundation.Availability of data and material: Survey responses are be available upon request.Code availability: Not applicable for this publication.Ethics approval: The Swiss Cantonal Ethics Committee was informed about the study.Prior presentation: The abstract of this manuscript was presented as a poster at the 2021 European Society of Therapeutic Radiology and Oncology (ESTRO) annual meeting.