Conversely, there was no significant difference between the 19-gauge conventional needle and 22-gauge Franseen needle (p = 0.838) in this regard. The 19-gauge Franseen needle could collect more samples than the other needles, contributing to giving a more precise pathological diagnosis and more information, including genomic profiling.Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) enables easy and accurate pathological assessment. Here, we compared and assessed the area of samples on glass slides for three needle types: a 19-gauge Franseen needle , a 22-gauge Franseen needle, and a 19-gauge fine-needle aspiration (FNA) needle . Among patients with suspected pancreatic cancer, with a ≥20 mm tumor located in the pancreatic body and tail, and who underwent EUS-FNA or FNB between June 2018 and March 2020, 10 were randomly selected to test each needle. The areas of histological tissue and blood clot samples were measured using the BZ-X800 imaging software . Baseline patient characteristics and pathological sample data showed no significant differences among the needles. The 19-gauge Franseen needle obtained significantly more histological tissue samples than the 19-gauge conventional needle ( Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe and efficient procedure for pancreatic masses ,2. In a This was a retrospective study performed at a single tertiary care referral center where more than 100 EUS-FNBs are performed yearly . The study protocol was approved by the institutional review board of each participating institution  and registered at the university hospital medical information network (UMIN) clinical trials registry (UMIN ID: UMIN000044058).We performed EUS-FNA or FNB using three types of needles: 19-gauge and 22-gauge Franseen needles  and a 19-gauge conventional FNA needle  .Among patients who underwent EUS-FNB between June 2018 and March 2020, 10 patients were randomly selected to evaluate the three needles. The choice of needle depended on the performance period. Initially, we used a 19-gauge conventional needle , followeEUS was performed as an in-patient procedure using a curved linear echoendoscope  connected to an ultrasound scanning system . The patients underwent EUS-FNA or FNB under conscious sedation with midazolam and their vital signs were monitored. Two experienced endosonographers (who perform the procedure for more than 50 cases per year) conducted the EUS-FNB in all cases. The procedure was performed as previously reported . The lesThe specimen was then macroscopically evaluated and the whitish portions  were collected and placed on a small piece of filter paper. The sample was then placed in formalin solution for histological examination and the remaining material was smeared on glass slides for cytological examination.As our institution does not have an on-site pathologist or cytologist, punctures were repeated up to three times until a whitish material was macroscopically observed. If the third puncture was not successful, the lesion was diagnosed based only on the histological examination.All the collected specimens were sent for histological examination. After formalin fixation, the specimens were embedded in paraffin, sectioned, and subjected to hematoxylin-eosin staining and appropriate immunostaining according to the suspected diagnosis. All the histological diagnoses were made by two pathologists who specialized in the pancreatobiliary field at Toyama University Hospital. Final diagnoses were based on surgical pathology or a minimum six-month clinical follow-up.In this study, 12 of the total of 30 patients underwent surgical resection for pancreatic cancer, while the rest were diagnosed by disease progression or death due to the primary disease. The areas of the histological tissue and blood clots were measured separately using imaging software  for each EUS-FNA and FNB pass . The dat® software . The χ2 test and Fisher’s exact test were used to compare categorical parameters, and the Steel–Dwass test was used to compare continuous variables. Continuous parameters are presented as the median (IQR). p < 0.05 was considered statistically significant.All the analyses were performed using JMPBaseline characteristics of patients and solid pancreatic lesion details are listed in p = 0.010) and 22-gauge Franseen (p = 0.008) needles. Conversely, the difference between samples from the 19-gauge conventional needle and the 22-gauge Franseen needle was nonsignificant (p = 0.838).The EUS-FNA and FNB outcomes and pathological sample data are shown in p = 0.162; 19-gauge Franseen needle vs. 22-gauge Franseen needle, p = 0.111; 19-gauge conventional needle vs. 22-gauge Franseen needle, p = 0.981). In addition, there were no significant differences among the groups in terms of the rate of the blood clots area/total area .Regarding the median area of blood clots, there were no significant differences among the groups  and that obtained with 22-gauge Franseen needle .A scatter plot showing the amount of tissue obtained is shown in In the present study, we demonstrated that 19-gauge Franseen needles obtained significantly more histological tissue than 19-gauge conventional and 22-gauge Franseen needles among patients with pancreatic cancer. There were no differences among the groups regarding the median area of blood clots or the blood clots area/total area.The pathological diagnosis of solid pancreatic masses is important for ensuring that suitable therapy is administered and the optimum prognosis is achieved ,14. ObtaFirst, a larger amount of tissue provides pathologists with more detailed pathological information. It has been reported that the obtainment of only a small amount of a fragmented atypical epithelial cluster may make it difficult for a general pathologist to differentiate the cancer cells from gastric foveolar epithelial cells or normal pancreatic acinar cells that have atrophied due to inflammation ,16. In aSecond, collecting a large amount of biopsy tissue may allow macroscopic assessment, such as macroscopic on-site evaluation (MOSE). Although a large amount of sample does not always guarantee a good macroscopic evaluation, it has the potential to lead to more accurate evaluations. The rapid on-site cytological evaluation (ROSE) of EUS-FNA samples performed by a cytopathologist influences the diagnostic performance of EUS-FNA, along with the location, size, and tissue firmness of the lesion, and the experience of the endoscopist ,18,19. Ip = 0.02). In multivariable modeling, only FNB  was associated with sufficient sampling for genomic testing [Third, recent molecular pathological studies have been performed for various types of cancer. Unfortunately, pancreatic cancer typically has low-cellularity tumors with abundant stromal components. The content of tumor cells in pancreatic cancer is reported to be approximately 5–20%, which makes the analysis of next-generation sequencing (NGS) relatively difficult . TherefoFranseen needles have emerged as a preferred alternative to conventional needles, as they can easily obtain larger tissue samples. For example, Mukai et al. reported that a 22-gauge Franseen needle provides approximately five times the median area of tissue sample for histological evaluation compared to that of the same gauge conventional needle . In thisp = 0.838). This suggests that 22-gauge Franseen needles may have the same diagnostic ability as 19-gauge conventional needles. In addition, the amount of obtained tissue with a 19-gauge Franseen needle was approximately three times as large as that obtained with a 19-gauge conventional needle or with a 22-gauge Franseen needle. This suggests the ability of the 19-gauge Franseen needle to obtain larger tissue samples  consisting of arterial mucosal bleeding that required endoscopic hemostasis using two clips . Mukai eThe present study had a few limitations. First, the retrospective single-center study design and a small number of patients are associated with risk of bias. In this study, to minimize potential confounding and selection biases among the groups, we only included patients suspected of pancreatic cancer with a tumor size of ≥20 mm located in the body and tail of the pancreas. Under these conditions, the highest priority was to make the characteristics of all the subjects as equal as possible. As a result, each group had 10 cases. However, there is still a potential risk of selection bias. Second, the choice of the needle mainly depended on the performance period. Initially, we used a 19-gauge conventional needle , followeIn conclusion, the 19-gauge Franseen needle can obtain samples approximately three times larger than those of other needles, which can be useful for obtaining a more precise pathological diagnosis and information, including genomic profiling.


In most countries, healthcare workers (HCWs) represent a priority group for vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to their elevated risk of COVID-19 and potential contribution to nosocomial SARS-CoV-2 transmission. Concerns have been raised that HCWs from ethnic minority groups are more likely to be vaccine hesitant  than those of White ethnicity, but there are limited data on SARS-CoV-2 vaccine hesitancy and its predictors in UK HCWs.Nationwide prospective cohort study and qualitative study in a multi-ethnic cohort of clinical and non-clinical UK HCWs. We analysed ethnic differences in SARS-CoV-2 vaccine hesitancy adjusting for demographics, vaccine trust, and perceived risk of COVID-19. We explored reasons for hesitancy in qualitative data using a framework analysis.11,584 HCWs were included in the cohort analysis. 23% (2704) reported vaccine hesitancy. Compared to White British HCWs (21.3% hesitant), HCWs from Black Caribbean (54.2%), Mixed White and Black Caribbean (38.1%), Black African (34.4%), Chinese (33.1%), Pakistani (30.4%), and White Other (28.7%) ethnic groups were significantly more likely to be hesitant. In adjusted analysis, Black Caribbean , Black African , White Other ethnic groups  were significantly more likely to be hesitant. Other independent predictors of hesitancy were younger age, female sex, higher score on a COVID-19 conspiracy beliefs scale, lower trust in employer, lack of influenza vaccine uptake in the previous season, previous COVID-19, and pregnancy. Qualitative data from 99 participants identified the following contributors to hesitancy: lack of trust in government and employers, safety concerns due to the speed of vaccine development, lack of ethnic diversity in vaccine studies, and confusing and conflicting information. Participants felt uptake in ethnic minority communities might be improved through inclusive communication, involving HCWs in the vaccine rollout, and promoting vaccination through trusted networks.Despite increased risk of COVID-19, HCWs from some ethnic minority groups are more likely to be vaccine hesitant than their White British colleagues. Strategies to build trust and dispel myths surrounding the COVID-19 vaccine in these communities are urgently required. Emphasis should be placed on the safety and benefit of SARS-CoV-2 vaccination in pregnancy and in those with previous COVID-19. Public health communications should be inclusive, non-stigmatising and utilise trusted networks.UKRI-MRC and NIHR. We searched Pubmed using the following search terms ((COVID-19).ti,ab OR (SARS-CoV-2).ti,ab) AND ((vaccine).ti,ab OR (vaccination).ti,ab OR (immunisation).ti,ab)) AND .ti,ab OR .ti,ab OR (doctor).ti,ab OR (nurse).ti,ab OR .ti,ab)) AND ((hesitancy).ti,ab OR .ti,ab OR (uptake).ti,ab)). The search returned 60 results, of which 38 were excluded after title and abstract screening, 11 studies were not conducted in a population of healthcare workers, 20 did not present data on vaccine intention or uptake, 5 were related to vaccines other than the SARS-CoV-2 vaccine, 1 was unrelated to vaccination and 1 had been withdrawn. The 22 remaining articles were survey studies focussed on SARS-CoV-2 vaccine intention in healthcare workers. Estimates of SARS-CoV-2 vaccine acceptance varied widely from 27•7% - 94•5% depending on the country in which the study was performed, and the occupational group studied. Only 2 studies (both conducted in the USA) had a sample size greater than 10,000. Most studies found females, non-medical healthcare staff and those refusing influenza vaccine to be more likely to be hesitant. There was conflicting evidence about the effects of age and previous COVID-19 on hesitancy. Only 3 studies , presented data disaggregated by ethnicity, all finding Black ethnic HCWs were most likely to be hesitant. Common themes amongst studies that investigated reasons for vaccine hesitancy were concerns about safety of vaccines, fear of side effects and short development timeframes. We did not find any studies on SARS-CoV-2 vaccine hesitancy in UK healthcare workers in the published literature.This study is amongst the largest SARS-CoV-2 vaccine hesitancy studies in the literature. It is the largest study outside the USA and is the only study in UK HCWs. Our work focusses on the association of ethnicity with vaccine hesitancy, and we are the first study outside the USA to present results by ethnic group. The large number of ethnic minority HCWs in our study allows for examination of the outcome by more granular ethnicity categories than have previously been studied, allowing us to detect important differences in vaccine hesitancy levels within the broad White and Asian ethnic groupings. Our large sample size and the richness of our cohort study dataset allows us to control for many potential confounders in our multivariable analysis, and provide novel data on important potential drivers of hesitancy including discrimination, COVID-19 conspiracy beliefs, religion/religiosity and personality traits. Additionally, we combine quantitative with qualitative data providing a deeper understanding of the drivers of hesitancy and potential strategies to improve vaccine uptake in HCWs from ethnic minority communities.Around a quarter of UK healthcare workers reported SARS-CoV-2 vaccine hesitancy. In accordance with previous studies in other countries, we determined that female sex and lack of influenza vaccine in the previous season were important predictors of SARS-CoV-2 vaccine hesitancy in UK HCWs, although in contrast to most studies in the published literature, after adjustment we do not demonstrate differences in hesitancy levels by occupational role. Importantly, previous literature provides conflicting evidence of the effects of age and previous SARS-CoV-2 infection on vaccine hesitancy. In our study, younger HCWs and those with evidence of previous COVID-19 were more likely to be hesitant. This study provides novel data on increased hesitancy levels within Black Caribbean, Mixed White and Black Caribbean, Black African, Chinese, Pakistani and White Other ethnic groups. Mistrust  and misinformation appear to be important drivers of hesitancy within HCWS in the UK. Our data indicate that despite facing an increased risk of COVID-19 compared to their White colleagues, UK HCWs from some ethnic minority groups continue to exhibit greater levels of SARS-CoV-2 vaccine hesitancy. This study provides policy makers with evidence to inform strategies to improve uptake.Alt-text: Unlabelled box1An unprecedented global research effort has resulted in effective vaccines against the causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,23 despiVaccine hesitancy is defined by the World Health Organisation (WHO) as refusal or delay in vaccine acceptance The UK's Scientific Advisory Group for Emergencies (SAGE) ethnicity subgroup has identified the following key factors underlying vaccine hesitancy in ethnic minority groups: physical barriers to access; lower trust and confidence in vaccine efficacy and safety, and general lack of trust in healthcare and health research due to structural and institutional racism and discrimination; lower perceived risk; and contextual factors such as gender, education, socioeconomic status and family decision-making Studies of COVID-19 vaccination intentions and uptake in HCWs since December 2020 show variability in uptake between countries and, as with general populations, variability by occupational and demographic groups ,22,31,32To date there have been very few large-scale studies of COVID-19 vaccine hesitancy among ethnically diverse HCWs. We undertook an analysis to understand levels of vaccine hesitancy and the factors predicting this in UK HCWs using interim data from the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH), integrating survey data from a nationwide prospective longitudinal cohort study and qualitative data from HCWs nationwide.22.1th December 2020 with interim data downloaded 19th February 2021), and qualitative data from UK-REACH interviews and focus groups (undertaken from December 2020 to March 2021). Both studies took place in healthcare settings in all four nations of the UK with clinical and non-clinical HCWs from diverse ethnic backgrounds; see study protocols for methodological details ) depending on their distribution. We compared groups  with chi-squared tests for categorical variables, and t-tests and analyses of variance for continuous measures, with non-parametric equivalents used as appropriate. Due to the number of tests being performed we considered associations statistically significant at p≤0•001. We checked 2 way interactions of ethnicity with other significant predictors of hesitancy using complete cases, and used a likelihood ratio test to determine whether there was an improvement in model fit by inclusion of the interaction term.We used univariable and multivariable logistic regression to determine unadjusted and adjusted associations of variables described above with SARS-CoV-2 vaccine hesitancy.mice (Multiple Imputation by Chained Equations) v3·13·0 in R version 4·0·4, using predictive mean matching (pmm) for all variables, with 20 imputations and five iterations per imputation (See We used multiple imputation (MI) to replace missing data in all logistic regression models using the package tion See .2.32.3.1A purposive sample of clinical and non-clinical HCWs aged 16 or older from ethnic minority and White backgrounds with experience of working in UK healthcare settings during COVID-19, recruited through study partners, community organisations, and NHS organisations across the UK.2.3.2Data were collected through in-depth semi-structured interviews and focus groups using a piloted topic guide. The topic guide explored experiences of working during the COVID-19 pandemic, fears and concerns, stigma, discrimination, racism, views on the COVID-19 vaccine, challenges participants encountered in accessing information, and their perceived risk. Interviews and focus groups were recorded and transcribed prior to analysis. We also collected data on participant gender, ethnicity, age, country of birth, and job role. Free text data collected through the cohort study in response to the following three questions were also included: “What are your thoughts on why people from ethnic minorities working in health and care have been more severely affected by COVID-19?”, “How do you see society changing as a result of COVID-19?” and “How do you see your own future changing as a result of COVID-19?” [38]We used framework analysis to analyse anonymised transcripts from interviews and focus groups, and free text data from the cohort study. We developed the initial framework based on a preliminary thematic analysis of the data and the WHO framework for behavioural considerations for acceptance and uptake of COVID-19 vaccines 2.4Both studies were approved by the Health Research Authority . All participants gave written informed consent.2.5We worked closely with a Professional Expert Panel of HCWs from a range of ethnic backgrounds, occupations, and genders, as well as with national and local organisations (see study protocols) ,34.2.6The funders had no role in study design, data collection, data analysis, interpretation, writing of the report33.13.1.1th December 2020 and 19th February 2021, professional regulators sent 1,052,875 HCWs email invitations with a link to the study website, and 21 National Health Service (NHS) Hospital Trusts publicised the questionnaire to their staff and invited staff by email. Approximately 46% of the emails  sent by the regulators were received/open. As of 19th February 2021, 24,601 participants had clicked through to the study website and registered.Between 4th February 2021, 15,151 participants had started the questionnaire. The analysed interim cohort were formed of 11,584 participants who both completed the questionnaire and answered the question about their sex. This gives an effective response rate of 47.1% of those who registered on the study website . See As of 193.1.2Hesitant participants scored higher on the ‘COVID-19 conspiracy beliefs’ scale , were less confident their employer would address a concern about unsafe clinical practice (63·3% vs 73·3% p<0·001) and were more likely to have laboratory evidence of previous SARS-CoV-2 infection  compared to the non-hesitant cohort. 136 pregnant HCWs were included in the analysis, of whom 86 (63·2%) were SARS-CoV-2 vaccine hesitant. Reasons for hesitancy: Among those who reported reasons for SARS-CoV-2 vaccine hesitancy, the White group  were less concerned than other ethnic groups about potential vaccine side effects or about the vaccine not having been tested in diverse ethnic groups, and they were less likely to want to delay until others had the vaccine. Reasons for hesitancy overall and by broad ethnic grouping are given in 3.1.3Demographic predictors of SARS-CoV-2 vaccine hesitancy: Trust, COVID-19 risk and psychological predictors of SARS-CoV-2 vaccine hesitancy and refusal: Greater belief in COVID-19 conspiracies was significantly associated with increased odds of hesitancy . Increasing confidence that concerns raised about unsafe practice would be addressed by their employer decreased the odds of hesitancy . Those who had received the influenza vaccine in winter 2019/2020 were around half as likely to be SARS-CoV-2 vaccine hesitant compared to those who had not . HCWs who reported testing positive for SARS-CoV-2 by PCR or serology, were significantly more likely to be hesitant than those testing negative . Pregnant HCWs were over 7 times as likely to be hesitant . 2 way interaction terms between ethnicity and other significant predictors did not improve model fit.Significant predictors of vaccine hesitancy on multivariable analysis remained unchanged when we coded participants who had accepted the vaccine as non-hesitant (even if they had considered not having the vaccine)(data not shown).3.23.2.1We included 99 individuals, 41 recruited through interviews (n=24) and focus groups (n=17), and 58 from the longitudinal cohort study (free text comments provided about vaccinations). Among the 41 qualitative participants, 13 were Asian (32%), 12 were Black (29%), and 10 were White (24%). 27 (66%) were women, and 24 were born in the UK (59%). 18 participants were allied health professionals, pharmacists, and dentists (44%), whilst 9 were doctors (22%), 3 were nurses or midwives (7%), and 11 were non-clinical (27%). Among the 58 cohort participants, 42 were White (72%), 8 were Asian (14%), and 4 were Black (7%). 48 participants (83%) were women, and 44 (76%) were born in the UK. 26 (45%) of participants were allied health professionals, pharmacists, or dentists, 7 were doctors (12%), whilst 23 (40%) were nurses or midwives.3.2.2We identified four intersecting themes describing key drivers of and ways to address vaccine hesitancy among HCWs: Trust, Perceived risk, Health information and messaging, and Improving delivery , others were concerned about the potential lack of equity for those who chose not to have the vaccine, and that mandating vaccination could create further ethnic divides between communities and increase stigma and discrimination. Participants also discussed how ensuring equity in accessibility and opportunity to have the vaccine would be paramount for improving delivery.Outreach through involvement: Participants described how the vaccine roll-out could be improved through better engagement with and involvement of HCWs, particularly those from ethnic minority communities. The narratives pointed to the lack of inclusion of marginalised communities throughout the pandemic, and the potential benefit of increasing visibility of less well represented groups in the media to promote vaccine uptake and trust.Participants also discussed the importance of promoting vaccination through trusted networks, and the value of more proactive involvement and engagement of healthcare workers from diverse ethnic backgrounds. An important aspect of both building trust and increasing accessibility was acknowledging cultural differences in understandings of and access to vaccines. Participants highlighted how the involvement of minoritised communities can play an important role in bridging cultural divides, and the potential benefit of outreach activities for addressing logistical challenges in delivering the vaccine.4In this analysis of interim data from nearly 12,000 HCWs across the UK, approximately a quarter of participants reported SARS-CoV-2 vaccine hesitancy. HCWs from Black Caribbean, Black African and White Other ethnic groups reported higher hesitancy than those from the White British group after adjusting for other predictors. Additional factors predicting hesitancy were scoring higher on the COVID-19 conspiracy beliefs scale, lower trust in employer, pregnancy, and previous COVID-19. Qualitative data showed information and messaging influenced vaccine concerns. Speed of vaccine development, experiences of discrimination and structural inequalities also contributed to a lack of trust in the vaccine.Our finding of 23% of UK HCWs being SARS-CoV-2 vaccine hesitant is in keeping with a recent systematic review of COVID-19 vaccine uptake, which found an average acceptance of 57% (range 28%-78%) across countries and occupation groups Due to the novel nature of COVID-19, the evidence base for barriers to SARS-CoV-2 vaccination in ethnic minority communities is limited. However, UK's SAGE ethnicity subgroup identified barriers to vaccine uptake amongst ethnic minority groups including lower trust in vaccine efficacy/safety (particularly speed of vaccine development), mistrust of healthcare organisations , lack of representation in vaccine trials, and institutional racism and discrimination These results have important implications for public health measures aimed at improving vaccine uptake. It has been reported that mandatory SARS-CoV-2 vaccination is being considered for care home staff in the UK We found that higher scores on the COVID-19 conspiracy beliefs scale was associated with vaccine hesitancy, and this was also more likely in ethnic minority groups as compared to those of White ethnicity. To our knowledge, we are the first to show this effect in a HCW population. A general population survey in the UK found that belief in COVID-19 conspiracies was more likely in those who were SARS-CoV-2 vaccine hesitant and in ethnic minority groups We found that those with evidence of previous COVID-19 were more likely to be vaccine hesitant than those who tested negative by PCR/serology Pregnancy was a strong predictor of vaccine hesitancy in our cohort. This may be because during the early phase of the vaccine rollout pregnant women were advised to delay receipt of SARS-CoV-2 vaccination until after delivery We found some evidence that vaccine hesitancy was becoming less frequent as time moved forward which may indicate increasing confidence/experience in the UK vaccine programme although further work is required to understand this.This is the largest study of SARS-CoV-2 vaccine attitudes in a multi-ethnic sample of UK HCWs at the start of a vaccine roll-out. The combination of quantitative and qualitative data provides an in-depth understanding of hesitancy among different ethnic groups. Despite these strengths, our study also has a number of limitations. There was the potential for self-selection/responder bias and we were not able to directly compute response rates by different ethnic groups due to information governance processes but the cohort respondents’ characteristics were broadly similar to the wider NHS workforce thus indicating that our sample is likely to be representative, albeit with a smaller proportion of ancillary staff. Overall the cohort included a relatively small number of ancillary staff. Similarly, we used the Office for National Statistics 18 ethnicity categories to provide more granular, policy-relevant, information and this resulted in some of the ethnicity categories having small numbers. Due to the rapidly evolving nature of the vaccination programme, questions relating to vaccination were changed midway through the baseline questionnaire rollout which could have impacted on outcome, although we have controlled for questionnaire version in the multivariable analysis. Our outcome measure of vaccine hesitancy is based upon the WHO's definition of refusal or delay in vaccine acceptance which means that some individuals who initially delayed acceptance but then went on to receive the vaccine would still be classified as hesitant. We think this is valid as HCWs delaying vaccine uptake during a global pandemic should be classed as hesitant. This may slightly overestimate the degree of hesitancy but we think the effect is likely to be minimal as our overall figure for hesitancy is in keeping with other published reports. The relevant sections of the baseline questionnaire were not designed to capture actual vaccine uptake as an outcome but rather attitudes towards vaccination and thus we cannot determine whether access to vaccination could be a driver in vaccine hesitancy in our sample, however this will be captured in follow-up questionnaires.In summary, we have identified key predictors of SARS-CoV-2 vaccine hesitancy in HCWs and demonstrate clear ethnic differences in hesitancy levels. Importantly, we have established drivers behind vaccine hesitancy in HCWs, which include belief in COVID-19 conspiracies and mistrust  and suggest that these factors may account for some of the observed ethnic differences in hesitancy. Strategies to improve vaccine confidence are urgently required to prevent these ethnic disparities from widening. Such strategies may include building trust and involvement/engagement of ethnic minority HCWs in the vaccination rollout, promoting vaccination and overcoming misinformation utilising trusted networks in ethnic minority communities.MP conceived of the idea and led the application for funding with input from MDT, KK, ICM, KW, RF, LBN, SC, KRA, LJG, ALG and CJ. The survey was designed by KW, MP, ICM, CMel, CJ, ALG, LBN, RF and CAM. Online consent and survey tools were developed by LB. KW, CAM, ICM, and LBN wrote the first draft of the manuscript with input from MP and all co-authors. All authors approved the submitted manuscript.To access data or samples produced by the UK-REACH study, the working group representative must first submit a data and material request form to the Data Access Committee (DAC) providing details for all manuscript proposals. The DAC will establish priorities for core and ancillary projects. For ancillary studies outside of the core deliverables, the Steering Committee will make final decisions once they have been approved by the Core Management Group and the DAC. Decisions on granting the access to data/materials will be made within eight weeks. Third party requests from outside the Project will require explicit approval of the Steering Committee once approved by the Core Management Group and the DAC.The lead authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.UK-REACH is supported by a grant from the MRC-UK Research and Innovation (MR/V027549/1) and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19.Core funding was also provided by NIHR Biomedical Research Centres.KW is funded through an NIHR Career Development Fellowship (CDF-2017-10-008).CAM is an NIHR Academic Clinical Fellow (ACF-2018-11-004).LBN is supported by an Academy of Medical Sciences Springboard Award (SBF005\1047).ALG was funded by internal fellowships at the University of Leicester from the Wellcome Trust Institutional Strategic Support Fund (204801/Z/16/Z) and the BHF Accelerator Award (AA/18/3/34220).MDT holds a Wellcome Trust Investigator Award (WT 202849/Z/16/Z) and an NIHR Senior Investigator Award.KK is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC EM).KK and MP are supported by the NIHR Leicester Biomedical Research Centre (BRC).MP is supported by a NIHR Development and Skills Enhancement Award.This work is carried out with the support of BREATHE -The Health Data Research Hub for Respiratory Health [MC_PC_19004] in partnership with SAIL Databank. BREATHE is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK.The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. This research was funded in whole, or in part, by the Wellcome Trust [WT204801/Z/16/Z and WT 202849/Z/16/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.KK is Director of the University of Leicester Centre for Black Minority Ethnic Health, Trustee of the South Asian Health Foundation, Chair of the Ethnicity Subgroup of the UK Government Scientific Advisory Group for Emergencies (SAGE) and Member of Independent SAGE. SC is Deputy Medical Director of the General Medical Council, UK Honorary Professor, University of Leicester. MP reports grants from Sanofi, grants and personal fees from Gilead Sciences and personal fees from QIAGEN, outside the submitted work. KW, ICM, CAM, LBN, ALG, CM, LB, MG, FW, AAO, OH, AG, CJ, MDT, SS, BG, AA, SZ, RR and LJG have no competing interests to declare.


The pregnant population experienced unique COVID-19 physical and psychosocial stressors such as direct health concerns related to the virus and loss of access to resources since the COVID-19 emerged as a global pandemic in early 2020. Despite these COVID-19-related stress and concerns, the maternal experience of bonding with their unborn children has not been well studied. This work aimed to study the association between mental health history, current mental health symptoms, psychological factors, COVID-19-related worries, and self-reported maternal-fetal bonding of pregnant women.This online, survey-based cross-sectional study focused on women pregnant during the pandemic and assessed 686 women using data collected from May 19, 2020 to October 3, 2020. Enrolled respondents completed assessments in which they self-reported maternal-fetal bonding, mental health symptomatology, psychological factors, and COVID-19-related worries regarding health, pregnancy, and resources.Depressive symptoms in pregnant women were associated with lower quality maternal-fetal bonding, while a higher level of anxiety was positively associated with bonding; however, past history of depression or generalized anxiety diagnosis did not appear to be as relevant as active symptomatology. Maternal resilience, but not distress tolerance, appeared to be a protective factor resulting in improved bonding. Higher levels of worry regarding impact of COVID-19 on health were significantly associated with improved bonding, while worries regarding the impact of COVID-19 on the pregnancy or resources were not significantly associated with bonding. The study also found associations between different sociodemographic variables and bonding, including a strong positive association between first time motherhood and bonding and a negative association between higher education and income and bonding.This study was the first to report potential protective and risk factors to the maternal-fetal bonding process in women pregnant during the COVID-19 pandemic. Unique COVID-19 concerns exist; however, anxiety and COVID-19 concerns do not appear to undermine maternal-fetal bonding while active depressive symptomatology may negatively influence bonding; interventions increasing maternal resilience may be particularly valuable. The Coronavirus Disease 2019 (COVID-19) has presented unique stressors on the pregnant population since its emergence as a global pandemic in early 2020 , recent Maternal-fetal bonding, the process of forming a relationship and an emotional connection to the fetus , 19, is This study aimed to examine the associations between mental health history, current mental health symptoms, maternal psychological factors, worries related to the COVID-19 pandemic, and self-reported maternal-fetal bonding in pregnant women.This was an online, survey-based cross-sectional study focused on women pregnant during the pandemic and at the time of data collection. Details of the broader study design and methodology can be found elsewhere , 16.Recruitment and data collection took place online between May 19, 2020 and October 3, 2020; recruitment was national and utilized word of mouth, email list-serves, and social media.Participant eligibility criteria were female gender, aged 18 years or older, living in the United States, at least 6 weeks pregnant at the time of enrollment and data collection.Prior to any data collection, those eligible and interested in participating were asked to review an overview of the study including procedures, risks, benefits, participant rights, and study team contact information. Those who remained interested in study participation were asked to provide informed written consent of the study. This was obtained by participants selecting the statement “I agree to participate in the study” at the end of the informed consent. No compensation was provided for enrollment in or completion of the study. Participation was self-selecting and opt-in, and participants were able to withdraw their participation at any time.All procedures were approved by the Mass General Brigham Institutional Review Board.Study participation constituted enrolled respondents participating in a 30-to-45-min survey administered online through REDCAP about pregnancy, experiences related to COVID-19, and psychological well-being as part of the PEACE  2020 Study. Participants completed the survey on average 121 days after March 13, 2020, at which the pandemic was declared a national emergency in the United States. Data quality was ensured by embedding various human verification steps such as reCAPTCHA as well as number counting tasks, and attention checks, including three multiple choice questions with the correct answer being purposely against common sense that required close reading comprehension of the prompt, in addition to inspections to assess for any response irregularities among various measures. These checks were designed to ensure that answer choices throughout the study were not made at random or insincere.Attempts to address potential bias introduced by a self-selecting patient sample included lowering barriers to participation to encourage as widespread and representative enrollment as possible. In the United States, 85% of women own a smartphone, and over 91% of adults own either a computer or a smartphone , 41. By N = 686).The study size was determined by the number of responses to the online survey during the study period. Data from all participants meeting eligibility requirements, with survey responses passing data quality standards and complete responses to all variables were used in the analysis  2020 Study as detailed above. This dataset is proprietary but can be made available upon reasonable request to the lead author.This factor was calculated as a sum score of four items from the Coronavirus Health Impact Survey (CRISIS) that were designed to evaluate an individual’s concern about COVID-19 directly affecting the health of oneself, family, and friends  through COVID-19-related pregnancy worries, an 8-item measure developed for this study, evaluated worries specific to pregnancy during the COVID-19 pandemic. Participants indicated their level of concern about the potential impact of COVID-19 on their pregnancy, including concerns related to vertical transmission, prenatal care, and birth partner restrictions. The measure also incorporated their self-reported stress about visiting the hospital due to the COVID-19 pandemic. Cronbach’s alpha indicated good reliability (α = 0.810).COVID-19-related resource worries, a 6-item measure , evaluatThe 10-item Connor-Davidson Resilience Scale  was usedThe 15-item Distress Tolerance Scale  was usedThe Life Events measure inquired about participant experience over the past 6 months with 13 events, using a binary ‘yes’ or ‘no’ response. Examples of items on the measure include job loss, deployment, divorce, jail time, and homelessness .The Center for Epidemiologic Studies-Depression (CES-D)‘s 20- item self-report measure was used to evaluate the severity of depression in participants . When suThe Generalized Anxiety Disorder Scale (GAD-7 ) was useTo assess maternal-fetal bonding, we used the Maternal Antenatal Attachment Scale (MAAS ). This 1The duration of the pandemic was defined as the period of time, in days, between when each respondent started the survey and the date when COVID-19 was declared as a pandemic .Maternal Age, Maternal Race, Maternal Education level, Maternal Income, Gestational age of the fetus, Past Psychiatric History of Major Depressive Disorder or Anxiety, and Nulliparity were also included in the analysis as covariates.> 16, consistent with recommendations for a cutoff score [> 10, in keeping with the cutoff score for moderate anxiety recommended by developers of the measures [Probable clinical depression was defined as CES-D ff score , with prmeasures . ‘High lN = 686). Multiple regression analysis was conducted with maternal-fetal bonding regressed on sociodemographic characteristics (Block 1), mental health history (Block 2), current mental health symptoms (Block 3), psychosocial factors (Block 4), and COVID-19-related worries (Block 5), such that the contributions of potential confounders of maternal-fetal bonding were controlled via a blocked structure to the analysis. The variables were normally distributed and predictors indicated acceptable levels of collinearity (VIF < 5). Sensitivity analyses were not performed. Two subgroups were examined in more detail: those reporting high levels of worries about COVID-19 influencing their mental or emotional health, and those reporting high levels of worry that COVID-19 will affect their ability to bond with their baby, with CES-D and GAD-7 scores compared to the remainder of the cohort in the former subgroup, and MAAS scores in the latter subgroup, and analyzed in both cases with Student’s t-tests.Data were analyzed in SPSS version 24 using descriptive and inferential statistical methods including Student’s t-test, Pearson’s correlation coefficient, and multiple regression analysis. For all analyses, only pregnancies with complete data on all variables of interest for this study were included, such that the total sample size for all analyses is constant . The mean score of 14.31 on the CES-D corresponds to participants reporting that they have experienced the majority of response items for 1–4 days over the past week, with each item representing a depressive symptom. A mean score of 6.34 on the GAD-7 may be conceptualized as representing a response of ‘several days’ over the past two weeks for most items relating to anxiety symptom frequency, or ‘nearly every day’ for several items. Using the aforementioned binary cutoffs, 37.2% of respondents reported symptom levels indicating probable clinical depression and 24.2% reported symptom levels indicating probable clinical anxiety. These states were highly comorbid, with 83.1% of women with probable clinical anxiety also experiencing probable clinical depression and 54.1% of women with probable clinical depression testing above the binary threshold for anxiety as well. Among our sample, 71.4% of women with probable clinical depression had no prior history of diagnosed depression, while 54.8% of women with probable clinical anxiety had no prior history of diagnosed anxiety.The mean scores for depression and anxiety symptoms assessed from standardized measures  are shown in Table p = 0.701).The mean number of potentially distressing life events was 1.35 (SD = 1.33), with the three most commonly experienced life events being ‘I argued with my husband or partner more than usual,’ ‘My husband, partner, or I had a cut in work hours or pay,’ and ‘A close family member was very sick and had to go to the hospital.’ The average score for Resilience was 27.44 (SD = 6.13), and for Distress Tolerance was 53.68 (SD = 11.99). The mean scores for COVID-19-related worries were 12.02 (SD = 3.70) for health worries, 20.15 (SD = 6.42) for worries regarding impact on pregnancy, and 11.48 (SD = 4.24) for worries regarding access to resources. Finally, participants had an average sum 71.82 (SD = 7.29) out of a total possible score of 90 on the MAAS; a sum of 71 or below, corresponding to less than 80% the maximum MAAS, may be interpreted to represent low antenatal bonding [p < 0.0001) and higher GAD-7 scores . High levels of worries on this single item response produced a positive predictive value of 48.0% for probable clinical depression (CES-D > 16) and 35.7% for probable clinical anxiety (GAD-7 > 10). Given this study’s particular interest in bonding, groups of higher and lower levels of worries were compared for the specific response item in the COVID-19 pregnancy-specific worries scale about COVID-19 affecting their ability to bond with their unborn baby. While 15.3% (105/686) of women reported high levels of worries about their bonding, there was no significant difference in MAAS scores between the higher and lower levels of worries groups .Overall, women were more likely to be concerned about their mental and emotional health than about contracting COVID-19 itself. High levels of worries about COVID-19 influencing their mental or emotional health were experienced by 24.9% of women. This subset of women also had significantly higher CES-D scores  for all blocks besides mental health history. GA , first pregnancy  and mothers reporting being Hispanic/Latino  appeared positively associated with bonding. Higher incomes  and educational levels  did not appear protective. After accounting for sociodemographic characteristics as well as the pandemic duration, history of a mental health diagnosis (depression or anxiety) did not exhibit any significant association with maternal-fetal bonding. However, with prior mental health history taken into account, higher levels of endorsed depression symptoms during pregnancy were associated with lower levels of maternal-fetal bonding  and higher levels of anxiety symptoms with higher levels of maternal-fetal bonding . When considering depressive and anxiety symptoms, higher levels of resilience were correlated with higher levels of maternal-fetal bonding , while distress tolerance and disruptive life events were not significantly correlated. Lastly, reported worries about COVID-19 related health were showed to contribute to the model based on the control of sociodemographic characteristics, mental health history, mental health symptoms, and psychosocial factors. Higher levels of COVID-19-related health worries were associated with higher levels of maternal-fetal bonding , whereas higher levels of COVID-19-related resource worries demonstrated a trend toward lower levels of maternal-fetal bonding  and pregnancy-specific COVID-19 worries were not significant . COVID-19-related worries accounted for 18.5% of the model variance with regards to maternal-fetal bonding.Table This study aimed to examine the association between mental health history, current mental health symptoms, psychological factors, worries related to COVID-19, and the self-reported maternal-fetal bonding experiences of pregnant women during the COVID-19 pandemic. Identifying the risks and protective factors for maternal-fetal bonding during the COVID-19 pandemic can facilitate tailored counsel to patients and clinicians.Those completing the study were predominantly White, well-educated, and financially secure women in their early thirties experiencing their first pregnancies. When reflecting upon COVID-19-related worries, participants rarely expressed worries about their ability to obtain COVID-19 testing and treatment. However, the majority of women expressed high levels of worries about the risk posed to their personal health. Entering the hospital and the labor and delivery process were of particular concern as a source of potential exposure. Although preliminary evidence doesn’t indicate vertical transmission is a significant risk , 54, motA number of factors appear to be protective of maternal-fetal bonding including greater GA, first pregnancy, those who identify as Hispanic/Latino, and high resilience scores. Higher incomes and educational levels were associated with poorer bonding. These associations were largely consistent with what has been reported in the literature under non-pandemic conditions , 30, 32.Of psychological factors assessed by this study, resilience appeared to be a meaningful protective factor for maternal-fetal bonding. Past research has demonstrated resilience as a protective factor against prenatal anxiety and depression both in non-pandemic  and pandNotably, past psychiatric history was not associated with bonding. Considering most women reporting probable clinical depression or anxiety had no prior diagnoses of depression or anxiety, this suggests clinically relevant distress may be newly emerging in many pregnant women and all patients should be screened carefully. Those presenting to clinics with anxiety symptoms should also be screened for depression given the high degree of comorbidity and disparate potential impacts on maternal-fetal bonding and because prenatal anxiety is associated with later postpartum depression .This study has some limitations presented by the voluntary and self-selecting nature of participant enrollment, which resulted in demographics that are highly weighted toward highly educated, higher income, White women. Minimal concern regarding resource acquisition may reflect the relative financial stability of most completing the survey. These factors all may limit the generalizability of the study findings, and in the future additional focus on racial/ethnic minority and disadvantaged groups will be needed. As well, it is possible that women with COVID-19-related worries were more interested in engaging with the study, which could result in an overinflation of estimates of worry/anxiety symptoms; similarly, those with very high levels of depressive symptoms impairing concentration and attention may have been screened out by quality control attention checks and thus be underrepresented. However, the design of the study may also allow it to be particularly well-poised to capture the group of women who are most likely to be presenting questions and concerns to their obstetricians at this time.Based on these findings, we conclude that COVID-19-related worries, in addition to depressive and anxiety symptoms, may influence maternal-fetal bonding during the pandemic. This work has several clinical implications. OB/GYN providers should plan to screen all pregnant women for depression, early and often, regardless of mental health history and to speak to their patients regarding their mood . Clinici


Case Presentation. We report two cases of CAPS in which the diagnosis was confirmed by genetic tests and an evaluation of the therapeutic response to anti-tumor necrosis factor (anti-TNF) agents.  Cryopyrin-associated periodic syndromes (CAPSs) are a group of autoinflammatory disorders caused by a mutation in the NLRP3 gene. NLRP3 mutations increase inflammasome activation; therefore, IL-1 targeted therapies are frequently used in the aforementioned disorders.  IL-1 inhibitors are highly effective in treating CAPS patients. Most patients with severe symptoms such as neurologic involvement improve with IL-1 blockade. Anti-TNF agents might be effective in reducing mild manifestation; however, they are not effective in improving more severe complications. Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory disorders caused by a gain-of-function mutation in the NLRP3 CIAS1) gene located on the long arm of chromosome 1. CAPS are a spectrum of disorders with a range of severity. The moderate form of the CAPS is Muckle–Wells syndrome, often inherited as an autosomal dominant trait. The main clinical manifestations include recurrent episodes of fever, urticaria-like rash, and ocular and articular involvement. The severe form of the CAPS is the chronic infantile neurological cutaneous and articular (CINCA) disease that is presented with urticaria-like rash, mental delay, arthritis, and sensorineural hearing loss  gene loc.α may play a role in regulating and activating the NLRP3 inflammasome [Formation of NLRP3 inflammasome leads to caspase 1-mediated release of the proinflammatory cytokines such as IL-1B and IL-18. Since NLRP3 mutations can result in increased inflammasome activation and IL-1 production, IL-1 targeted therapies are used frequently in the patients. Interleukin 1 receptor antagonists such as anakinra can improve CAPS symptoms and prevent major complications such as hearing loss and amyloidosis –9. Some ammasome , 10.α in the pathogenesis of the disorders.We will describe two cases of CAPS and evaluate the responses to anti-TNF agents and IL-1 inhibitors. The current study aims to describe the relative effectiveness of anti-TNF agents in improving CAPS symptoms, highlighting the role of TNF-A 1-year-old boy was brought to our clinic with joint pain and swelling in his left ankle and knees that had lasted for more than 14 days. Since birth, he had had a recurrent urticarial rash that was not triggered by cold or other physical stimuli . Often pEchocardiography expressed normal ventricular function and no pericardial effusion. He had normal bone marrow aspiration and biopsy. Due to prolonged fever, arthritis, and an increase in acute phase reactants, the diagnosis of systemic juvenile idiopathic arthritis was established for him. Therefore, he was treated with prednisolone, methotrexate, and naproxen. At the age of three, he was readmitted to the hospital because of his inability to walk due to arthritis, persistent fever, and urticarial rash. An X-ray of the knees indicated metaphyseal irregularity, widening of growth palate, and soft tissue swelling . In threA 2-year-old girl was referred to our clinic for periodic fever and rash. Fever often worsened at night; besides, she had abdominal pain during some febrile episodes. She had had a recurrent purpuric urticarial rash since three months . The rasThe signs and symptoms of the two patients are compared in It is important to know that autoinflammatory syndromes are rare; however, they should be considered in any patient with recurrent or persistent inflammation. Most patients with these disorders experience delays in diagnosis. Our first patient had a fever, urticarial rash, and arthritis. He had been treated with systemic juvenile idiopathic arthritis (SJIA) diagnosis, but he was diagnosed with CAPS after further evaluation. The second patient had a recurrent fever and urticarial rash, but there was no joint involvement. She was initially treated with a diagnosis of SJIA, but her final diagnosis was Muckle–Wells syndrome after more evaluation and genetic tests.The symptoms of cryopyrin-associated periodic fever syndromes are variable presented with a broad range of clinical manifestations . InheritIn young children with Muckle–Wells, hearing loss and amyloidosis does not usually occur, and the only manifestation of the disease may be recurrent urticarial rash and fever. The second case had typical symptoms of Muckle–Wells, including urticaria-like rash and fever. Nevertheless, she did not have joint involvement. The primary treatment for CAPS is the IL-1 inhibitors, which can completely relieve the disease's symptoms , 16, 17.Both of our patients were initially treated with anti-TNF agents because IL-1 inhibitors were unavailable. In the first case, joint involvement and fever were resolved with anti-TNF agents; yet, the urticarial rash did not respond to this therapy, and optic disc edema occurred during the anti-TNF therapy. The second case was initially treated with an anti-TNF agent (etanercept) too. Nevertheless, the response was transient, and relapse occurred after four months. Some of the CAPS manifestations, such as fever, were resolved with anti-TNF agents, but some of them did not resolve fully, and relapse might occur. After IL-1 inhibitors therapy, all of the symptoms resolved dramatically and entirely.α might play a regulatory role upstream of the NLRP3 inflammasome. Caspase 11-mediated inflammasome activation participates in driving the production of TNF-α. However, the cellular source of the TNF-α and the mechanism of generation are unclear. In patients with CAPS, proinflammatory cytokines such as IL-1B play an essential role in the development of symptoms. At least half of the patients with CAPS have a range of neurological manifestations at some course of illness. A few studies have shown that IL-1 inhibitors are effective for treating neurological symptoms and preventing severe CNS complications. The most common neurologic manifestations in CAPS are headache, aseptic meningitis, seizures, papilledema, and hearing loss. Serious neurological complications include optic atrophy and mental disability. Skin rash, fever, and arthritis are milder CAPS symptoms [TNF-symptoms –20.In case reports, causal inference is not plausible. Response to the treatment could be a mere coincidence. Accordingly, the effects of anti-TNF agents on clinical presentations from the current case report of CAPS cannot be generalized.α inhibitors effectively reduced mild manifestations such as fever and rash, they were not effective for improving more serious complications like papilledema and arthritis. Since CAPS is a rare disease, there are few reports of this disorder. Future studies are needed to evaluate the effect of such medical treatments on improving the various symptoms of CAPS.Based on our experiences in this study, although TNF-


A trend towards significant NOL index dissociation over time was observed between long COVID-19 participants without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904). Long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, that is reflected by the NOL index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia.Increasing numbers of COVID-19 patients, continue to experience symptoms months after recovering from mild cases of COVID-19. Amongst these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, headaches and hypoxia. However, the involvement of the autonomic nervous system, expressed by a dysautonomia, which can aggregate all these neurological symptoms has not been prominently reported. Here, we hypothesize that dysautonomia, could occur in secondary COVID-19 infection, also referred to as “long COVID” infection. 39 participants were included from December 2020 to January 2021 for assessment by the Department of physical medicine to enhance their physical capabilities: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. Heart rate variability (HRV) during a change in position is commonly measured to diagnose autonomic dysregulation. In this cohort, to reflect HRV, parasympathetic/sympathetic balance was estimated using the NOL index, a multiparameter artificial intelligence-driven index calculated from extracted physiological signals by the PMD-200 pain monitoring system. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. A significant NOL index dissociation over time between long COVID-19 participants with fatigue and control participants was observed  on December 16, 2020. Reported symptoms lead to disability with debilitating fatigue, breathlessness, headaches, muscle and/or joint pain, brain fog, memory loss, sensation of pressure on the chest, palpitations, nausea, dramatic mood swings in combination with exercise intolerance and a relapsing–remitting pattern of recurrence2. Among these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, and headaches3, and also respiratory symptoms, such as hypoxia4. Nevertheless, the involvement of the autonomic nervous system (ANS) which can aggregate all these neurological symptoms in COVID-19 infection has been under reported in the literature5. One of the last and recent hypotheses is that these symptoms could be the manifestation of a dysautonomia in long COVID-19 infection6.Increased numbers of COVID-19 patients, continue to experience symptoms several months after mild cases of COVID-195. Fatigue is one of the major clinical characteristic of dysautonomia in COVID-19 patients9.Dysautonomia is marked by the failure or the increased of the sympathetic or parasympathetic components activities in the ANS. Dysautonomia shows numerous clinical symptoms, such as fatigue, labile blood pressure, orthostatic hypotension, dysfunction in heart rate variability (HRV), apparition of impotence, dysfunction of bladder, and damages in bowel functions. Dysautonomia could be acute or chronic, progressive but also reversible and was associated with numerous pathologies, such as alcoholism, diabetes, or either Parkinson’s disease. Dysautonomia was also associated with viral infections, including hepatitis C virus, HIV, or Epstein-Barr virus10. HRV is mainly related to emotional, social, cognitive and health levels11. HRV is the main marker of the modulation of the sympathetic and parasympathetic branches of the ANS, and thus, of dysautonomia12. The low-frequency band reflects the modulation of sympathetic and parasympathetic branches on the heart13 and has been considered as an index of the sympathovagal imbalance14. In the current study, we apply the nociception level (NOL) index to estimate HRV and overall ANS balance. The NOL algorithm  is a multiparameter nonlinear combination of HR, HRV, amplitude of the finger photoplethysmogram, skin conductance level, and their time derivatives, obtained using a non-invasive finger probe, displayed on the monitor screen as a scale of 0–100 derived using a random forest regression15.HRV measurement is a commonly used method for cardiovascular follow-up in healthy participants, athletes and cardiovascular patientsHere, we hypothesize that dysautonomia could occur in secondary COVID-19 infection, also called “long COVID” infection. We aim to demonstrate this phenomenon by illustrating HRV dysregulation, reflected through the NOL index showing the sympathetic/parasympathetic balance, in long COVID-19 participants. We propose that the symptoms secondary to COVID-19 could be directly related to this virus or its immune-related dysregulation to the ANS, leading to transient or long-term dysautonomia.The present study prospectively included 39 participants from December 2020 to January 2021: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. COVID-19 diagnosis was defined as positive polymerase chain reaction (PCR) test, serologic test or computed tomography (CT) scan. Participant’s eligibility for inclusion in the study was assessed during their long COVID-19 follow-up in the Department of physical medicine and rehabilitation of the Foch hospital . This follow-up aims to enhance the participants in physical activity through a personalized program of exercises-long COVID-19 rehabilitation. Exclusion criteria were age inferior to 18 years, Nociception level unusable, vasoactive medication, toxicological or alcoholic participants, BMI superior to 35, previous intensive care unit (ICU) hospitalization and participants legally protected or deprived of their freedom.15 obtained continuously using a non-invasive finger probe. The NOL is based on the advanced statistical and machine learning techniques to combine multiple signals into a single composite index. The NOL is a multiparameter nonlinear combination of HR, HRV, PPGA and SCL derived from random forest regression displayed on a scale from 0 to 100. Random forest is an algorithmic modeling approach that enables combining multiple parameters of different origin and discovering their complex nonlinear interactions16.HRV was reflected using the NOL index, initially developed in the operating theater to guide analgesia administration during surgery. The NOL index was calculated from the extracted signals by the PMD-200 pain monitoring system. The NOL is based on a nonlinear combination of nociception-related physiologic parameters: HR, HRV (at the 0.15 to 0.4 Hz band power), amplitude of the photoplethysmography wave, skin conductance level, and their time derivatives18. Measures were performed each five seconds.All study participants underwent the following protocol of measurements with the NOL index during their long COVID-19 follow-up consultation: step 1, five minutes lying down, step 2, five minutes standing, step 3, thirty seconds of flexion/extension and step 4, two minutes sitting down. This measure method shows many advantages as an easy and quick accessibility, a short recording time not disturbing the participant’s recovery and a lower sensitivity to breathing pattern than spectral variablesThe study was approved by the Foch IRB: IRB00012437  on December 16, 2020. A non-opposed consent was obtained for all participants.The following clinical data were collected: age, gender, weight, height, body mass index (weight (kg) divided by height (m2)), heart rate, systolic, diastolic blood pressure, oxygen saturation, comorbidities , loss of taste and smell, previous oxygen therapy , and duration from first symptoms of COVID-19 diagnosis.19, PCL-5 test superior to 2020 and 30 s of up and down test inferior to 321.Fatigue was defined by clinicians as at least two of the following criteria: loss of body mass exceeding 10%, NIJMEGEN superior or equal to 23P value < 0.05.Characteristics of the study population were described as median and interquartile range (IQR) for continuous variables. Categorical variables were described as absolute numerical values and proportions. Comparisons between groups were performed using Kruskal–Wallis test for continuous variables and Chi-squared test for categorical variables. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. Statistics were performed using SAS software . Significance was defined by a All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The study was approved by the Foch IRB: IRB00012437  on December 16, 2020. A non-opposed consent was obtained.A non-opposed consent was obtained for all participants.Informed consent was obtained from all individual participants included in the study.p = 0.085), gender (p = 0.594), comorbidities (hypertension (p = 0.688), diabetes (p = 0.377) and respiratory diseases (p = 0.224) between the three groups of the study population). 2 patients of the long COVID-19 group with fatigue and only one patient of the long COVID-19 group without fatigue were hospitalized and received oxygen therapy (p = 0.399). None of the participants of the study were hospitalized in ICU. 6 (54.6%) patients of long COVID-19 group with fatigue and 8 (53.3%) patients of the long COVID-19 group without fatigue presented loss of taste and smell (p = 0.951) (Table Characteristics of the participants were described in Table p = 0.157). Long COVID-19 participants with fatigue presented higher values of NIJMEGEN and PCL-5 scores  but not for loss of body mass exceeding 10%  and the 30 s of up and down test  than long COVID-19 participants without fatigue. No neurological symptoms were reported during COVID-19 episode, except loss of taste and smell for 14 patients, but with no difference between the two groups (p = 0.951). No cardiac damage were reported by the patients . A trend towards significant dissociation over time was observed between long COVID-19 without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904).Figure As our data show, possible interesting clinical aspects arise when the population is stratified between fatigue and non-fatigue long COVID-19 patients. Our population presented no significant differences in comorbidities , hemodynamic parameters (i.e. blood pressure) and duration from first symptoms. We used NIJMEGEN score and PCL-5 score to discriminate patients according to fatigue status.22. HRV is one of the main marker of dysautonomia12. HRV could be an important “window” for better understanding the inflammatory mechanism and neuroimmune system involved in long COVID-19 patients.We observed that HRV, reflected by the NOL index, was significant different in long COVID-19 participants with fatigue compared to control participants. In our study, the NOL index, a non-invasively measured multi-parameter index, was used to highlight the dysautonomia hypothesis in long COVID-19 participants. The variables that make up the NOL cover both sympathetic and parasympathetic activities of the ANS24. However, this non-invasive approach to evaluate the activity of the ANS remains too little understood and requires further investigations. Recognition of dysautonomia symptomatology in long COVID-19 patients could enhance the involvement of appropriate therapy.Recent but few experimental studies have shown the possible interest of HRV as physiological measurement parameter for COVID-19 patientsSome etiologies may explain dysautonomia in long COVID-19 patients including neurotropism, hypoxia, and inflammation. However, it remains unclear whether dysautonomia associated with long COVID-19 results directly from autonomic-virus pathway or post-infectious immune-mediated processes.25. COVID-19 virus in the airways could pass by the epithelial barrier invading the blood and lymph circulation and thus, propagate towards the CNS. The diameter of the COVID-19 virus is 60 to 140 nm, allowing it to pass through the blood–brain barrier (BBB) and gain entry into the CNS26. Other hypotheses highlighted a possible polarization of neurons leading to hyposmia due to conductive loss or neural loss27. Possible damages to the afferent hypoxia-sensing neuros could be due to the direct effect of COVID-19 by binding ACE2 expressed in capillary endothelium of BBB to gain access into the CNS28 or by indirect effect with cytokine storm on mitochondria or on nerve fibers29. Recent PET (positron emission tomography) scan findings have highlighted that COVID-19 neurotropism could occur in patients with impairment of olfactory bulb but also in other limbic structures, including thalamus/hypothalamus, cerebellum and the brainstem31. Moreover, the neuro-invasiveness of COVID-19 could have a direct role in hypoxia32. Excessive accumulations of acid metabolites in brain and anaerobic metabolites in mitochondria inducing edema and obstruction of the cerebral blood flow lead to hypoxia33.COVID-19 infection could be responsible for invasion of the central nervous system (CNS) by a direct hematogenous and neural propagation34. Pulmonary receptors expressed on afferent vagal nerve terminals in the lung have mechanical or chemical stimuli, which translocate in the brainstem by small-diameter myelinated (Aδ) or unmyelinated (C)-fiber nerve axons. C-fiber afferents respond to inflammatory markers and could have a major role in prominent action in dyspnea and breath difficulty but also a major role in coughing34. Vagal C-fiber afferents innervate the larynx response to laryngeal discomfort while the afferent information arrives from the vagal and glossopharyngeal nerves to merge at the nucleus of the tractus solitarius (NTS), a key site of critical homeostasis pathway. Thalamus, somatosensory cortex, amygdala and insular cortex were implicated in breath perception. However, the biological phenomenon underlying the dissociation between hypoxemia and overt dyspnea remain unknown in COVID-19 patients. Nevertheless, the observed disassociation could be present in patients presenting lesions in the glossopharyngeal or vagus nerves due to cranial nerve damages4. Impairs of the HRV may be explained by the acute dysautonomia enhancing by afferent baroreflex failure. This mechanism leads to several damages at the afferent baroreceptor signaling, which starts from baroreceptors in carotid bodies to the vagal and glossopharyngeal nerve fibers, and then, to the NTS5.The glossopharyngeal afferents, which innerve the carotid body and the vagal afferents enhancing the respiratory tract, present a key action in the monitoring organelle mechanism and modulating homeostasis by the stimulation of the ANS. Theses neurons are the primary sensory inputs of numerous reflex circuits modulating several major functions, such as HR, BP, and airway caliber29. This phenomenon has been called “happy”29 or “silent”36 hypoxemia. Nevertheless, this phenomenon is baffling to physicians and explanations remain unclear and hypothetic. This suggests that at least some sensory information could reach the brainstem to elicit a partial compensatory reflex respiratory response that is sufficient to lower the CO2 level, which diffuses more rapidly across the alveoli than oxygen. Respiratory pathology involves autonomic reflexes Projections from the brainstem to the cortex allow the brain to process homeostatic afferent signaling. A signal of internal hypoxia was received by the brain to ensure a rise of sensation of “air hunger” and needing to breathe, which is curiously absent in severe COVID-19 patients4.One of the aspects of COVID-19 patients’ complications is the presentation of low blood oxygenation but no sensation of dyspnea37. COVID-19 infection was associated with a cytokine storm characterized by the release of large amounts of pro-inflammatory cytokines and chemokines39. The relationship between HRV and inflammatory factors has been well extensively studied. Inflammatory factors might across the compromised BBB and cause brain damages. Thus, inflammation caused by viral infection could trigger and propagate chronic neuronal dysregulation40. A recent meta-analysis demonstrated an inverse relation between HRV and inflammation41. The measure of HRV was inversely correlated with CRP42. In the current COVID-19 infection, involvement of CRP became the vital monitoring patients’ inflammatory factor39. Nevertheless, the biological mechanism for the relationship between ANS and immune system interacted to impact the HRV has not been well understood37.Moreover, the ANS responds quickly to changes in physiological states, it may offer signals, in the form of HRV, that can warn of an impending cytokine storm sooner than other currently employed laboratory tests43. The data were collected regarding standardized protocols that add validity to our study’s results. Very few studies have investigated dysautonomia in COVID-19 participants and comparison to previous literature is difficult. One major limit was the relatively small sample size limiting the statistical power of the analyses. Consequently, we cannot exclude the possibility that some of the negative findings were due to lack of statistical power. Few patients of our population were hospitalized for COVID-19 (only 3 patients received oxygen therapy), the small sample size of our population did not allowed us to investigate the aspect of the different severity of the disease and dysautonomia aspect. Main part of the study population presented mild or moderate COVID-19 disease, only 3 patients needed oxygen therapy, but no additional data for the severity of the disease was collected and can appear as a main limitation. The small sample of patients receiving oxygen therapy did not allow us to perform subgroup analyses. A main limitation of our protocol was that steps of measurements with NOL index were not randomized. Moreover, possible delayed and overlapping effects could be not exclude due to the “fast” (12 min) experimental protocol.The main strength of our study was the use of the NOL index, which is a validate parameter to estimate HRVLong COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, reflected by the NOL index, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 participants, such as fatigue and hypoxia. Future clinical studies are needed to validate this hypothesis, with direct measurement of HRV and with specify focus on ICU or hospitalized patients, to allow better care of these participants during long COVID-19 rehabilitation.


Background: Benign prostatic hyperplasia (BPH) is one of the most prevalent and costly chronic conditions among middle-aged and elderly men. Prostatic urethral lift (PUL) and convective water vapor thermal therapy (WVTT) are emerging minimally invasive surgical treatments as an alternative to traditional treatment options for men with moderate-to-severe BPH. This study evaluated the cost-effectiveness and budget impact of PUL and WVTT for men with BPH using long-term clinical outcomes.Methods: The cost-effectiveness and budget impact models were developed from a US Medicare perspective over a 4-year time horizon. The models were populated with males with a mean age of 63 and an average International Prostate Symptom Score (IPSS) of 22. Clinical inputs were extracted from the LIFT and Rezum II randomized controlled trials at 4 years. Utility values were assigned using IPSS and BPH severity levels. Procedural, adverse event, retreatment, follow-up, and medication costs were based on 2019 Medicare payment rates and Medicare Part D drug spending. One-way and probabilistic sensitivity analyses (PSAs) were performed.Results: At 4 years, PUL was associated with greater retreatment rates (24.6% vs 10.9%), lower quality-adjusted life-years (QALYs) (3.490 vs 3.548) and higher total costs (US$7393 vs US$2233) compared with WVTT, making WVTT the more effective and less costly treatment strategy. The 70% total cost difference of PUL and WVTT was predominantly driven by higher PUL procedural (US$5617 vs US$1689) and retreatment (US$976 vs US$257) costs. The PSA demonstrated that relative to PUL, WVTT yielded higher QALYs and lower costs 99% and 100% of the time, respectively.Conclusions: Compared to PUL, WVTT was a cost-effective and cost-saving treatment of moderate-to-severe BPH. These findings provide evidence for clinicians, payers, and health policy makers to help further define the role of minimally invasive surgical treatments for BPH. Benign prostatic hyperplasia (BPH) is one of the most prevalent and costly chronic conditions among middle-aged and elderly men.Available BPH treatment options differ by their degree of invasiveness, efficacy, adverse event (AE) profiles, and cost consequences. First-line therapy for patients with moderate-to-severe LUTS is often pharmacotherapy.In recent years, less invasive surgical treatments have evolved for patients with BPH. Prostatic urethral lift  and convective water vapor thermal therapy  are emerging FDA-cleared minimally invasive surgical treatment options for men with moderate-to-severe LUTS due to BPH. For a PUL procedure, permanent intraprostatic implants are inserted between the prostate lobes to relieve prostatic obstruction.While the safety and efficacy of PUL and WVTT have been demonstrated,We conducted a cost-effectiveness analysis (CEA) comparing PUL and WVTT from a US Medicare perspective over a 4-year time horizon. An Excel-based  Markov model was developed using safety and efficacy data from the LIFTPatients entering the model were assigned to treatment with either PUL or WVTT . After tClinical inputs for PUL and WVTT, including IPSS, LUTS-related AEs, and retreatment rates, were derived from the LIFTFollowing the initial PUL or WVTT procedure, patients could experience improvement, stabilization, or progression of their IPSS relative to baseline in each model cycle. Post-procedural catheterization rates were 51.4%LUTS-related AEs for PUL and WVTT were extracted at 0-3 and 4-12 monthsPatients requiring retreatment could undergo the same initial PUL or WVTT treatment, BPH medical therapy, TURP, or open prostatectomy. Retreatment rates were calculated based upon the CONSORT diagrams from the LIFTPatients were assumed to require two office visits within the first 3 months following the initial procedure. Thereafter, one office visit per year was assigned for patients with mild and moderate LUTS and two office visits per year were assigned for patients with severe LUTS. Additionally, one post-void residual test per year was assigned for patients with moderate and severe LUTS. The assumptions regarding health-care resource use, including the number of office visits, post-void residual tests, and the proportion of patients who needed an office visit for catheter removal, were all reviewed and validated by a medical expert based on the clinical practice in the United States.Patient QOL was reflected in the model as health utilities and disutilities. Utility values for BPH severity levels and disutility values associated with post-procedure catheterization, LUTS-related AEs, and retreatments, were derived from the published literatureThe model included all relevant costs to Medicare: procedural costs, costs associated with AEs, retreatment costs, and follow-up care costs . PUL andFor the BIM, differences in post-operative global payment periods had to be taken into consideration. Post-operative global payment periods are a policy determined by Medicare for medical services “to ensure that Medicare Administrative Contractors pay physicians for the same services consistently across all jurisdictions.”For the CEA, a one-way sensitivity analysis (OWSA) was conducted to assess the impact of individual parameters on the cost-effectiveness results by varying all clinical and cost parameters by ±10%. A probabilistic sensitivity analysis (PSA) was performed based on 1000 randomly drawn simulations of parameter values and a US$50 000/QALY threshold.For the BIM, an OWSA was conducted to evaluate the impact of parameter uncertainty on budget impact results by varying all clinical and cost inputs by ±10%. Additionally, a scenario analysis was performed to evaluate the budget impact of different post-operative global payment periods.PUL was associated with higher retreatment rates compared with WVTT (8.0% vs 3.1%) beginning in year 1 . RetreatAt 1 year, PUL was associated with lower QALYs (0.917 vs 0.928) and higher total costs (US$6449 vs US$1813) compared to WVTT . The samA tornado diagram illustrating the 10 most impactful parameters in descending order of influence on model results at 4 years is depicted in The PSA simulations  demonstrPUL procedural costs were substantially higher than those of WVTT (US$5617 vs US$1689). The results of the BIM demonstrated that PUL was associated with higher total Medicare costs per patient (US$7445 vs US$2257) than WVTT at 4 years . ApproxiWhen standardizing the global payment periods, PUL costs for AEs and follow-up care at 1 year decreased from US$581 to US$244 with a 90-day global period. The costs of AEs and follow-up care at 1 year for WVTT increased from US$62 to US$302 with a 0-day global period. PUL total costs at 4 years remained substantially higher than WVTT total costs, regardless of the global payment period . OWSA of the BIM demonstrated that WVTT remained cost saving relative to PUL when model parameters were varied by ±10%. PUL and WVTT procedural costs, as well as the costs and rates of retreatment following PUL, were the most impactful model parameters.This study used long-term efficacy and safety data from the PUL and WVTT RCTs to evaluate the cost-effectiveness and budget impact of PUL and WVTT from a US Medicare perspective for men with BPH experiencing moderate-to-severe LUTS. The CEA showed that WVTT was more effective and less costly than PUL. The BIM demonstrated that WVTT was a cost-saving strategy compared to PUL, primarily due to lower procedural and retreatment costs. Given shared decision-making between health-care providers and men with BPH is at the center of BPH treatment selection,PUL and WVTT are minimally invasive surgical treatment options for the treatment of moderate-to-severe BPH recommended by the American Urological Association Guideline for BPH.Patients with LUTS due to BPH have been shown to experience a significant reduction in QOL.Sensitivity analyses demonstrated that the CEA model results were robust to changes in the model parameters. The OWSA revealed that IPSS change from baseline for PUL and WVTT, and the initial treatment costs of PUL, had the greatest impact on model results. The PSA demonstrated that WVTT was less costly than PUL 100% of the time from a Medicare perspective and yielded greater QALYs 99% of the time. Given the robustness of these results, it is highly likely that WVTT would also produce cost savings from other payer perspectives, such as US commercial payers.In addition to the CEA, the BIM analysis revealed that WVTT had lower per-patient costs compared to PUL, with the key cost drivers being lower procedural and retreatment costs. The procedural cost of WVTT was 3 times less than that of PUL. Additionally, WVTT had lower retreatment rates, thus contributing to lower retreatment costs from year 1 to year 4.Scenario analyses of the BIM were conducted to understand the impact of standardizing the post-operative global payment periodsThis study provides insight into the QOL impact to patients and the long-term costs to Medicare that result from treatment of BPH with PUL and WVTT. To our knowledge, there was only one other published CEA that examined the cost-effectiveness of PUL and WVTT. Ulchaker et al. assessed the cost-effectiveness of PUL, WVTT, conductive radio frequency thermal therapy, pharmacotherapy, photovaporization of the prostate, and TURP, and found that WVTT was more cost-effective compared to PUL.There are a few limitations of this study. First, all model-based analyses are subject to result uncertainty and biased input. To minimize these modelling issues, we performed a number of sensitivity analyses and engaged urology and health-care finance experts to validate model assumptions and inputs. Second, our analyses were based on the clinical outcomes of the LIFTWVTT was the dominant (more effective and less costly) treatment strategy compared to PUL for the minimally invasive treatment of moderate-to-severe LUTS associated with BPH. WVTT was a cost-saving treatment option to Medicare relative to PUL, and the cost difference was predominantly driven by the lower procedural and retreatment costs of WVTT. These findings provide compelling evidence for clinicians, payers, and policy makers to help differentiate minimally invasive surgical treatments for BPH.Bilal Chughtai, MD, is Associate Professor at the Department of Urology, Weill Cornell Medicine (bic9008@med.cornell.edu); Sirikan Rojanasarot, PhD, is Principal Health Economist at Boston Scientific (sirikan.rojanasarot@bsci.com); Kurt Neeser, DVM, MPH, is Senior Director at Certara Germany GmbH (kurt.neeser@certara.com); Dmitry Gultyaev is Senior Analyst at Certara Germany GmbH (dmitry.gultyaev@certara.com); Stacey L Amorosi, MA, was Director, Health Economics Center of Excellence at Boston Scientific at the time of writing; Neal D Shore, MD, FACS, is Medical Director at Carolina Urologic Research Center (nshore@gsuro.com).Drs. Bilal Chughtai and Neal Shore are paid clinical consultants to Boston Scientific. Sirikan Rojanasarot is a full-time employee and stock holder of Boston Scientific. Kurt Neeser and Dmitry Gultyaev are full-time employees at Certara Germany GmbH. Certara Germany GmbH received consultation fees from Boston Scientific for the economic analysis and for the support in writing the manuscript. Stacey Amorosi was a full-time employee of Boston Scientific at the time of writing.