Background: The National Surveys of Sexual Attitudes and Lifestyles COVID study  was designed to understand the impact of COVID-19 on Britain’s sexual and reproductive health (SRH). Natsal-COVID Wave 1 survey and qualitative follow-up interviews were conducted in 2020. The Wave 2 survey was designed to capture one-year prevalence estimates for key SRH outcomes and measure changes over the first year of the pandemic. We describe the Wave 2 survey methodology and assess the sample representativeness.Methods: Natsal-COVID Wave 2 was conducted March-April 2021; approximately one year after the start of Britain’s first national lockdown. Data were collected using an online web-panel survey administered by Ipsos. The sample comprised a longitudinal sample of Wave 1 participants who had agreed to re-contact plus a sample of participants residing in Britain, aged 18-59, including a boost sample comprising people aged 18-29. Questions covered reproductive health, relationships, sexual behaviour and SRH service use. Quotas and weighting were used to achieve a quasi-representative sample of the British population. Comparisons were made with recent national probability surveys, Natsal-3 (2010-12) and Natsal-COVID Wave 1 to understand bias.Results: A total of6,658 individuals completed the survey. In terms of gender, age, ethnicity, and rurality, the weighted Natsal-COVID Wave 2 sample was like the general population. Participants were less likely to be married or to report being in good health than the general population. The longitudinal sample  were broadly like participants who only took part in Wave 1 but were older. Among the sexually active, longitudinal participants were less likely to report multiple sexual partners or a new sexual partner in the past year compared to those who only took part in Wave 1.Conclusions: Natsal-COVID collected longitudinal, quasi-representative population data to enable evaluation of the population-level impact of COVID-19 on SRH and to inform policy. It follows our previous work describing the Wave 1 study methodology. Physical contact with anyone outside one’s household or support bubble was not permitted for the duration of that year.At the time of Natsal-COVID Wave 2 data collection (March-April 2021), COVID-19 lockdown restrictions in Britain were being eased following a second national lockdown between January and March 2021. Some form of restrictions and physical distancing requirements had been in place throughout the preceding year to understand early changes in sexual and reproductive health (SRH) service use and need, sexual behaviours, and relationships during this time. Wave 2 aimed to capture SRH behaviour and outcomes during the first year of the COVID-19 pandemic, including sexual behaviours, sexual function, relationship quality, intimate partner violence, reproductive health outcomes and SRH service use. It was designed to produce one-year prevalence estimates of key SRH outcomes and behaviours. The study also aimed to measure change over time, both between-person variation through repeat cross-sectional analyses and within-person variation through longitudinal analyses. This paper describes the methods used in Wave 2 of Natsal-COVID and assesses the representativeness of the data.Natsal-COVID survey Wave 1 and qualitative follow-up interviews were conducted in 2020. The target longitudinal sample size at Wave 2 was 4,000.Natsal-COVID Wave 1 was an online web-panel survey conducted in July-August 2020, which used quotas and weighting to obtain a quasi-representative sample of 6654 people aged 18–59 years old living in Britain. The Wave 2 sample was drawn first from those who participated in Wave 1 and agreed to re-contact . No quotas were set for this group. To complete the Wave 2 sample, new participants were sampled from Ipsos’s online panels. Sample quotas were set by gender, age, region, and social grade. The new sample included a boost of 500 people aged 18–29 years old, ensuring an overall sample of 2000 participants in this age-group. The complete Wave 2 sample was designed to ensure overall representativeness of the population aged 18–59 years old by age, gender, region, and social grade. Full details of sample size calculations for Natsal-COVID have been reported elsewhereWe obtained ethics approval for the study from University of Glasgow Medical, Veterinary and Life Sciences College Ethics Committee (reference 20019174) and London School of Hygiene and Tropical Medicine Research Ethics committee (reference 22565). Participants provided informed consent to participate via an online consent form before starting the survey.. The dataset for Wave 1 can be found in the UK Data Archive. Wave 2 additionally included questions about pregnancy, contraception changes, HIV testing, chlamydia testing, abortion, relationship formation and dissolution, and IPV with a focus on the year since the start of the first lockdown  and patient health questionnaire two item (PHQ-2) scales, lonelinessEthnicity, country of birthSexual identityEmployment statusEducationNumber of opposite-sex, same-sex, and transgender partners in different time periods Condomless sex with new opposite-sex, same-sex, and transgender partners since lockdownSexual behaviours since lockdownSexual functionPregnancy (including the London Measure of Unplanned Pregnancy)Chlamydia testingAccess to sexual and reproductive health (SRH) services Unmet need for SRH servicesMethod of accessing sexually transmitted infection (STI) testing servicesContraception used since lockdownCondom access since lockdownChanges in sexual relationships since lockdownIntimate relationships and difficultiesIntimate Partner Violencee.g., sexual behaviours, reproductive health, SRH service use. The introduction of IPV questions using remote collection methods in Natsal-COVID Wave 2 required careful consideration regarding potential risk to participants and data quality, while acknowledging the importance of collecting these data during the COVID-19 pandemic. A variety of measures were put in place to mitigate the risks. We minimised the number of IPV items, avoided very sensitive questions  and included an explicit ‘prefer not to answer’ option at every question in the module. Immediately before sensitive question modules (including IPV), reminders about the voluntary nature of each question and confidentiality were displayed. Appropriate signposting to support services was provided after each sensitive module and at the end of the survey. Natsal surveys have always involved sensitive question topics,Wave 2 survey data were collected from 27 March 2021 to 26 April 2021. Approximately 150,000 panellists, including those from Wave 1 who were willing to be re-contacted, were contacted via email. Of those emailed, 38,731 started the survey; 79% came from Ipsos’s own panel, with ‘top-up’ from three other panel providers used by Ipsos. Of these participants, 11,708 were ineligible or did not provide consent, 17,230 were diverted from completing the survey because their quota was full, 2,376 abandoned the survey before completion, 490 failed quality checks, and 269 experienced a technical error. In total, 6,658 participants completed the survey and are included in the analysis. Of these, 2,098 were longitudinal participants and 4,556 were new. The recruitment process is shown inParticipants completed the survey on a smartphone (53%), a laptop/desktop (42%) or a tablet (6%).Ipsos Wave 2 Technical Report).To increase numbers of participants aged 18–29 years old, all other quotas  were relaxed toward the end of fieldwork. Cross-sectional and longitudinal weights were produced to achieve a quasi-representative sample of the British population by gender, age, region, social grade, ethnicity, and sexual identity. The cross-sectional weight for the full Wave 2 sample had a weighting efficiency of 83.8% , the 2018 Health Survey for England (HSE) , the 2018 APS report , and the 2010-12 Natsal-3 study . More recent versions of HSE and APS have been published since we carried out analysis of Natsal-COVID Wave 1 representativeness. However, we decided to use consistent comparators in our assessment of the Natsal-COVID Wave 2 sample to facilitate comparisons with Wave 1. The archived datasets were accessed from the UK Data Archive and Office for National Statistics (ONS) website. Data analysts  had access to the datasets.The Natsal-COVID Wave 2 sample was compared with Wave 1, and with the following probability sample surveys to assess representativeness : the 201i.e., no upper age limit) in APS. The over-representation of non-heterosexual identities in the unweighted Natsal-COVID sample can be partially explained by the younger age range of participants.As expected, due to quotas and weighting, the weighted Wave 2 sample was similar to Wave 1 and external datasets for gender, age, region, ethnicity, and sexual identity . Like WaRegarding other sociodemographic variables, patterns were largely similar between Wave 1 and Wave 2. The Wave 2 sample under-represented participants who reported being married (40.4%) compared to the 2019 APS (47.5%) and under-represented those who reported ‘very good’ or ‘good’ general health (73.3%) compared to the 2018 HSE (79.9%).The weighted proportion of Wave 2 participants reporting any previous partnered sexual experience  (93.9%) was lower than in Natsal-3 (98.8%). Among participants with at least one sexual partner in their lifetime, there was a higher proportion of Natsal-COVID Wave 2 participants reporting zero partners in the past five years (16.9%) compared with Natsal-3 (3.8%).To characterise the sample of individuals who participated in both Waves of Natsal-COVID, we compared the unweighted and weighted characteristics and behaviours (reported at Wave 1) of those who did not participate in Wave 2  with those who did  . For mos. Natsal-COVID Wave 2 data generated one-year prevalence estimates for a range of key SRH behaviours and outcomes one year after the start of the first COVID-19 lockdown in Britain. The second wave of the survey also provides an opportunity to examine change over time during the first year of the pandemic.Natsal-COVID is a large, multi-wave, national study that was undertaken when data were urgently needed to understand the impact of the pandemic on SRH services and inform policy. Initial findings from Natsal-COVID Wave 1 have been used in SRH policy and practice in Britaini.e., online versus in-person), sampling bias or, most likely, a combination of these factors.Key sociodemographic characteristics and reported sexual behaviours were generally similar in the weighted Natsal-COVID data when compared to external probability surveys and Natsal-3. However, we noted bias in several important characteristics that remained after weighting. The Natsal-COVID Wave 2 sample under-represented individuals who were married and those who self-reported ‘very good’ or ‘good’ general health. Among those with at least one sexual partner in their lifetime, a higher proportion of Natsal-COVID Wave 2 participants reported having no sexual partners in the past five years compared with Natsal-3 (conducted ten years ago). This difference could reflect pandemic restrictions, differences in the question wording, mode effects  demonstrated high survey attrition, particularly among young people. The sample bias is likely due to quotas not being applied to longitudinal sample recruitment and a lower response propensity among younger adults. Among sexually active participants, the longitudinal sample were less likely to report multiple sexual partners in the past year or a new sexual partner in the past year compared to participants who only participated in Wave 1 of Natsal-COVID. These differences in sexual behaviour estimates are likely attributable to sample bias predominately driven by age. Researchers conducting longitudinal analysis using Natsal-COVID data should bear in mind sample attrition and its associated bias when interpreting findings. The application of weights to the longitudinal sample reduced the magnitude of difference but did not correct them entirely.. There are known sources of bias in web-panel surveys that may affect survey estimates. Although the Natsal-COVID findings are likely to be largely generalisable, caution in the interpretation of prevalence estimates is advised particularly when analysing the longitudinal sample.Natsal-COVID did not use probability sampling methods and therefore inference to the general population should be undertaken with cautionIn conclusion, the Natsal-COVID Wave 2 survey has enabled us to identify impacts of the COVID-19 pandemic throughout the year following the first national lockdown in Britain and to monitor change over time in the same period.http://doi.org/10.5255/UKDA-SN-8865-1. The Natsal-COVID Wave 1 dataset has been deposited with the UK Data Archive (an open access repository) with safeguarded access . The dataset is available to users registered with the UK Data Service.natsal@ucl.ac.uk) for interim access, with appropriate considerations about confidentiality and data protection.Wave 2 data will be deposited at the same location within 10-12 weeks. Given the sensitive nature of the content of the data, a thorough disclosure risk assessment and the application of disclosure control measures are necessary prior to safe deposit. In the meantime, interested researchers or reviewers may contact the Natsal team  used in this analysis are publicly available via the UK Data Archive. Datasets can be accessed through registration with the UK Data Servicehttp://doi.org/10.5255/UKDA-SN-8632-4.UK Data Service: Annual Population Survey, January–December, 2019.http://doi.org/10.5255/UKDA-SN-8649-1.UK Data Service: Health Survey for England, 2018.http://doi.org/10.5255/UKDA-SN-7799-2.UK Data Service: National Survey of Sexual Attitudes and Lifestyles, 2010-2012.safeguarded access and can be accessed by accepting theEnd User Licence.The datasets held in the UK Data Service are underONS website. This dataset is available under the terms of theOpen Government License v3.0.The published 2019 Annual Population Survey sexual identity tables are available as a downloadable Excel file on the This research note provides a comprehensive overview of the methodology of the wave 2 of the Natsal-COVID study. The primary objective of this second wave was to capture one-year prevalence estimates for a range of sexual and reproductive health measures. The survey, which took place in March-April 2021, involved both a re-issue of the wave 1 questionnaire to respondents willing to be recontacted and the recruitment of a fresh sample from a web panel. In addition to detailing the methodology, this paper includes a representativeness analysis using a diverse set of measures from high-quality probability samples. Additionally, the authors address the principal limitations of the research design and their potential impact on data analysis, building upon the explanations provided in the research note on wave 1 recruitment .Brief description of the panel recruitment methodology. The recruitment methodology of the panel is likely to affect the quality of survey estimates . It is understood that a comprehensive explanation of the panel recruitment methodology may be beyond the scope of this research note, but it would be informative to have a few more details about the panel recruitment methodology (if these details are available to the authors).The benchmark estimates are also subject to error. The benchmark estimates used in the representativeness analysis come from probability surveys and are also subjected to measurement and representation errors. Furthermore, when considering Natsal-3 (2010-12), in addition to survey errors, it should be factored in the influence of time and its potential effects on the target population. This temporal aspect may partially account for some of the observed differences.Confidence intervals (CIs) in the representativeness analysis. In the representativeness analysis, where comparisons are made between Natsal-COVID survey estimates and benchmark data (Tables 1 and 2), the 95% confidence intervals are provided for the estimates from the probability surveys and the Natsal-COVID survey. The authors could provide some information about how they estimated the standard errors, especially in the case of the estimates from the Natsal-COVID study, a nonprobability sample . Providing some insight into the estimation of confidence intervals would help readers better interpret the information presented in the table.Quota sampling and panel attrition. In the discussion section , the authors suggest that attrition between waves 1 and 2 may be attributed to quotas not being applied in the recruitment of the longitudinal sample. However, the paper that presents the design of wave 1 states that quotas were used in recruitment , and it is not clear how the quotas could be implemented in the second wave of a longitudinal study since they would harm the sample size and the feasibility of conducting longitudinal analyses. An explanation of this point could help clarify their idea. The paper provides a detailed and clear overview of the wave 2 design, which will be helpful for researchers and other data users. Now, I discuss four minor points that might help the authors to refine the paper:Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Survey methodology.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This very interesting and relevant methodology paper reports a second wave of data on prevalence of key SRH outcomes. The paper also compares the second wave data with the first wave data to track changes in SRH outcomes over a one-year period. The methodological strength of this manuscript is its rigour, which is evident in use of a representative sample, methods of data collection and analytical techniques. Notably, authors identified and reported known sources of bias and caveats within which the research results and conclusions are to be understood and interpreted.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Global Public Health, Sexual and Reproductive Health, Population Health, Blood-borne Viruses and Sexually Transmissible Infections, Adolescents Sexual and Reproductive Health and Rights, Research Methods.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The Natsal-COVID Wave 2 methodology paper clearly describes the design and procedures of data collection and compares the wave 2 ands wave 1 cohort characteristics. The limitations of the methods are detailed in the discussion so that researchers using the dataset for longitudinal versus cross sectional analyses are aware of limits to generalisability. Where information is not presented in this publication it is signposted in the references. This is an important study for a number of reasons; we now know that the UK live birth rate temporarily dropped during pandemic; to what extent that reflected changes in sexual and reproductive health practices is an important question that this dataset could address. The reporting by sexual and gender identity reflects the society we live in and ideally all contemporary surveys should be designed to report on the experience and views of LGTBQ+ people. There are few contemporary longitudinal datasets that capture information on IPV, making this dataset very useful. I hope that further waves of data are collected so that we can understand to what extent there are long term pandemic effects on intimate relationships and sexual health.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Psychiatric epidemiology, reproductive health, behavioural science and women's health.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


There is a variety of specialized outpatient and residential Alcohol and Other Drugs (AOD) services, but research on outcomes of these services is limited. Given the chronic, relapsing nature of AOD problems, there is a need for longitudinal research on outcomes after treatment in various AOD services.Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience Measures (PREMs) are hardly used in the AOD field but provide excellent tools and a framework to monitor progress and outcomes in these services based on experiences of service users.The objectives of the OMER-BE study are to:1. Assess and compare patient characteristics at baseline in various treatment modalities2. Test and prepare the routine measurement of PROMs and PREMs in AOD services using a self-report tool3. Assess patient-reported experiences qualitatively in various treatment modalities for AOD patientsThe overall goal is to continuously assess and improve AOD services.We have set up a naturalistic, longitudinal cohort study for which we will engage and follow up 250 AOD users as they present themselves in selected AOD services in four different treatment modalities .Sociodemographic and clinical factors and PROMs will be assessed at baseline. PROMs and PREMs will be assessed at 45-, 90-and 180-days follow-up. The questionnaires that will be used during the baseline and follow-up assessments are based on the ICHOM Standard Set for Addictions , a set of brief validated questionnaires to measure and monitor treatment outcomes routinely in AOD services.Following the 6-month follow-up we will perform a qualitative study in a subset of N=20 participants . These participants will be invited to take part in an in-depth interview with one of the researchers, where the following topics will be discussed: treatment history, recovery experiences, helping and hindering factors in recovery, and experiences with different treatment modalities.47 participants have been recruited in the OMER-BE study up until October 2022. 38 (81%) of the participants were born male, 9 (19%) were born female. The average age of participants is 33, with ages ranging from 19 to 47 years old.Preliminary findings will be presented at the congress.Further recruitment of study participants up to a total of 250 will be undertaken until the end of 2023.The OMER-BE study aims to assess and improve AOD services by using a self-report tool, measuring PROMs and PREMs.None Declared


The use of high-frequency Transcranial Magnetic Stimulation (HF-rTMS) of the right dorsolateral prefrontal cortex (DLPFC) in treating Post-traumatic Stress Disorder (PTSD) is currently regarded as a level B intervention (probable effectiveness). HF-rTMS has attracted interest as a neuromodulation therapeutic method for PTSD. Prolonged exposure and reactivation therapy are also regarded as first-line treatments for PTSD. Randomized controlled clinical studies examining the effectiveness of several HF-rTMS sessions coupled with psychotherapy have not yet been completed. In total, 102 patients with refractory PTSD will be randomly assigned (1:1) to reactivation therapy, in addition to either active HF-rTMS (20 Hz) or sham HF-rTMS, for 12 sessions in a nationwide, multicenter, double-blind controlled trial. The impact on PTSD symptoms and neurocognitive functioning will be assessed. The primary outcome is the PTSD severity score measured based on the Clinician-Administered PTSD Scale (CAPS-5) at one month. If this additional therapy is successful, it may strengthen the case for regulatory authorities to approve this additional technique of treating PTSD. Additionally, it expands the field of neurostimulation-assisted psychotherapy. Post-traumatic stress disorder (PTSD) is defined as a set of symptoms that occur after being exposed to a traumatic incident . PTSD is ranked as one of the top ten public health issues by the World Health Organization (WHO) . In FranTraumatic reactivation therapy is effective, but remission is achieved in only 40% of subjects . Much ofPreliminary studies suggest that transcranial magnetic stimulation of the right dorsolateral prefrontal cortex has a positive effect . RepetitAlthough evidence is limited, HF rTMS may improve PTSD symptoms by modulating the prefrontal cortex activity. The mechanisms by which rTMS might exert its effects to mediate symptom improvement in PTSD remain unclear. The most recent meta-analysis  on PTSD The combined sample consisted of 377 subjects . The total number of female participants was 195. The rTMS was an augmentative treatment, i.e., a previously used drug and/or psychological intervention. The authors conclude that additional research is needed, but both HF and LF rTMS can alleviate PTSD symptoms. HF rTMS could improve the primary and related symptoms of PTSD. HF rTMS demonstrated an improvement in the PTSD total score: pooled SMD (pre-post treatment), 3.24; 95% CI 2.24–4.25 . The dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex were the most promising sites of stimulation ,11,12,13n = 54) or sham (n = 49) low-frequency (LF) rTMS sessions (1/week) associated with CPT [p = 0.023, one-tailed). It was a predominantly military population with different traumas from civilian injuries . LF rTMS sessions were performed before psychotherapy.Furthermore, two trials ,15 combiThe rTMS has shown promise as a potential treatment for PTSD, with some studies suggesting that high-frequency stimulation may improve symptoms by modulating prefrontal cortex activity. However, further research is needed to determine the optimal stimulation parameters and patient populations for this intervention. Additionally, more extensive trials exploring the combination of rTMS with trauma-focused psychotherapy may help elucidate whether these treatments have additive effects on PTSD symptom improvement. Considering Yan’s meta-analysis and Kozel’s results, the heterogeneity in rTMS protocols and the limited number of rTMS studies combining cue exposure make it difficult to draw conclusions about the role of rTMS in PTSD. There is a need for intensive clinical trials in this area. We hypothesize greater efficacy of high-frequency (HF) rTMS compared to low-frequency (LF) rTMS , as wellThe present study protocol aims to elucidate the effect of multiple sessions of HF-rTMS on PTSD symptoms, cognition, and brain functioning. We will conduct a multicenter, double-blind, randomized controlled trial with 102 PTSD patients randomized (1:1) to either 10 sessions of active HF-rTMS + reactivation therapy or 10 sessions of sham HF-rTMS + reactivation therapy. We will investigate the effect of active versus sham HF-rTMS treatment on measures of symptoms and cognition. We expect reduced symptomatology and improved functioning of neurocognitive tasks in the active HF-rTMS-treated group compared to the sham HF-rTMS-treated group. Our protocol proposes a larger number of pulses than the existing literature. We will evaluate the efficacy of combining neuromodulation through rTMS with script-driven imagery in civilian patients who respond insufficiently to first-line treatments with antidepressants.We aim to assess the efficacy of high-frequency (HF) rTMS stimulation over the right dorsolateral prefrontal cortex (DLPFC) in patients with PTSD resistant to a first pharmacological line of treatment. The rationale for focusing on this subgroup of patients is twofold: (1) there is a critical need for alternative treatment options for PTSD patients who do not respond to antidepressants, and (2) in these individuals, combining rTMS with reactivation of traumatic memory may be particularly effective by targeting both the prefrontal cortex (activated by rTMS) and the amygdala (reactivated by script-driven imagery). Our study offers another urgently needed treatment option for PTSD patients who are non-responsive to antidepressants. This is the first clinical research study to combine HF rTMS with memory reactivation in a civilian PTSD population resistant to a first-line of a pharmacological agent.Pairing rTMS with trauma-relevant cues may represent a novel approach to treating PTSD patients. HF-rTMS over the dorsolateral prefrontal cortex (DLPFC) could correct the deficient cortical activation observed in some treatment-resistant PTSD patients. The efficacy of HF-rTMS treatment may be enhanced by combining it with trauma cue exposure (neuro-enhanced psychotherapy), which would engage the prefrontal cortex during sessions. Restoring the activity of prefrontal regions could effectively enhance the executive control of fear responses, thus improving PTSD symptoms. Therefore, this study aims to investigate the efficacy and underlying mechanisms of 10 add-on HF-rTMS sessions as part of a reactivation therapy protocol for PTSD patients resistant to 6 weeks of first-line conventional treatment.The primary objective of this study is to evaluate the efficacy of brain modulation by rTMS, combined with simultaneous traumatic memory reactivation, in patients presenting PTSD resistant to one pharmacological agent compared to sham rTMS, with simultaneous traumatic memory reactivation at one month (M1) after the last rTMS session (V13).Different dimensions of PTSD assessed using CAPS-5 at M3 and M6 post-treatment;The severity of PTSD assessed using PCL at each visit;Anxiety symptoms at V13 (end of treatment), M1, M3, and M6 post-treatment;Depressive symptoms at V13 (end of treatment), M1, M3, and M6 post-treatment;Changes in social cognition at M3 post-treatment;Changes in quality of life at M1, M3, and M6 post-treatment;The safety of the intervention.The secondary objectives of this study are to assess the efficacy of brain modulation via 20 Hz rTMS targeting the right dorsolateral prefrontal cortex, in conjunction with simultaneous traumatic memory reactivation, on the following aspects:The TRAUMASTIM study is designed as a national multicenter randomized, double-blinded, shamed controlled trial comparing two parallel arms (1:1): rTMS with simultaneous reactivation of traumatic memory in resistant PTSD versus sham rTMS and simultaneous reactivation of traumatic memory.This study will be approved by the Medical Ethical Committee (IDRCB No 2021-A02532-39-B). Written informed consent will be obtained before screening for inclusion and exclusion criteria takes place.Presenting PTSD according to DSM-5 criteria;Patient with persistent symptoms (PCL > 44) after 6 weeks of treatment with SSRI;Patient with health insurance (AME excepted);Signed written informed consent.Cochlear implants;Cardiac pacemaker or intracardiac lines, or metal in the body;Strong dissociative tendencies, evidenced by an average score > 20 on the DES;Lifetime psychotic or bipolar disorder;Antisocial personality or borderline personality;Brain injury defined by medical report;Current substance dependence ;Acute suicidal ideation;No adequate mastering of the French language or no ability to consent;Pregnancy (confirmed by a urine beta-HCG) or breastfeeding;Absence of birth control;Patient under legal protection measures and/or deprived of freedom;Participation in any other interventional study or in the exclusion period of any other interventional study.The intervention consists of 12 HF-rTMS sessions in the right DLPFC (rDLPFC) on 12 workdays. The HF-rTMS parameters of the active intervention are as follows: active high-frequency 20 Hz, 3 to 4 sessions of 10 min per week, 2000 pulses/session, and a motor threshold of 110%. In our centers, we regularly offer 3 to 4 rTMS sessions per week for patients with depression, which has proven to be both feasible in terms of logistics and well accepted by the patients receiving the treatment. The number of sessions per week will be determined based on the logistical constraints of the investigating centers and the patients being stimulated. The device used will be an electromagnetic stimulator, which is used to artificially provoke a functional activity (GMDN 13762) CE marked, Class IIa.The rDLPFC will be located at position F4 using the International 10–20 EEG system or a neuronavigation system. During the stimulation, participants will be seated on a comfortable chair with extra neck support. One stimulation session will take approximately 10 min.The motor threshold will be determined at rest before the first stimulation session, using single-pulse TMS in combination with motor-evoked potentials. The optimal spot on the scalp for stimulation of the right abductor pollicis brevis muscle will be located, and the motor threshold will be established by delivering single stimulations to the motor cortex. The motor threshold, defined as the lowest stimulation intensity producing five motor evoked potentials (MEPs) of at least 50 μV in 5 out of 10 stimulations, will be measured by gradually increasing the stimulation intensity. The intervention will be applied by an rTMS-trained researcher.Sham rTMS will be delivered, following the same procedure. The trauma memory reactivation procedure will be the same as that in the experimental group. Sham rTMS will be performed with a special probe for sham procedures. The instruction to use sham rTMS will be the same as that for the active device. A sham coil providing the same noise, heat, clicks, and sensations as the active coil will be used without any magnetic pulse.The reactivation therapy consists of the development of a traumatic script where participants will describe their traumatic event during a “script” preparation session, which will be used to reactivate the traumatic memory before each rTMS session. The intervention will be performed by a reactivation therapy-trained physician.There will be 8 national sites involved, located in hospitals (outpatient or inpatient settings).Participants in this clinical investigation will be identified using the following format: site number (3 digits); sequential enrollment number for the site (4 digits); surname initial and first name initial. This unique reference number will be used throughout the duration of the clinical investigation. A randomization number will also be assigned when the participant is randomized, following the RXXX format, in accordance with the sponsor’s procedures.A computer-generated randomization list  will be created by the Unité de Recherche Clinique (URC) of Saint-Antoine Hospital (AP-HP). Randomization will be block-balanced and stratified by site, with block widths undisclosed to investigators. The rTMS operator will perform randomization through a web interface  during the inclusion visit or before the first rTMS session.The allocated arm (active or sham rTMS) will not be documented in the medical record. Blinding will be maintained for the patients included and for investigators involved in participant inclusion and follow-up.Two independent staff members will be designated to receive the randomization email and forward it to the rTMS operator. These individuals and the rTMS operator, who will be aware of the sham or active condition, will not be involved in the participant follow-up or evaluation. A sham coil producing the same noise, heat, clicks, and sensations as the active coil but without any magnetic pulses will be used.If deemed essential, the investigator can request unblinding for a specific patient by contacting the DRCI and the DRCI project advisor, whose contact information is provided on the protocol cover page. In this trial, no emergency unblinding request is mandatory.Patients will be recruited during an appointment at a participating specialized trauma unit (trauma center). Patients may be either hospitalized or treated as outpatients. During the selection visit and prior to any research-related examination, the physician will propose the study to the patient, informing them about the objective, the nature of the constraints, the computerized processing of the data that will be collected during this research, and their rights of access, opposition, and rectification to these data. During this visit, the eligibility criteria will be verified by the investigator or co-investigator. An information form summarizing these points will be provided to the patient. If they are interested, informed consent will be signed, and the participant will be screened for inclusion and exclusion criteria. If a patient meets all the inclusion criteria and none of the exclusion criteria, they will be included in the study by the researcher.A computer-generated randomization list (1:1) will be created by the Clinical Research Unit (URC) of Saint-Antoine Hospital (AP-HP). Randomization will be block-balanced and stratified on-site. The width of the blocks will not be disclosed to investigators. Randomization will be performed using a web interface  at the inclusion visit or before the first rTMS session by the rTMS operator. The allocated arm (active or sham rTMS) will not be included in the medical records. The blinding of the allocated treatment will be applied to both the included patients and investigators involved in the patient’s inclusion and follow-up. The operator performing the rTMS will be the only one aware of the sham or active condition. This operator will not be involved in the patient’s follow-up and evaluation.In the event of recruitment challenges, a recruitment assistance service (Cline Research) may be considered to facilitate the dissemination of information about the study to the general public, enable online pre-screening, and potentially involve external referral sources.For an overview of the intervention, instruments, order of assessment, and moment of assessment, see General patient characteristics such as age, handedness, educational level, and use of medication will be assessed. The Mini International Neuropsychiatric Interview (MINI) will be used to determine whether the participant has any psychiatric DSM-IV diagnoses.The primary assessment criterion is the PTSD severity score measured using the Clinician-Administered PTSD Scale (CAPS-5) at the one-month follow-up (V13).PTSD severity scores at M3 and M6  measured using CAPS-5 (structured interview);PTSD severity score measured using the PTSD Checklist (PCL-5 self-questionnaire) at M1, M3, and M6;Dissociative symptom severity scores assessed by the Clinician-Administered Dissociative States Scale (CADSS), the Multidimensional Assessment of Interoceptive Awareness (MAIA), and the Dissociative Experiences Scale (DES) at V1, V13, M1, M3, and M6.The severity scores of the dimensions of anxiety (measured using HAM-A) and depression (measured using HAM-D) at M1, M3, and M6.Social cognition at M0 and M3 assessed using the Eckman test, “reading the Mind in the Eyes” test , Empathy Quotient questionnaire (Baron-Cohen), and Toronto Alexithymia Scale (TAS-20).Quality of life assessed using WHOQOL EuroQol Health Measure, EQ-5D-5L;Proportion of adverse events during the active treatment phase and during the follow-up.® software (version 9.4 or the updated version).The current study is the first to investigate the effect of multiple reactivation therapies enhanced by 20 Hz HF-rTMS sessions on PTSD score severity six months after the last stimulation session. To the best of our knowledge, no studies have investigated the effect of rTMS on PTSD after such a period. A detailed analysis plan will be defined before the database lock. The analysis will be performed by a statistician from URC-Est after data review and database lock. Therefore, no interim analysis is planned. Analyses will be performed using SASt-test, East 6, Cytel). Considering 10% of non-evaluable patients, 102 randomized patients are needed. We anticipate fewer non-evaluable patients than in Kozel’s study (4). Our reactivation memory is less demanding for patients than that of Kozel’s program. Regarding the CAPS score at inclusion, we anticipate a comparable score for the overall severity. This score is close to that reported in Yan’s meta-analysis (3) on the efficiency of rTMS in PTSD. There is empirical evidence regarding the value of prolonged exposure to a wide range of injuries. However, clinical trials have shown that less than 50% of patients improve with exposure therapy and only 15% achieve complete remission [p-value of <0.05 will be considered significant.Based on the literature, we estimate that the CAPS total severity score at M1 in the sham rTMS + memory reactivation procedure group will be at 50 ± 24 . Assumiemission . In our The baseline characteristics of the patients will be described overall and for each group. Qualitative data will be described with frequencies and percentages and quantitative data will be described with mean and standard error or with median and interquartile interval according to the distribution of the variable.An analysis will be conducted based on the intent-to-treat (ITT) population.t-test. In the case of a non-normal distribution, transformation will be performed. Sensitivity analyses on available data and on per protocol population using the same methods will be performed.The CAPS total severity score at M1 will be compared between groups using the Student PTSD severity scores at V15 and V16  measured with CAPS (structured interview) will be described by mean and standard deviation, and the mean difference between groups will be calculated using its 95% confidence interval (CI). Each score  will be analyzed in the same way at V14, V15, and V16. Graphical representations of the evolution over time will be performed. The mean difference between groups and 95% CI will be calculated.Based on the PTSD severity score measured using the PTSD Checklist (PCLS self-questionnaire), a linear mixed regression model may be performed with the patient as a random effect and the group as a fixed effect. In the case of a non-normal distribution of the interest variable, a transformation will be performed.Social cognition at V0 and 15 will be assessed by the Eckman test, “Reading the Mind in the Eyes” test , Test ofThe proportion of at least one adverse event observed during the active treatment phase and during the follow-up will be described and compared between groups using Fisher’s exact test. The proportion difference between groups and their 95% CI will also be calculated. Each type of adverse event will also be described by the group.This article presents a multicenter double-blind randomized clinical trial protocol investigating whether 12 sessions of reactivation therapy enhanced by active 20 Hz HF-rTMS, compared with the same reactivation protocol with sham HF-rTMS, improves the treatment outcomes of PTSD. The choice of 12 sessions and 20 Hz was justified by a review of the literature, and in particular by a recent meta-analysis , which fOne of the main challenges of this study will be the completion of the entire follow-up procedure since participants will be called at three and six months to assess symptom severity. The strength of this study is that it investigates the effect of multiple HF-rTMS sessions in order to enhance reactivation therapy. So far, only a few studies have looked at neuro-enhanced psychotherapy.If this study reveals decreased severity scores in the active stimulation group compared with the sham stimulation group, and the active HF-rTMS induces negligible side effects, this may lead to a shift in PTSD treatment and a need for larger clinical trials on neuro-enhanced psychotherapy for other disorders. Furthermore, future studies will be needed to compare the sensitivity and specificity of our protocol against standard treatments. This could eventually result in approval by regulatory authorities as an additional treatment method for PTSD; for instance, the Food and Drug Administration has approved HF-rTMS for the treatment of depression or OCD .


Older women with early-stage estrogen receptor-positive (ER+) invasive breast cancer (IBC) are at risk for overtreatment. Guidelines allow for sentinel lymph node biopsy (SLNB) and radiotherapy omission after breast-conserving surgery (BCS) for women 70 years of age or older with T1, clinical node negativity (cN0), and ER+ IBC. The study objective was to evaluate radiotherapy and SLNB de-implementation in older women with low-risk IBC after the resource limitations of the COVID-19 pandemic.An institutional database was analyzed to identify women 70 years of age or older who received BCS for IBC from 2012 to 2022. The patients were divided into two cohorts: (1) patients with low-risk IBC  who were eligible for radiotherapy and SLNB omission and (2) patients with high-risk IBC  who were ineligible for therapy omission. Clinicopathologic variables in both cohorts were analyzed.p = 0.04). In contrast, radiotherapy usage among the patients with high-risk IBC was stable from 2012 to 2022 . Among the patients with low-risk IBC, SLNB rates decreased from 86% in 2012 to 56% in 2022, but this trend predated those in 2020. The factors significantly associated with SLNB and receipt of radiotherapy among the patients with low-risk IBC were younger age, larger tumors, grade 3 disease, and involved nodal status (p < 0.01).The study enrolled 881 patients. For the patients with low-risk IBC, the annual rates of radiotherapy were stable from 2012 to 2019. However, radiotherapy utilization decreased significantly from 2020 to 2022 (58% in 2012 vs 36% in 2022; This study demonstrated appropriate and sustained de-escalation of radiotherapy in older women with low-risk IBC after the COVID-19 pandemic. Given the substantial benefits associated with eliminating overtreatment, there is significant interest in identifying the barriers and facilitators to the de-implementation of low-value care.Estimates suggest that more than 30% of U.S. health care expenditure is spent on low-value care, which accounts for more than $100 billion annually.2 Most efforts to de-escalate breast cancer treatment have focused on women 70 years of age or older, who account for approximately one third of all patients with newly diagnosed disease.3 The diagnosis for more than 80% of these patients is hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER-2)/neu-negative (HER2–) breast cancers with favorable tumor biologies, resulting in estimated 10-year breast-cancer specific survival rates higher than 98%.4 At the same time, however, older patients are more likely to have significant medical comorbidities and are at the highest risk of harm related to overtreatment.Early-stage breast cancer is an ideal target for studying the de-implementation of low-value care given its rich history of successive clinical trials demonstrating excellent long-term results after the de-escalation of surgical and adjuvant breast cancer treatment.9 Similarly, the Society of Surgical Oncology (SSO) and the Choosing Wisely initiative since 2016 have recommended against routine sentinel lymph node biopsy (SLNB) for women 70 years of age or older with cN0 early-stage HR+ IBC.10 This recommendation is based on retrospective data and interpretation of CALGB 9343, in which more than 60% of women did not receive axillary staging, with no impact on survival outcomes.11 Despite these long-standing recommendations, national data demonstrate that more than 80% of women meeting the criteria for SLNB omission and 65% of women meeting the criteria for radiotherapy omission continue to receive these therapies, with minimal change in utilization patterns over time.13Based on data from two randomized clinical trials (Cancer and Leukemia Group B 9343 [CALGB 9343] and Post-Operative Radiotherapy in Minimum-Risk Elderly II [PRIME II]) that failed to show a survival benefit associated with adjuvant radiation for older women with low-risk invasive breast cancer (IBC), the National Comprehensive Cancer Network (NCCN) since 2004 has allowed for the omission of adjuvant radiotherapy after breast-conserving surgery (BCS) for women 70 years of age or older with estrogen receptor-positive (ER+), clinically node-negative (cN0) T1 tumors who receive adjuvant endocrine therapy.14 There were national efforts from multiple organizations to highlight the harms associated with overtreatment and to prioritize the re-distribution of health care utilization from low-value to high-value targets.16 However, very little data exist to show whether any sustained changes in the de-implementation of low-value care breast cancer care occurred due to these efforts.At the start of the COVID-19 pandemic in early 2020, experts speculated that the resource-limited environment in the acute phase of the pandemic had the potential to eliminate low-value health care.The objectives of this study were to determine whether the rates of SLNB and adjuvant radiotherapy for women 70 years of age or older with low-risk breast cancer have been reduced since 2020 and to identify the factors associated with SLNB and radiotherapy utilization for patients eligible for omission of these therapies.A prospective institutional database registry of breast cancer patients who received multidisciplinary care was reviewed. The study enrolled all women 70 years of age or older with IBC who received BCS between January 2012 and September 2022. The study excluded patients who initially received BCS but subsequently underwent a mastectomy for tumor-involved margins before initiation of adjuvant therapies and patients who received neoadjuvant chemotherapy or neoadjuvant endocrine therapy.The patients were divided into two cohorts based on their eligibility for omission of SLNB and adjuvant radiotherapy per NCCN and Choosing Wisely guidelines. The low-risk cohort comprised patients with cN0, pathologic T1, ER+, and HER2– IBC who were eligible for omission of axillary staging and radiotherapy. Although Choosing Wisely does not specify T stage or HER2– status as part of their recommendation for SLNB omission, the criteria provided by NCCN for radiotherapy omission were applied to identify a single low-risk cohort that would be eligible for omission of both therapies. The high-risk cohort comprised patients with clinically node-positive (cN+), pathologic T2-T4, triple-negative, or HER2+ IBC who were not eligible for de-escalation of axillary staging and radiotherapy.Demographic and clinical information including patient age, race, tumor size, clinical and pathologic T and N stages, tumor grade, and histology, as well as ER, progesterone receptor (PR), and HER2 receptor status were evaluated. Treatment information including type of axillary operation (SLNB vs axillary lymph node dissection [ALND]) and receipt of adjuvant chemotherapy, radiotherapy, or endocrine therapy were determined. Due to the contemporary timeline of this study, only initiation of endocrine therapy was evaluated.The primary study outcome was utilization of axillary staging and adjuvant radiotherapy among women70 years of age or older who received BCS for IBC from 2012 to 2022. The secondary outcomes were patient and tumor factors associated with the utilization of SLNB and radiotherapy for women with low-risk breast cancer who were eligible for omission of these adjuvant therapies. All research was performed after institutional review board approval.t test, Fisher’s exact test, or a chi-square test as appropriate. Similar analyses were performed to compare the characteristics of the patients eligible for SLNB and radiotherapy omission who received SLNB, radiotherapy, or both compared with those who did not. Multivariate logistic regression with control for patient and tumor factors was performed to independently evaluate the impact that year of operation had on receipt of axillary staging and adjuvant radiotherapy in both the low- and high-risk patient cohorts. Multivariate logistic regression also was used to examine factors independently associated with receipt of SLNB or adjuvant radiotherapy by those eligible for omission of these therapies.The demographic and clinical characteristics of the patients with low-risk tumors who were eligible for SLNB and radiotherapy omission were compared with those of the patients with high-risk tumors who were not eligible for omission of these therapies using a two sample p values lower than 0.05 were considered statistically significant.All statistical analyses were performed using STATA 16.1 , and two-sided During the study period, 881 women 70 years of age or older received BCS. The low-risk cohort consisted of 520 patients who were eligible for omission of axillary staging and adjuvant radiotherapy. The high-risk cohort had 361 patients who were not eligible for de-escalation of axillary staging and adjuvant radiotherapy.p ≤ 0.03). Overall, 64.7% of the patients eligible for omission received SLNB compared with 74.8% of the patients not eligible for omission (p <0.01).The characteristics of the patients who were eligible for omission of these therapies compared with those who were not are shown in Table p < 0.01). Of the patients eligible for omission, 51% received adjuvant radiotherapy compared with 66.8% of the patients who were not eligible for omission (p < 0.01). Significantly more patients in the high-risk cohort received treatment with chemotherapy than patients in the low-risk cohort . The ER+ patients in the two cohorts did not differ in receipt of endocrine therapy.Among the patients who received axillary staging, 11% of the patients eligible for omission had tumor-involved lymph nodes, compared with 35.2% of the patients who were not eligible for omission of axillary staging  to 2020–2022 . In this cohort, the probability of radiotherapy receipt in 2012 was 79% compared to 79% in 2022, and year of operation was not an independent predictor of odds of radiotherapy receipt . The patients 70 to 75 years old were more likely to receive radiotherapy, whereas the patients 76 years or older were more likely to omit adjuvant radiotherapy (p < 0.01). The univariate analyses showed that the patients with grade 3 disease were more likely to receive both axillary staging and radiotherapy (p < 0.01), although the multivariate analyses showed that grade 3 disease was associated only with significantly higher odds of radiotherapy receipt  and not SLNB receipt . There was no difference in utilization of axillary staging (p = 0.14) or radiotherapy (p = 0.28) based on tumor histology.In both the uni- and multivariate analyses, older age was associated with significantly decreased odds for receipt of SLNB  or radiotherapy , whereas increased tumor size was associated with significantly increased odds for receipt of SLNB  or radiotherapy . Specifically, the patients in age categories of 70 to 75 years and 76 to 80 years were more likely to receive SLNB, whereas the patients 81 years old or older were more likely to omit SLNB (p < 0.01), but chemotherapy receipt did not differ between the patients who received axillary staging and those who did not (p = 0.97). The multivariate analyses showed that the patients with tumor-involved nodes were at significantly higher odds of radiotherapy receipt , whereas the patients who did not receive axillary staging had significantly lower odds of radiotherapy receipt . The univariate analyses showed that significantly more patients who underwent radiotherapy were treated with chemotherapy and endocrine therapy (p < 0.01). However, the adjusted multivariate analyses showed that receipt of endocrine therapy was not associated with increased odds of radiotherapy utilization .The univariate analyses showed that significantly more patients who received SLNB were treated with radiotherapy and endocrine therapy  and the Surveillance, Epidemiology, and End Results (SEER) program will not be available for analysis for several years. Additionally, due to the contemporary nature of this study, there are no long-term data on whether patients for whom radiotherapy was omitted completed their recommended course of adjuvant endocrine therapy. However, the decision to omit radiotherapy is based on clinical judgment as to whether a patient is likely to tolerate adjuvant endocrine therapy, so evaluating initiation of endocrine therapy is likely an appropriate surrogate.Patient age and tumor characteristics alone do not capture the nuances involved in the decision for a patient to omit or receive axillary staging and radiotherapy. The decision relies on shared decision-making regarding the potential risks versus the benefits of these therapies, and not every patient who has been identified in the low-risk cohort may be truly appropriate for omission of radiotherapy and SLNB.Finally, factors other than the COVID-19 pandemic may have affected the trends observed in this study. However, the sharp change in radiotherapy practice patterns in 2020 with little to no change in the years before suggests a strong correlation with the COVID-19 pandemic.In conclusion, this study demonstrated appropriate de-escalation of adjuvant radiotherapy for women 70 years of age or older with cN0, T1, ER+, HER2– IBC during the COVID-19 pandemic without a change in rates of radiotherapy receipt among patients with high-risk breast cancer. This reflects intentional, evidence-based change in provider practice patterns to avoid low-value care, which has been sustained over time. Although there has been de-implementation of SLNB for patients eligible for omission of axillary staging since 2012, this trend appears to predate 2020 and did not change with the COVID-19 pandemic. This demonstrates that reduction in low-value care offers an opportunity for dissemination of strategies to reduce overtreatment at other institutions and at a national level.


Whether the fascia iliaca compartment block (FICB) involves the obturator nerve (ON) remains controversial. Involvement may require that the injectate spreads deep in the cranial direction, and might thus depend on the site of injection. Therefore, the effect of suprainguinal needle insertion with five centimeters of hydrodissection-mediated needle advancement (S-FICB-H) on ON involvement and cranial injectate spread was studied in this radiological cadaveric study. Results were compared with suprainguinal FICB without additional hydrodissection-mediated needle advancement (S-FICB), infrainguinal FICB (I-FICB), and femoral nerve block (FNB). Seventeen human cadavers were randomized to receive ultrasound-guided nerve block with a 40 mL solution of local anesthetic and contrast medium, on both sides. Injectate spread was objectified using computed tomography. The femoral and lateral femoral cutaneous nerves were consistently covered when S-FICB-H, S-FICB or FNB was applied, while the ON was involved in only one of the 34 nerve blocks. I-FICB failed to provide the same consistency of nerve involvement as S-FICB-H, S-FICB or FNB. Injectate reached most cranial in specimens treated with S-FICB-H. Our results demonstrate that even the technique with the most extensive cranial spread (S-FICB-H) does not lead to ON involvement and as such, the ON seems unrelated to FICB. Separate ON block should be considered when clinically indicated. Benefits, in theory, include superior pain control, improved patient satisfaction, prevention of postoperative delirium, and reduced opioid consumption4. The use of RA is particularly relevant for (lower) extremity surgery due to its painful characteristics5. Numerous injection techniques targeting the hip, anterior thigh and knee have been developed, one of which is the fascia iliaca compartment block (FICB).Regional anesthesia (RA) techniques, such as fascial plane blocks and peripheral nerve blocks, have become a central component of multimodal analgesic strategies6. Reports of inconsistent LFCN and ON blockade then led to studies that investigated the anatomical relations of the inguinal region, and local anesthetic distribution during 3-in-1 block8. These studies ultimately resulted in the establishment of a loss-of resistance technique, now known as FICB, targeting the fascia iliaca compartment (FIC)8. Later modifications of the technique include the incorporation of ultrasound guidance and more recently, the growing popularity of suprainguinal (S-FICB) over infrainguinal (I-FICB) injection sites11. However, although S-FICB was developed to acquire more consistent results when compared to I-FICB, debate persists over clinical superiority regarding coverage of the ON20.The origins of FICB can be traced back to Winnie’s 3-in-1 block, an anterior landmark approach to the lumbar plexus that targets the femoral nerve (FN), lateral femoral cutaneous nerve (LFCN) and obturator nerve (ON)21. However, recent anatomical reports have shown that the ON does not transverse the FIC, but rather passes through the psoas, retro-psoas and retroperitoneal compartments  is required to spread outside of the FIC in order to involve this nerve. While these studies agree on the closure of the FIC on its posteromedial border, they offer conflicting views on the existence of a cranially located opening to the retroperitoneal compartment and ON13. If this cranial path indeed exists, successful blockade of the ON with FICB would likely mandate overflowing the FIC, or a cranial injection site within the FIC.Similar to other fascial plane blocks, FICB provides analgesia on the assumption that an injectate can open the potential space between the fascia iliaca (FI) anteriorly and the psoas major and iliacus muscles posteriorly, and spread towards the nerves within by means of bulk flow and diffusionTherefore, we set up a radiological cadaveric study to determine the effect of a cranial injection deep under the FI using suprainguinal needle insertion with five centimeters of additional hydrodissection-mediated needle advancement (S-FICB-H) on coverage of the ON. Further, we measured cranial injectate spread and involvement of the FN and LFCN. Results were compared with S-FICB without additional hydrodissection-mediated needle advancement, I-FICB, and femoral nerve block (FNB). We hypothesized that the injectate would reach most cranial for S-FICB-H, but that none of the nerve block techniques would result in reliable coverage of the ON.22.A convenience sample of 17 fresh, unfrozen and unembalmed adult human cadavers was included in this study. Cadavers were bequeathed to the Amsterdam University Medical Centers (location AMC) to serve research and educational purposes. Written informed consent for donation was given during life, in accordance with the Dutch Burial and Cremation act (BWBR0005009). The Medical Ethical Committee of the Amsterdam University Medical Centers (location AMC) provided a waiver for approval of this study. Further, experiments were performed according to relevant international and institutional regulations and ethics guidelines. The presented findings are reported according to the Anatomical Quality Assurance (AQUA) checklist23. Ultrasound guidance was used to visualize the different anatomical structures, to guide the needle tip to the correct plane, and to observe injectate spread. Nerve blocks were placed by two anesthesiologists specialized in regional anesthesia . Study procedures were completed within six hours of arrival at the Amsterdam University Medical Centers.Nerve blocks were performed bilaterally, but each side was randomized individually. Thus, totaling eight or nine nerve blocks per injection technique Table . The inj9. In the S-FICB-H group, we subsequently advanced the needle tip an additional five centimeters under the FI (using hydrodissection) in order to achieve a pronounced cranial position not previously documented in the literature for a single-shot technique. I-FICB was performed at the lateral third of the line connecting the pubic tubercle and the anterior superior iliac spine, one centimeter caudal to the inguinal ligament10. The injection was placed at the inguinal crease, adjacent to the FN, in case of (ultrasound-guided) FNB.S-FICB was applied by puncturing the skin approximately one centimeter cranial to the inguinal ligament in caudal to cranial fashion13. Further, FN and LFCN coverage were other secondary outcome parameters.The primary outcome parameter of this study was ON coverage. Additionally, we measured cranial injectate spread as a function of the injectate’s ability to migrate to the debated cranial opening (in the FIC) and ONInjectate spread was documented 15 min after injection using whole-body computed tomography (CT) . A musculoskeletal radiologist blinded to the injection technique assessed the locoregional contrast medium spread. Perineural presence of contrast was assessed by visualization and inspection of the anatomical location of the relevant structures in axial, sagittal and coronal planes, with additional reformatting when deemed necessary. For example, the full path of the ON between its origin and exit through the obturator foramen was inspected. Cranial diffusion was measured in coronal reformatted images from the femoral head (in centimeters) and is also described in relation to the corresponding vertebra.P-value smaller than 0.05 was deemed statistically significant. IBM SPSS Statistics, Version 28.0.1.0, was used for statistical analysis .Data for cranial injectate spread was tested for normality using histograms and the Shapiro–Wilk test, and is presented as mean ± standard deviation. Cranial injectate spread was subsequently compared across the study arms by applying one-way ANOVA and Tukey post-hoc testing. Other outcome measures were summarized as frequencies with percentages. A Cadavers were predominantly male . Further baseline characteristics and details about prior medical history were unavailable, due to the anonymous nature of the body donation program.The ON was involved in one (S-FICB) of 34 nerve blocks, while none reached the lumbar plexus. The nerve block that did reach the ON was found to involve this nerve in the retroperitoneal compartment, at a level corresponding to the first sacral vertebra Fig. . This waThe FN and LFCN were consistently involved in S-FICB-H, S-FICB and FNB, while these structures were considerably less often involved in I-FICB . Details of nerve involvement are summarized in Table Spread of the injectate towards the lumbar plexus was measured in relation to the femoral head. Truncal spread was found in only two of nine 22%) I-FICBs and as such, I-FICB was excluded from statistical analysis. The mean cranial spread of S-FICB-H 14.00 ± 3.16 cm) was significantly more than that of S-FICB , or FNB . Injectate reached higher for S-FICB than for FNB (p = 0.008). Similar distribution patterns were observed when cranial injectate spread was related to the vertebral column, as shown in Table 2% I-FICB.16 cm waThis radiological cadaveric study supports the hypothesis that S-FICB-H leads to the most cranial injectate spread of the techniques targeting the FIC. Concurrently, however, our findings also demonstrate that pronounced cranial injectate spread will not result in reliable blockade of the ON. I-FICB resulted in less involvement of the FN and LFCN than S-FICB-H, S-FICB and FNB.The ON is a mixed sensory and motor nerve that derives from the anterior divisions of the second, third and fourth lumbar spinal nerves. Its branches innervate the adductor muscles of the thigh, and the hip and knee joints. Further, the ON contributes, in some patients, to the sensory innervation of a section of the medial thigh. Therefore, inclusion of ON blockade in FICB would improve analgesia after lower extremity procedures, such as hip fracture surgery.24. Meanwhile, (both primary and secondary) cadaveric dissection is prone to disrupt the integrity of fascial layers, and is therefore at risk of false positive research results. This study therefore applied CT-imaging of a LA-based contrast mixture, as it allowed for precise and objective  measurements of injectate spread. Additionally, CT-imaging allowed us to include 34 samples, a number which would have been unrealistic to obtain with dissection . Further, the advanced CT scanner used here provided us with similar information as would have been obtained with MRI.However, it is still debated whether the ON can indeed be covered during FICB. Clinical examination after FICB may be ambiguous due to the highly variable cutaneous innervation of the ON and co-innervation to the adductor muscles17. Literature details differing success rates for I-FICB30. Interestingly, our results are similar to that of authors who performed I-FICB based on the description that was also the foundation of the technique applied in this study28. The current study supports the conclusion that S-FICB leads to more cranial spread and better FN and LFCN involvement than I-FICB, yet our results indicate less cranial distribution patterns for conventional S-FICB and I-FICB than previously reported in a volunteer study17. The 40 mL injectate allowed FNB to behave as a field block, while the inguinal injection site might have facilitated more efficient migration towards the FN and LFCN than possible for I-FICB.The data presented here for S-FICB  deviates from previously reported success rates of ON involvement, but is closely aligned to reported rates of FN and LFCN blockade11. However, anatomical reports have shown that the ON does not travel within the FIC and suggested an alternative mechanism of action: cranial diffusion from the FIC to the retroperitoneal compartment13. Assuming this path exists, lack of ON involvement can be hypothesized to be caused by either an inadequate injection volume and injection force, or a too distal injection site, placing the LA out of reach from the retroperitoneal compartment. This scenario could explain the unusually high—compared to the FIC’s capacity of 23 mL—minimum effective volume of 62.5 mL found in a recent cadaver dissection study that applied a step-up, step-down algorithm to determine the optimal injectate volume14. However, it is as of yet unknown what effect a large injectate volume, or high injection pressure, has on fascial plane integrity . Similar to needle misplacement in the retroperitoneal compartment, disruption of the fascial compartment could lead to creation of an artificial opening in the FI and diffusion towards the ON15. This, however, would not be a true fascial plane block and constitutes a different mechanism than sought after with a FICB. We speculate that this mechanism is the explanation for the case in which the ON was successfully involved in our study, and the underlying reason for the limited replicability of studies.The ON’s path between its origin and the obturator foramen is of importance as the aforementioned nerve block approaches are all based on the presumption that the ON can be reached by an injectate in the FIC25. Thus, overall, achieving reliable ON blockade using a FIC approach seems not possible, as illustrated by the presented data, the considerable number of published methodological variations, and the differences in reported success rates between studies that applied the same injection technique.Alternatively, this investigation assessed whether advanced needle insertion into the cranial direction would result in ON involvement. The lack thereof shown here contradicts the existence of an easily accessible cranial route from the FIC to the retroperitoneal compartment. Further, as reported in other studies, posteromedial spread was limited and remained removed from the ONA limitation of this study is the reliance on (human) cadavers as tissue quality might have deteriorated after death. However, specimens were fresh, unfrozen and unembalmed, allowing for near-normal block procedures as shown by the pattern of spread after nerve blocks.In summary, neither S-FICB-H nor any other technique targeting the FIC leads to reliable ON involvement, and as such the ON seems to be unrelated to fascial plane blocks targeting the FIC. Addition of a separate ON block to S-FICB (or large volume FNB) should be considered when clinically indicated.


With the emergence of mutant versions that lead to continual spreading and recurrent infections of SARS-CoV-2, the COVID-19 vaccines can assist protection for high risk groups, particularly health workers. Even while booster shots have been widely used, longitude studies on immune responses in healthy subjects are uncommon.Eighty-five healthcare workers who received the BBIBP-CorV vaccine were prospectively enrolled and monitored for up to ten months. Automated Pylon immunoassays were used to quantify total anti-SARS-CoV2 antibody levels (TAb), surrogate neutralization antibody levels (NAb), and antibody avidities over the course of the follow-up. Additionally, hematology analyses were performed.Pylon antibody testing revealed that every participant tested negative at the beginning, and 88.2% of them tested positive about 14 days after receiving their second dosage. The TAb levels and NAb levels peaked in 76.5% and 88.2% of the subjects, respectively, at the same time. Age was connected with the peak antibody levels, but not with gender, BMI, or baseline hematological factors. The positive rates and the antibody levels had already started to decline three months following the second injection. The antibody levels and avidities quickly increased following the booster doses to levels that were considerably greater than the peak antibody responses before to the booster shots. Hematology testing revealed no safety concerns with immunizations.In healthy workers, the two doses of BBIBP-CorV were able to induce humoral immunity; however, 3 months following vaccination, the antibody levels started to decline. The BBIBP-CorV booster injections increase both the quantity and quality of antibodies, which gave support for utilizing booster doses to prolong the duration of the vaccine’s protective effects. Since its initial discovery in December 2019, the coronavirus disease (COVID-19) has been a global pandemic . SARS-CoEighty-five healthcare workers eligible to receive the inactivated SARS-COV-2 vaccine  were prospectively enrolled. All the participants completed vaccinations by administering two doses of the vaccine 1 month apart. Blood samples were collected on the day of the first and second shots of the vaccines, as well as one month, three months and 6 months after the second shot from each participant. Forty-five out of the eighty-five participants had the third shots of the vaccine, the booster shots, approximately 10 months after the first shots. For those forty-five participants, additional blood samples were also collected approximately one month after the booster shots. EDTA anti-coagulated whole blood samples were used for analysis by a hematology analyzer and a flow cytometry within 24 hours. Serum samples were prepared by centrifugation and stored at -80°C for the measurements of antibodies in batches. The study was approved by the institutional ethical committee and complied with the Declaration of Helsinki. Written informed consent were obtained from each participant.The anti-SARS-CoV-2 Abs in the serum samples were assessed by Pylon TAb assays and Pylon NAb assays, which were probe-based fluorescent immunoassays performed on the Pylon 3D analyzer . The details of both assays were described previously . In brieThe avidities of Abs reflected affinity maturation and multivalent binding development of Abs. In this study, they were measured by the relative dissociation rates (dRs) of the Abs-RBD bindings using the reagents of Pylon TAb assays. The slower the dRs were, the higher the avidities were. The method was reported previously and shown to correlate well with a Bio-Layer Interferometry avidity assay . To measHematology analysis was performed using Mindray BC-6000 according to the standard operating procedure of the clinical laboratory in Shanghai East Hospital (south Branch). In brief, EDTA-K2 anti-coagulated whole blood was collected and hematology analysis was automatically performed within 30 minutes of collection. After hematology analysis, the above sample was used to measure the level of CRP (C-reactive protein) by Ottoman automatic real-time detection analyzer .To determine the effects of vaccination on lymphocyte’s absolute number, the cell counts of T lymphocytes, B lymphocytes, NK cells and the subgroups (CD4+ or CD 8+) of T cells were determined by BD Multitest 6-color TBNK reagents on a BD FACSLyric flow cytometry  according to the package insert. In brief, well-mixed whole blood samples were incubated with the 6-color TBNK reagents for 15 minutes in dark at 20-25°C in BD Trucount™ tubes before the red cells in the samples were lysed by adding the BD lysing solution. Then the samples were loaded and cell counts were measured on the flow cytometry and analyzed by BD FACSuite software.Categorical variables are expressed as percentages. Continuous variables are expressed as the mean ± SD or median (interquartile) according to normal or non-normal distribution. Statistical differences between groups were compared using the χ2 tests for categorical variables, the Kruskal-Wallis tests for non-normally distributed continuous variables and the One-way ANOVA for normally distributed variables. T-tests and Wilcoxon tests were used to compare the paired results. All the statistical analysis was performed using MedCalc version 20.009.Eighty-five healthcare professionals participated in the study and their characteristics were summarized in Serum samples collected at all seven-time points during the study period were measured by Pylon TAb assays and Pylon NAb assays. The positive rates at each time point were provided in Pylon TAb assays and Pylon NAb assays provided quantitative measurements of total anti-RBD antibody levels and surrogate neutralization abilities respectively. Both the total anti-RBD antibody levels and the surrogate neutralization abilities gradually increased after vaccination Figure 2p =0.0003, Wilcoxon test; NAb: p =0.002, Wilcoxon test) and at the second doses   and further around 6 months after the second shots  in both assays. Yet, around 6 months after the second shots (TP6) the antibody responses were still significantly higher than those at the baseline , but they were not associated with weight, BMI or gender. The peak responses in the participants younger than 30 years old were higher (Before the booster shots (between TP1 and TP6), the total anti-RBD antibody levels (TAb) reached peaks around two weeks after the second dose (TP3) in sixty-five out of eighty-five participants (76.5%), while in seventy-five out of eighty-five participants (88.2%) the maximum neutralization abilities (NAb) were achieved around the same time. The peak antibody responses negatively correlated to ages  were significantly higher after the booster shots   (p = 0.1915)  during the study. The percentages of total T cells, cytotoxic T cells, T-helper cells and natural killer cells had very little variations during the study Figure 6One of the most crucial methods for controlling and preventing COVID-19 is vaccination, and many platforms and technologies have been employed to create and use vaccines across diverse nations. The conventional inactivated viral vaccines are also efficacious for COVID-19, despite the fact that mRNA vaccines, which got their first-in-class licensures during this pandemic, are readily available worldwide. One of the inactivated viral vaccines that is frequently utilized in China is the BBIBP-CorV vaccination. The longitudinal investigations on the immune responses of immunized healthy volunteers offer crucial proof of the vaccine’s efficacy and perhaps even details on the length of protection offered by each dosage. In this study, we monitored the kinetics of the antibody responses in eighty-five healthcare workers who received the BBIBP-CorV vaccine over the course of about 10 months. Throughout the study time, they were all free of infection, hence this research offered information on vaccination in healthy individuals.p<0.001), but were not associated with gender, BMI and hematology test results. The participants younger than 30 years had significantly higher TAb levels than the others , surrogate neutralization antibody levels (NAb), and antibody avidities. At the beginning, every participant tested negative. Using Pylon TAb assays (29.4%) and Pylon NAb assays (11.8%), the seroconversion was detected as early as the time of the second doses, which were administered one month following the first doses. After the second dose, the positive rates grew even further, reaching 88.2% between two weeks and one month Figure 1e others  and othee others  that shoe others , but thap = 0.0382, Wilcoxon test) and the NAb inhibition abilities . Furthermore, for the first time, the antibody avidities in healthy subjects after the vaccination of BBIBP-CorV were measured and significantly higher antibody avidities were observed after the booster shots . That indicated that the maturation of antibody affinity could take place in healthy subjects by multiple shots of BBIBP-CorV vaccines, similar to the antibody maturation in COVID-19 patients  increased antibody levels and neutralization ability on mutated variants and improved protection of hospitalization, severe cases and mortality . In thispatients . TherefoIt was noted that the study had several limitations. A small number of participants were included although a relatively long follow-up period was achieved. Also, due to the limitation of resources and facilities, we were not able to study the humoral responses to live viruses or different virus mutants. Finally, the quantitative results reported here would not be able to compare directly with other studies due to lack of the standardization among SARS-CoV-2 antibody assays in general. However, it should not affect the longitude analysis of antibody kinetics in this study.In conclusion, our findings showed that the two doses of the inactivated viral vaccine BBIBP-CorV may induce humoral immunity in healthy individuals, which degraded three months after immunization. The BBIBP-CorV booster shots increase both the quantity and quality of antibodies, providing proof that booster shots should be given to prolong the benefits of vaccination.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the medical ethics committee of Shanghai East Hospital. The patients/participants provided their written informed consent to participate in this study.JW, HM and XP analyzed and interpreted the data. WG was a major contribution in writing the manuscript. All authors contributed to the article and approved the submitted version.