Aims: To determine real-life biologic/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) retention rates in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), explore reasons for switching and to compare results to previously published data.Methods: Time-to-event analysis for mean treatment duration , b/tsDMARD failure, and b/tsDMARDs switching was performed for 230 patients  who commenced their first b/tsDMARD between 2008 and 2018. Patients were managed in a dedicated “biologics” clinic in a tertiary hospital; the choice of b/tsDMARD was clinician driven based on medical factors and patient preferences. The effect of covariates on switching risk was analysed by a conditional risk-set Cox proportional-hazards model. Treatment retention data was compared to a historical analysis (2002–2008).Results: The proportions remaining on treatment (retention) were similar, throughout follow-up, for the first, second and third b/tsDMARDs across all patients (p = 0.46). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients [Hazard Ratio (HR) = 0.50], but no different in AS patients (HR = 1.0). The respective restricted mean (95%CI) treatment durations, estimated at 5 years of follow-up, were 3.1 , 4.1 , and 3.3  years, for RA, PsA, and AS, respectively. Age, gender, disease duration, smoking status and the use of concomitant csDMARDS were not associated with the risk of bDMARD failure. The most common reasons for switching in the first and subsequent years were secondary (n = 62) and primary (n = 35) failure. Comparison with historical data indicated no substantive differences in switching of the first biologic for RA and PsA.Conclusion: Similar retention rates of the second and third compared to the first b/tsDMARD in RA, PsA, and AS support a strategy of differential b/tsDMARDs use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years. Biologic (b-) and targeted synthetic (ts-) disease-modifying anti-rheumatic drugs (DMARDs) represent a major therapeutic advance in rheumatology. However, response rates to b/tsDMARDs are variable ; the eviThe efficacy of a drug can be reliably determined by its retention rate or persistence , 7. DataAlthough international guidelines are available on the prescription of biologics in rheumatic disease, these do not generally recommend any single agent or class . The iniMultiple studies, including real-life studies, have analysed cycling to another agent with the same MoA and also looked at switching to an alternative agent, in patients who have failed or have been intolerant to their current biologic agent , 16. TheThis study was conducted to assess retention rates of the first-, second-, and third-b/tsDMARDs in RA, PsA and AS in a tertiary hospital clinic setting. We also sought to compare b/tsDMARD retention rates between these diseases, assess the effect of concomitant DMARDs, explore trends of and reasons for switching, and compare with the historical data from this clinic.The current prescription of b/tsDMARDs in Australia is mandated by the Australian Medicare system, which provides subsidised treatment at a uniform cost, regardless of the type of b/tsDMARD. A patient becomes “eligible” for a b/tsDMARD following failure of csDMARDs for RA and PsA, or for AS, failure of a trial of non-steroidal anti-inflammatory drugs. The choice of b/tsDMARD  is physician-driven and directed by patient demographics, comorbidities, and patient preferences. Specifically, to qualify for PBS subsidised b/tsDMARDs for RA and PsA, patient must have at least 20 active (both swollen and tender) or 4 active large joints. Patients who present with axial disease in the context of PsA are classified as AS. Patients with AS require to have radiographic sacroiliitis , and failure of at least 2 NSAIDs, to qualify for access to a b/tsDMARD. In Australia, bDMARDs were introduced for the treatment of rheumatic conditions around 2003, with Infliximab and Etanercept as the initial agents, followed by Adalimumab (2004), Abatacept and Rituximab (2007), Tocilizumab (2009), Golimumab and Certolizumab (2010), Ustekinumab and Secukinumab (2016). Tofacitinib, a synthetic small molecule Janus kinase (JAK) inhibitor, is a tsDMARD and was available in 2015.The Southern Adelaide Local Health Network (SALHN) in Adelaide, South Australia, comprises of three teaching hospitals offering rheumatological services, which include a dedicated, weekly, registrar-run and consultant-supervised, biologics clinic, established in 2002. Approximately 500 patients are enrolled in this clinic with the patient database being maintained by a dedicated “biologics” nurse. The majority of patients on b/tsDMARDs for RA, PsA, and AS, diagnosed within SALHN are referred to and managed in this clinic.In this retrospective, longitudinal, observational study, we included all adult (>18 years) patients with RA, PsA, and AS, commencing first and subsequent b/tsDMARDs between July 1, 2008 and June 30, 2018. The diagnoses of RA, PsA and AS were made by their treating rheumatologist and at the time of enrolment, all patients were biologic naïve. We excluded patients if they did not receive or take b/tsDMARD treatment (despite enrolment), those with incomplete data or those who were subsequently lost to follow-up. Biologics for non-radiographic axial spondyloarthritis (nr-AxSpA) were not available on the PBS for most of the period covered by this study, and this group of patients were also excluded. This study was submitted to and approved by the Southern Adelaide Clinical Human Research Ethics Committee to proceed and to be published. However, because this study was designed for and intended to lead to iterative refinement in service provision, the Southern Adelaide Clinical Human Research Ethics Committee determined that it did not require a full formal ethical review.Data was collected retrospectively from the patient medical records. Data collected included demographics, duration of disease prior to commencing their first b/tsDMARD, csDMARD and prednisolone use, reasons for and dates of commencement and switching of b/tsDMARDs. Reasons for switching were classified as primary or secondary failure, adverse events, extra-musculoskeletal manifestations, comorbid conditions, infection or other.Since there is no universally accepted consensus definition of primary and secondary failure, for the purposes of this study, primary failure was defined as not demonstrating efficacy with treatment within 3–6 months of treatment initiation and secondary failure as an initial response, subsequently lost on continued treatment. Persistence was defined as the time from initiation to discontinuation of biologic therapy.Data was also compared to previous similar analysis undertaken in this centre prior to 2008 .All statistical analysis was performed in Stata v16.1 . The proportion of patients remaining on their prescribed b/tsDMARD therapy (retention) was analysed using time-to-event analysis methods for censored data to account for incomplete follow-up in patients without b/tsDMARD failure. Results were initially explored by Kaplan-Meier curves, but as patients experienced up to three b/tsDMARD failure events, further analysis was performed using conditional risk set time-to-event regression models for multiple failures .Summary measures of the b/tsDMARD treatment retention curves over time included the %bDMARD retention and the mean treatment duration, both estimated at 5 years of follow-up. The mean treatment duration was estimated as the Restricted Mean Survival Time (RMST) , definedhttps://www.digitizeit.xyz/) software, and integration of the area under the curve using the trapezoidal rule.Point estimates of the mean treatment duration at 60 months (5 years) from previously published  historicPatient-level predictors for b/tsDMARD treatment failure were evaluated by a Cox regression model, with results reported as Hazard Ratios (HR). Reasons for b/tsDMARD treatment failure were compared using a competing risks analysis of the individual cause-specific cumulative incidence functions over time, estimated using the Stata ado program “stcompet” .The study included 230 patients: 147 RA (81% seropositivity), 46 PsA and 37 with AS . The medThe most common initial b/tsDMARD was a TNFi, prescribed in 109 (74%), 44 (96%), and 37 (100%) of RA, PSA, and AS patients, respectively. However, there was diversification in the class of newly prescribed b/tsDMARD over the second and third treatment episodes, with the proportion of patients prescribed another TNFi declining in all three diagnosis groups . The mosTabulation of all b/tsDMARD switching events in RA  demonstrAs expected, the majority of b/tsDMARD switching in both PsA and AS patients was within TNFi. In PsA, 3/16 patients who switched treatment switched from TNFi to secukinumab, and a further two switched to ustekinumab. In AS, 3/21 patients who switched treatment switched from TNFi to secukinumab.plogrank test = 0.46, plogrank test = 0.016, b/tsDMARD retention was estimated as the proportion remaining on treatment from Kaplan-Meier curves. Treatment retention and the restricted mean treatment duration at 5 years of follow-up for each treatment and each diagnosis are reported in A summary of b/tsDMARD retention for each diagnosis is reported in p = 0.66).Patient-level determinants of b/tsDMARD failure were explored by multivariable cox regression with results reported as hazard ratios (HR), . When cob/tsDMARD retention rates were also compared to historical, non-overlapping data from the same clinic , for whin = 62), primary failure (n = 35) and side effects (n = 24), n = 12) included pregnancy, malignancy and non-compliance.The most frequent reasons for b/tsDMARD failure/switching were secondary failure  appear to be generally similar to those reported previously, with 12-month retention rates reported as 62.2–68.9% , 42–56% Data on the long-term retention of b/tsDMARDs in PsA and AS, in comparison to those in RA, are limited. In a study by Lyu et al. , bDMARD In a recent study by Murray et al. , b/tsDMARetention rates of second and third b/tsDMARDs are more difficult to compare with our current study, as there are few studies that have analysed similar data. Two available studies on RA have reported results similar to ours with second b/tsDMARD (TNFi) retention rates of 46–56%  and 56.8One reason for the better than expected retention rates in our study with subsequent b/tsDMARDs may be our practise of switching to a b/tsDMARD with a different MoA, rather than to an alternative agent in the same class; this strategy is supported by previous studies , 20–25. Previous studies reflect our results of TNFi being the most commonly prescribed first line bDMARD . This isUnexpectedly, we did not find an association between b/tsDMARD failure and concomitant csDMARD use in RA, in contrast to previous studies that have demonstrated superior b/tsDMARD retention rates in RA, in particular with TNFis, with concomitant csDMARDs –60. In cAn increased use of tocilizumab, often as monotherapy without csDMARDs, especially during class switching, may also have contributed to the lack of an association between b/tsDMARD failure and concomitant csDMARD use in our study. Previous studies have demonstrated the equivalent efficacy  and reteWe also did not find any significant association with b/tsDMARD failure with female gender, smoking, age, and disease duration, or seropositivity. Courvoisier et al.  recentlyExisting literature confirms our findings of inefficacy (primary or secondary) as the most common reason for discontinuing or switching bDMARD therapy, followed by adverse events to the agent , 71–73.We did not find significant differences in the first bDMARD retention over time, as compared to previously published data from our clinic . This waThe strengths of this study lies in it being a real-world study representing contemporaneous clinical practise, rather than a RCT. Additionally, it is one of very few studies comparing data from three inflammatory arthritides, over a 10-year period, with a follow-up period of minimum 5 years, and with an added advantage of comparison with previous data from the same centre, enabling observations of changes in trends over time.The limitations of this study are its observational nature with relatively limited patient numbers and use of retrospectively collected data from patient medical records, that relied upon accurate documentation, which was not always present and led to those patients being excluded from the analysis. Although AS and PsA have a similar prevalence in Australia as compared to the rest of the world, the specialised clinic that this data is drawn from receives patient referrals from the Southern region of Adelaide, which may be a reason as to why sample size was limited; in addition, the Australian subsidised PBS criteria for access to biologics are relatively strict and inflexible. The latter reason means that some patient who would clinically benefit from addition of a b/tsDMARD are unable to access these drugs.In the absence of randomisation, patients may have been guided to a specific drug, producing selection bias. Additionally, in this long-term drug survival analyses, the number of patients at risk progressively decreased by time, being lower at the end of the evaluated follow-up period and this trend may partially influence the results. Some b/tsDMARDs were not available until later in the period and therefore their penetration in this study may have been limited.Similar retention rates of the second and third compared to the first b/tsDMARD support a strategy of differential b/tsDMARD use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Southern Adelaide Clinical Human Research Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.MW contributed to conception and design of the study. LB organised and maintained the database. VB and RH collected and entered patient data. SL performed the statistical analysis and wrote the results section. VB wrote the first draught of the manuscript. MW, SL, and VB wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To explore the impact of different intervention methods on physical health indexes of perimenopausal women.Seventy-eight perimenopausal women were divided into three groups. Group A received routine gynecological diagnosis and treatment and participated in centralized lifestyle health education. Group B was required to participate in all intensive education content, and professional dietitians gave individualized dietary guidance. Group C received intensive education, individualized diet intervention and intensified resistance exercise. Dietary scores, exercise habits, waist circumference, body mass index, fat and muscle mass were observed after three months.After the intervention, the total diet score of group C was higher than groups A and B, and the red meat score was significantly reduced. The number of patients in groups B and C who exercised >3 times per week and the number of resistance exercises were significantly increased, while the number of aerobic exercises per week in group C was significantly increased. The body fat and waist circumference were significantly reduced, and skeletal muscle weight was significantly increased. Body mass index, trunk fat ratio and waist-to-hip ratio were significantly decreased in groups B and C, while trunk muscle was significantly increased in group C.The combined intervention of the three methods can give full play to the synergistic effect of various interventions. The improvement effect of increasing the appropriate amount of resistance exercise is more obvious, which is worthy of further promotion and application. The perimenopausal period refers to the first signs of ovarian function decline until one year after the last menstruation in women. It refers to the transitional period from maturity to old age in women. The clinical manifestations of menstrual disorders are menopause, memory loss, irritability, tidal sweating, insomnia, joint pain and so on . EstrogeInclusion criteria: ① females with clear perimenopausal diagnoses; ② no systematic nutrition education; able to walk without assistance; ③ able to communicate normally. Exclusion criteria: ① having taken drugs for weight loss treatment within three months; ② having suffered from myocardial infarction, unstable cardiovascular disease or other diseases in the past three months; ③ chronic renal insufficiency or renal failure; ④ patients with diabetes on insulin treatment; ⑤ patients with upper or lower limb fractures or other exercise contraindications in the past three months; ⑥ neuromuscular diseases or taking drugs that affect neuromuscular function; ⑦ taking drugs that include hormone replacement medication or other drugs that could affect body composition.Seventy-eight perimenopausal women seen at the gynecology outpatient department of Beijing Pinggu Hospital from June 2018 to August 2018 were recruited as the research subjects, with an average age of 48.65 ± 3.06 years old. They were randomly divided into three groups, with 32 cases in each group. After the implementation of the study, some participants were unwilling to participate in the follow-up observation after attending intensive education. Group A was the collective education group with 18 cases and 14 dropped off. Group B was the individualized diet group with 28 cases, two suffered sudden illness and two had temporary withdrawal. Group C was the individualized diet + resistance exercise group with 32 cases. Seventy-eight patients completed all observation items, and the shedding rate was 18.75%. The Ethics Committee of our hospital reviewed this study, and all participants signed informed consent.Group A received routine gynecological diagnoses and treatments and participated in lectures by nutritionists, pharmacists and nurses. They learned about the characteristics of menopausal nutrition and metabolism, the meaning and principles of diet intervention, exercise methods and precautions, drug selection and administration methods. In addition to collective education, Group B followed individualized dietary guidance according to the DASH diet principles, recorded a diet diary three days a week and uploaded it to WeChat in time. Any unreasonable diet structure was corrected and demonstration meals were provided once a month. Group C received collective education and individualized dietary interventions. At the same time, professional sports coaches conducted on-site training and guidance. After three months of intervention, the changes in various observation indicators were reviewed.This study was improved based on the DASH diet score method of Shao et al.  and estaAerobic and resistance exercise can improve cardiovascular function and heart rate variability in perimenopausal women . Every MIt includes name, age, occupation, education, education level, waist circumference, height, production status, menopause status, exercise status, past medical history, including hypertension, diabetes and hyperlipidaemia, liver and kidney disease, etc., and medication status.For height (m), a height range finder was used , shoes were removed, and after strict calibration, the result was accurate to 0.1 cm.Waist circumference (cm) was measured at the midpoint between the ribs and the iliac ridge using a soft ruler made of non-stretchable material, and the scale was read to 0.1 cm.Body composition measurements used the InBody 770 Body Composition Analyser  to conduct body composition detection using the bioelectrical impedance method. Operation method: ① on an empty stomach or fasting four hours before the test, strenuous activities were stopped, excrement and urine were emptied, wearing fewer clothes and not carrying heavy items or accessories; ② research subjects stood barefoot on the detector, with both heels and forefoot on the foot electrodes, holding the hand electrodes with both hands, the thumb and the other four fingers were in close contact with the electrodes. The name, age, gender and height were entered, measurement was started after coding, the measurement time was two to three minutes, and body mass index, body fat mass, trunk fat ratio, waist-to-hip ratio (WHR), skeletal muscle and trunk muscle mass were recorded.2]). In accordance with the WS/T428-2013 Chinese adult weight judgment standard, average weight is 18.5– 23.99 kg/m2, overweight is 24–27.99 kg/m2 and obesity is ≥28 kg/m2. According to the “Guidelines for the Prevention and Control of Overweight and Obesity in Chinese Adults” published by the Department of Disease Control of Health and Family Planning Commission in 2003, BMI <18.5 kg/m2 is considered to be too thin, and 18.5 kg/m2 ≤ BMI ≤23.9 kg/m2 is considered average, 24.0 ≤ BMI ≤27.9 kg/m2 is overweight, BMI ≥28.0 kg/m2 is obesity and female waist circumference ≥80 cm is central obesity  (weight [Kg] / height [mx±SD). An ANOVA test was used to compare measurement data between groups. A paired t-test was used to compare measurement data before and after the intervention. A chi-square test was used to compare count data (and classification data). P < 0.05 indicated that the difference was statistically significant.SPSS 17.0 statistical analysis software was used for data processing. All measurement data were expressed as mean ± standard deviation . Before and after the intervention, there were no statistical differences in the intake scores of the three groups of fruits and processed meat (P > 0.05). Compared with before the intervention, after the intervention, vegetables in group C, processed meat and sweet drinks in groups B and C, the score of red meat intake in group A were increased, the score of red meat intake in group C was significantly decreased, the score of fat and animal viscera intake in groups A and B were significantly increased, and the difference was statistically significant (P < 0.05). Compared with group A, the total DASH diet and vegetable intake scores of groups B and C increased significantly, and the low-fat milk intake score of group B increased significantly. The intake scores of nuts, whole grains and desserts in group C were significantly improved, the intake scores of red meat in group C were significantly reduced, the frequency of red meat eating increased, and the difference was statistically significant (P < 0.05). After the intervention, the total diet score of group C was higher than A and B, and the difference was statistically significant (P < 0.05)  .P > 0.05). After the intervention, the number of regular exercises >3 times a week in groups B and C increased significantly, and the difference was statistically significant (P < 0.05)  .P < 0.05). Comparing the three intervention methods, the weekly aerobic exercises and resistance exercises in group C increased significantly, higher than those in groups A and B, and the difference was statistically significant (P < 0.05)  .P < 0.05). There was no statistical difference in waist circumference, BMI, WHR, body fat mass, trunk fat ratio and muscle mass index between the three intervention methods (P > 0.05)  .P < 0.05). It shows that different intervention methods can improve the dietary behavior of the population. The dietary behavior of group C improved more obviously, which may be related to the closer communication and contact with the nutritionist in the intensive resistance exercise group twice a week, which played a role in reminding and urging. This study also showed that the frequency of eating red meat in group C was significantly higher than in group A, and the difference was statistically significant (P < 0.05). It may be related to the emphasis on high-quality protein intake in the nutrition guidance, and local residents prefer to choose lean pork as a source of high-quality protein. It is necessary to strengthen targeted health education, correct past eating habits, appropriately reduce the frequency of eating red meat and increase the intake of white meat such as chicken, duck, fish and shrimp.Dietary Approaches to Stop Hypertension (DASH), also known as the “DASH diet” model, was proposed in the United States in 1997 as a dietary approach to prevent and control hypertension. It emphasizes the effect of the comprehensive diet model on blood pressure , 11. ForP < 0.05), indicating that health education + individualized diet guidance + intensive resistance exercise intervention can better improve diet and exercise habits, which is consistent with the results of Yi et al. and Liu and Yuan . This indicates that health education + diet guidance + intensive resistance exercise intervention can optimize the body composition of perimenopausal women.Clinical trial studies have confirmed that adipose tissue is the body's largest endocrine organ. It can release dozens of adipocytokines, such as leptin, resistin, adiponectin and tumor necrosis factors. They participate in the occurrence and development of obesity-related diseases by destroying islet 13 cells, inducing hyperinsulinemia and affecting fat metabolism . High enThere are shortcomings in this paper. This study used different food intake frequency rules to score the DASH diet. Except for the salt score, it does not score specific food intake and does not record and analyse energy and nutrient intake, which is required to further improve the scoring standards and perfect the design plan. This study records exercise frequency, method and time through WeChat check-ins without introducing information management systems and special equipment to evaluate the compliance and effectiveness of exercise intervention, which may affect the accuracy of the evaluation. The observation period is relatively short, and the number of research cases is small. It is necessary to further increase the sample size, extend the observation time and reduce the research bias.In summary, although pure health education or health education + dietary intervention can effectively improve diet and exercise habits, reduce waist circumference, body fat, trunk fat and increase skeletal muscle content, the comprehensive intervention of the three methods can give full play to the synergy of each intervention. Health education + diet guidance + intensive resistance exercise interventions can optimize the body composition of perimenopausal women, which is worthy of further promotion and application.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Beijing Pinggu Hospital . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SH and ST: designed the study. JingL, WL, and JingyL: analyzed and interpreted the data. XC and ZH: collected and sorted out of data. All authors wrote the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by Scientific Research Project of Beijing Pinggu District Health Commission, project number: pgwjw2018-09.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Vaccination has been recognized as a vital step for containing the COVID-19 outbreak. To ensure the success of immunization efforts as a public health containment measure, a high level of public vaccination compliance is essential. Targeted educational programs can be utilized to improve attitudes toward vaccination and improve the public's uptake of protective measures.Methods: In this cross-sectional study, we aimed to evaluate the impact of a concise educational program on perceived knowledge regarding the COVID-19 vaccine, vaccine importance and trust, protection and fear from COVID-19, trust in authorities, as well as individual resilience.Results: The study evaluated 503 participants that completed the questionnaire before and after viewing a concise video tutorial on vaccination. Following the educational program, scores of five variables increased significantly compared to their pre-viewing level: knowledge, personal resilience, trust in authorities, vaccine importance, as well as perceived protection. Those that were vaccinated and/or intend to be vaccinated (N = 394) report higher levels of knowledge, trust in authorities, vaccine importance, vaccine trust, and fear of being infected as compared to those that are unwilling to get vaccinated. Positive significant correlations were found between resilience and trust in authorities , vaccine importance , and feeling protected . Trust in authorities was positively correlated with vaccine importance  and vaccine trust . Vaccine importance was positively correlated with vaccine trust , but not correlated with knowledge score.Conclusion: The findings of the study demonstrate the benefits of educational programs on improving attitudes toward vaccination acceptability. Incorporation of such concise educational programs by authorities may improve uptake of COVID-19 vaccination and help overcome public vaccine hesitancy. We recommend that such a concise and easily implementable educational program be incorporated as a response component to the current and future outbreaks. From its onset in December 2019, the COVID-19 outbreak has resulted in widespread disturbances in health, economic, societal, and political systems worldwide, and has posed unprecedented challenges including massive morbidity and mortality rates . Given tad-hoc for pandemic containment purposes, Influenza is not considered a novel disease by the public. Nevertheless, convincing the public to accept the vaccine proved difficult and many vials purchased were discarded without being used during the H1N1 pandemic.As reported during the 2009 H1N1 pandemic, the acceptance of a novel vaccine showed unsatisfying results, as public willingness of inoculation ranged from 17 to 67% across Europe, America and Australia . Of noteVaccine skepticism or vaccine hesitancy continues to be a major hurdle for overall population inoculation during the COVID-19 outbreak , 13. WitSeveral studies during the H1N1 pandemic among healthcare workers established that social influences were also at play in the acquiescence or apprehension toward vaccination. If it was perceived that others  want you to be vaccinated or have already been vaccinated themselves, this was positively associated with the intention to be vaccinated , 16. It Thus, it is essential to identify measures that can positively impact on vaccine uptake, so as to enhance the capacity to contain pandemics. In this study, we evaluate the effect of a concise educational program on perceived knowledge regarding the COVID-19 vaccine, perceived vaccine importance and trust, perceived protection and fear from COVID-19, perceived trust in authorities, and lastly, individual resilience. We focus our analysis specifically on the state of Israel. Short educational programs have already been successfully shown to provide an easily implementable and effective way to educate and empower the public concerning understanding of emerging risks . The preAn interventional study was conducted in January 2021, in the midst of the COVID-19 outbreak, at the initial phase of vaccinating the population against the virus. The study was based on subjecting a representative sample of the Israeli population to a short informative video tutorial that focused on assorted elements regarding the COVID-19 vaccination.The research assessed attitudes toward the vaccine before and immediately after watching a concise (6 min) video-film, by responding to the same questionnaire at both times.http://www.ipanel.co.il). Since 2006, this company provides an operational platform for a wide variety of information collection services that maintains the strict standards of the European Society for Opinion and Marketing Research (ESOMAR). In line with the official data issued by the Israeli Central Bureau of Statistics, and to ensure an appropriate representation of the Israeli's population concerning age, gender, religiosity, place of residence and additional demographics, the sample population was defined, utilizing stratified sampling technique. The use of internet panels has greatly expanded in the past decade, after their validity has been shown broadly , the short educational program was based on a short 6 min video tutorial that was prepared following the development of the COVID-19 vaccine. The target population was defined as Israeli adults, as they were authorized to receive the vaccine. The tutorial aimed to influence and boost their knowledge and understanding of the COVID-19 vaccine. The video was specifically directed to relay vital information to the public concerning the characteristics of the COVID-19 vaccine, its development, its potential side-effects, conspiracy correction about the vaccine, and respective health guidelines and recommendations. The making of the educational tool was done by an expert team, proficient in the development of training programs. The information in the short tutorial was presented by a male paramedic while dressed in the official uniform of the National Israeli Emergency Medical Services . MDA is considered a highly prestigious foundation, that is highly trusted by most sectors of the Israeli public . RoutineThe framework of the conducted research included a literature review → the design of the short educational video tutorial → distribution of the assessment tool, that was filled for the first time by the sample of the internet panel → watching the short video tutorial → and lastly, the second filling of the assessment tool.Such a framework was formerly used by the researchers of the present study in another study that examined the impact of a brief educational intervention on the knowledge, perceived knowledge, safety and resilience of the Israeli public during COVID-19 crisis . The twohttps://www.openepi.com/SampleSize), requiring 385 participants. A representative sample of 503 respondents participated in all three phases of the study (before and after watching the film), after submitting their informed consent. The study was approved by the Ethics Committee of the Tel Aviv University . All the responses were accumulated anonymously, without any identifiable information collected.The sample size was computed based on OpenEpi ]. Content validity of the questionnaire was achieved through its examination by six content experts and its pilot testing with participation of 20 individuals, prior to the dissemination stage. The components of the questionnaire consisted of the following: (1) perceived knowledge assessed by three items encompassing characteristics of COVID-19, signs and symptoms after vaccination, proficiency of guidelines, and confidence in one's knowledge. The items were rated by a 5-point Likert scale, scaling from 1 = completely disagree to 5 = completely agree. Cronbach's Alpha for the perceived knowledge index was α = 0.654 and α = 0.692 for pre-post educational program, respectively; (2) perceived personal resilience portraying individual feelings of ability and strength in adaptation and recovery from illness, measured by two items ranked by a 5 point Likert scale, ranging from 1 = completely disagree, to 5 = completely agree ; (3) pert-test. The relationships between knowledge score, resilience, trust in authorities, and personal resilience for COVID-19 vaccination at T1 were analyzed based on Pearson correlation tests The differences in attitudes between the vaccination statuses (vaccinated or not vaccinated) at T1 were analyzed using the independent sample t-test. Statistical analyses were conducted using SPSS software version 25. P-values lower than 0.05 were considered to be statistically significant.The participants' demographic characteristics were presented by descriptive statistics . Respondents that were vaccinated or intend to be vaccinated were calculated as one group (hereto referred as vaccinated) vs. those who have no intention to be vaccinated. The differences, percentage of change (T2 – T1)/T1 × 100% and the effect sizes of the differences between T1  and T2  were examined by the Paired samples The study evaluated 503 participants (presented in p < 0.001), personal resilience (p < 0.001), trust in authorities (p = 0.002), vaccine importance (p = 0.002), as well as perceived protection (p < 0.001). The most substantial change was in perceived protection, presenting an effect size of 0.15, and an increase of 6.2% (from 2.75 to 2.92). Knowledge and resilience also increased by 2.4 and 2.5% respectfully, with both an effect size of 0.11.As presented in N = 394) report higher levels of knowledge, trust in authorities, vaccine importance, vaccine trust, and fear of being infected as compared to those that are unwilling to get vaccinated. The most substantial attitude difference between those that were or are scheduled to be vaccinated and those that are not, is concerning the vaccine importance with an effect size of 1.41. Knowledge and trust in authorities also indicated substantial disparities in attitudes between the groups, with effect sizes of 1.07 and 1.04 respectfully.Differences in attitudes between the varied vaccination statuses at T1 are presented in r = 0.241, p < 0.001), trust in authorities , vaccine importance , vaccine trust  and feeling protected . Positive significant correlations were found between resilience and trust in authorities , vaccine importance , and feeling protected . Trust in authorities was positively correlated with vaccine importance  and vaccine trust . Lastly, vaccine importance was positively correlated with vaccine trust , but not correlated with knowledge score. The correlations are presented in Before the educational program, a significant positive correlation was found between perceived knowledge and personal resilience , trust in authorities  and vaccine importance . Regarding gender, males compared to females reported a higher level of knowledge (3.85 vs. 3.61 p = 0.001), resilience (3.73 vs. 3.44 p < 0.001), vaccine importance (3.88 vs. 3.50 p < 0.001) and feeling protected (2.95 vs. 2.55 p < 0.001). Accordingly, they reported lower levels of feeling concerned (3.38 vs. 3.75 p < 0.001). Participants with higher levels of income reported higher levels of resilience compared to those with medium and lower levels . The same trend was seen for vaccine importance (4.04 vs. 3.65 and 3.60 p = 0.001). Significant differences were observed among lower and higher levels of income, both for level of resilience and for vaccine importance.The results indicate a positive significant correlation between age and knowledge  examined variables immediately following the educational program, to varying degrees of effect sizes. The findings of this study are in line with previous research involving educational programs in which short videos have been shown to be an effective method for improving knowledge, attitudes, and health behavior , 25–27. The study also identified that there are substantial differences in perceived levels of knowledge, trust in the authorities, vaccine importance and trust, and fear of being infected amongst those who are vaccinated (or intend to be vaccinated) and those that do not intend to get vaccinated. These differences are in line with previous findings which determined that higher levels of knowledge , 29, truThe study identified several positive associations between examined variables which coincide with the findings above. Particularly important are the findings which present the significant relationships between trust in authorities, perceived knowledge about the vaccine and personal resilience with deemed vaccine importance. The positive associations that were found in the study are of utmost importance, as they provide targetable factors which may impact on the uptake of protective behavior. In order to shape compliance to preventive behavior such as vaccination, authorities ought to consider making use of health communication strategies within the context of short interventional tools (such as the one utilized in this study) which aim to improve knowledge of the public regarding the vaccine, personal resilience, trust as well as convey that the war against COVID-19 is not yet over which may affect the perceived fear of the public toward infection. The outcomes of this research exhibit a cost-effective and quickly implementable research intervention design, which allows for the proactive and speedy dissemination of directed and tailorable material to meet particular objectives during emergencies and crisis.Additional results of this study expose several demographic factors that are associated with the evaluated variables. For example, males and those with higher levels of income reported higher levels of vaccine importance. These findings support conclusions from previous investigations regarding gender and socio-economic differences in the determinants of willingness to get the COVID-19 vaccine –38. WhilGiven that vaccine hesitancy in the context of the COVID-19 pandemic remains a hurdle , 13, theLimitations of this work are that it assesses attitudes toward vaccination cross-sectionally when the vaccination rollout campaigns began, even though it is possible that sentiments may adjust as more individuals are inoculated and additional studies are conducted which evaluate the efficacy and safety of such vaccines. In the future, this can be attended to by conducting the study longitudinally. Nonetheless, as understanding the sentiment of the population toward vaccination is vital during the initial stages of the vaccine campaign, there is great value in understanding the public's attitudes. Another limitation is that this study was conducted via the internet in order to ensure quick response collection. While this response methodology allowed for a quick collection of data and ensured a representative sample of the Israeli adult population, the conclusions must be limited to individuals who have high computing skills and access to an internet source. A further limitation is that the assessment of change was conducted directly after the respondents watched the video tutorial; it is vital that the continued effect over time is assessed in future studies. As is the case in all research based on questionnaires, social desirability bias cannot be fully dismissed, including concerning declaration of levels of trust. Nonetheless, as the study was conducted through an internet panel, iPanel that is entirely independent and unconnected to any response entity, the discussed above potential bias is most probably better controlled. Lastly, as this study was conducted in the Hebrew language, members of the Israeli society who are not fluent in the language were excluded from participating. Nevertheless, our findings have valuable implications as we show that an inexpensive and convenient short training programs can be an effective means for improving attitudes toward vaccination and utilized to overcome the vaccine hesitancy hurdles in the COVID-19 context and future such outbreaks. Conducted future research should assess the long-term impacts of such educational programs (such as the one conducted) on actual uptake of protective behavioral practices among study participants.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee, Tel Aviv University. The patients/participants provided their written informed consent to participate in this study.EJ: conceptualization, investigation, and resources. EJ and BA: methodology. BA and MS-T: validation. MS-T: formal analysis. AK and MS-T: data curation. AK: writing—original draft preparation. EJ, MS-T, and BA: writing—review and editing. BA: supervision. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Anisakidosis, caused by anisakid larvae, is an important fish-borne zoonosis. This study aimed to summarize the prevalence of anisakid infection in fish in China. A systematic review and meta-analysis were performed using five bibliographic databases . A total of 40 articles related to anisakid infection in fish in China were finally included. Anisakid nematodes were prevalent in a wide range of fish species, and the overall pooled prevalence of anisakid nematodes in fish in China was 45.5%. Fresh fish had the highest prevalence rate (58.1%). The highest prevalence rate was observed in Eastern China (55.3%), and fish from East China Sea showed the highest prevalence of anisakid nematodes (76.8%). Subgroup analysis by sampling year suggested that the infection rate was higher during the years 2001–2011 (51.0%) than the other periods. Analysis of study quality revealed that the middle-quality studies reported the highest prevalence (59.9%). Compared with other seasons, winter had the highest prevalence (81.8%). The detection rate of anisakid nematodes in muscle was lower  than in other fish organs. Our findings suggested that anisakid infection was still common among fish in China. We recommend avoiding eating raw or undercooked fish. Region, site of infection, fish status and quality level were the main risk factors, and a continuous monitoring of anisakid infection in fish in China is needed. Anisakis, Contracaecum, and Pseudoterranova  are paratenic hosts , 11, 12.Fish are one of the most important food sources in China, and a number of individual studies have reported the prevalence of anisakid nematodes in fish in China. Meanwhile, the first human case of anisakiasis in China has been reported . Herein,This study was performed following the PRISMA guideline  18). Fi. Fi18). After removing duplicates, the relevant articles were selected through an initial screen of identified abstracts and/or titles and a second screen of full-text articles. Qualified studies needed to meet all of the following criteria: (i) targeted objects must be fish (ii) selected fishing sites within China; (iii) cross-sectional study; (iv) the content of the studies must include the prevalence of anisakid nematodes; and (v) natural infection. Studies with the following characteristics were excluded: using the same data; incomplete data or article; fish from abroad; having internal data conflict; other nematodes; review article; river fish article . EligibiTwo reviewers (QW and JYM) independently extracted the following variables from each included study: Year of sampling, first author, publication year, study region, province, detection method, site of infection, collection season, sea, the total number of fishes, the number of positive samples, fish status, and fish category. The statistical geographic factor data  were acquired from the National Meteorological Information Center of China Meteorological Administration. The primary reviewer (QLG) confirmed all the extracted data. A “quality” assessment of each included study was made by using criteria derived from the GRADE  approach –21. The We performed meta-analysis using the package “meta” (version 4.11-0) in R software (version 3.5.2) . Prior tn, sample size; r, positive number; se, standard error.t, transformed prevalence; I-squared statistic. A P < 0.05 was considered to indicate statistically significant heterogeneity, and I2-values of ≥25, ≥50, and ≥75% correspond to low, moderate, and high heterogeneity, respectively , longitude (>120° vs. other longitudes), altitude , precipitation , humidity (<70% vs. other humidity categories), mean temperature (15–20°C vs. mean temperature of other groups), lowest average temperature (10–15°C vs. lowest average temperature in other groups) and highest average temperature (>25°C vs. highest average temperature in other groups). The R software code for meta-analysis is shown in In this study, a total of 358 relevant articles were found. Following initial screening and removal of duplicates, 92 articles were identified. Following full text review, 52 articles were further excluded. A further search was carried out based on the reference lists of relevant studies. However, no additional qualified articles were found. Finally, 40 full-text studies published between 2000 and 2020 were included in the quantitative analysis . Of whicI2 = 98.8%, P < 0.001) in the selected studies was observed  than other periods. Compared with other seasons, autumn had the lowest prevalence rate  .Analysis of study quality indicated that the middle-quality studies reported the highest prevalence rate . The detection rate of anisakid nematodes in muscle was lower  than in other fish organs. The meta-regression analysis showed that the heterogeneity can be explained by the province ranges from 0.00 to 31.93% after joint analysis with province .P < 0.05), which may account for the heterogeneity , the longitude range , and altitude . Compared with other groups, the prevalence of anisakid nematodes in fish in these geographic ranges was significantly higher (ogeneity .P < 0.05)  . We also < 0.05) –9 and fo < 0.05) –16 for a < 0.05) .Trichiurus haumela), chub mackerel (Pneumatophorus japonicus), yellow croaker (Pseudosciaena polyactis) and whitespotted conger (Conger myriaster) in East China Sea, and chub mackerel (P. japonicus) in Yellow Sea. Several previous studies showed that they were highly infected species (Hexagrammos otakii) and Korean rockfish (Sebastes schlegeli) from South Sea with high infection rate were not included in fish species sampled from South China Sea  and yellow croaker (Larimichthys polyactis) which were reported to be highly infected species of marine fish . Of which, speeding up the development of the aquaculture industry was included. Meanwhile, establishing and perfecting a system for monitoring the safety and quality of aquatic products was mentioned. Hence, 2001 was used to be a first cut-off point for subgroup analysis. The 12th Five-Year Plan on Fishery Development and the 13th Five-Year Plan on Fishery Development were released in June 2011 and December 2016, respectively, each gives a higher priority for epidemic prevention and control of aquatic animals as well as safety and quality of aquatic products than before. Thus, we chose 2011 as the cut-off point to analyze the prevalence of anisakid nematodes. It is worth noting that we found 19 studies published after 2011, but only 5 studies before 2001. Hence, we speculated that the pooled estimates after 2011 was more likely to reflect prevalence of anisakid nematodes in fish in China.Anisakis simplex, Anisakis pegreffii, and Pseudoterranova decipiens  in migration to the muscles of fish and to penetrate into the tissue of accidental hosts were found in several studies  is a commercially important marine fish, and its stomach, intestine and liver are considered to be a delicacy in China (Pseudorhombus cinnamoneus) is a frequently consumed marine fish in China , sablefish (Anoplopoma fimbria), and skipjack tuna (Katsuwonus pelamis) tested negative for anisakid nematodes. This may be due to the small sample size for each of these fish species, because infection of K. pelamis by Anisakis larvae has been reported  five databases were used to identify publications, which may exclude some qualified articles from other databases; (ii) parts of the subgroups (such as sites of infection) have included fewer articles, which may lead to unstable results; (iii) this study was not registered in Cochrane, however, our meta-analysis was carried out strictly in accordance with the steps of PRISMA; and (iv) the range of environmental temperatures in the sea area where fish live is quite different from that of the land area, and analysis based on different regions of land areas may only serve as a reference. It is suggested that the researchers should clarify the sampling locations and fishing sites (such as the latitude and longitude of the specific sea area), which can contribute to the assessment of the environmental factor.This study has shown that anisakid infection in fish was widespread in China, and the pooled prevalence varied among different fish species and provinces. Region, site of infection, fish status and quality level were the main factors affecting the prevalence rate. There is a need for continuous monitoring of anisakid infection in fish in China. Meanwhile, it is necessary to educate people, especially those living in coastal regions, about the risk of infection with anisakid nematodes and to avoid consumption of raw or undercooked fish.The original contributions presented in the study are included in the article/Q-LG and JJ contributed to conception and design of this analysis. QL, QW, and J-YM collected the data and built the database. QW and Q-LG analyzed the results. QL prepared the manuscript. Q-LG and X-QZ revised the manuscript. All authors contributed to manuscript editing and approved the final manuscript.Project support was provided by the Fund for Shanxi 1331 Project (Grant No. 20211331-13), the Research Fund for Introduced High-level Leading Talents of Shanxi Province, the Special Research Fund of Shanxi Agricultural University for High-level Talents (Grant No. 2021XG001), and Yunnan Expert Workstation (Grant No. 202005AF150041).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Personality disorder (PD) and childhood traumatic experience (CTE) are well- recognized risk factors for the development of schizophrenia (SZ) and major depressive disorder (MDD). The relationship between CTE and PD is extremely close, and both conditions can affect subsequent psychiatric disorders. Little is known about the differences of these factors in patients with SZ and those with MDD.Materials and Methods: A total of 1,026 outpatients participated in the study, including 533 (51.9%) with SZ and 493 (48.1%) with MDD who were sequentially sampled. The PD traits were assessed using the Personality Diagnostic Questionnaire Fourth Edition Plus (PDQ-4+). The Child Trauma Questionnaire Short Form (CTQ-SF) was used to assess childhood adversities. The scores and associations of PDQ-4+ and CTQ-SF between patients with SZ and those with MDD were compared.Results: The MDD group exhibited more PD traits and more childhood emotional neglect than the SZ group. In patients with MDD, the correlation between PD traits and CTE was significantly higher than that in patients with SZ. Patients with SZ vs. those with MDD showed different PD traits and CTE. The schizotypal and antisocial PD traits, as well as sexual abuse and physical neglect CTE, were significantly related to SZ. In contrast, the borderline, narcissistic and avoidant PD traits, and emotional abuse/neglect CTE were significantly associated with MDD.Discussion: These findings indicated a robust relationship between CTE and PD traits. Moreover, patients with SZ or MDD, have different interactive patterns. Both CTE and PD traits have the potential to be premorbid risk factors that could be targeted for preventative interventions. Increasing evidence shows that serious psychiatric disorders, such as schizophrenia (SZ) and major depressive disorder (MDD), are characterized by multiple personality pathology (MPP) –3, to a Although SZ is conceptualized as a neurodevelopmental disorder, initial evidence suggests that the presence of PD traits predicts the development of SZ , 13. SevIn this study, we aimed to replicate and build on previous findings on the differences in PD traits and CTE between patients with SZ and those with MDD in a larger sample, and to determine the differences in PD traits and CTE between the two groups. We predict that patients with SZ will have more psychosis-related PD traits, such as paranoid, schizoid, schizotypal PD traits, than patients with MDD. We also hypothesize that patients with MDD will show more affective and anxiety-related PD traits, such as histrionic, narcissistic, borderline, avoidant, dependent, obsessive PD traits, than patients with SZ. We hypothesize that the relationship between PD traits and CTE will vary and may be increased in patients with MDD compared with those with SZ.n = 533 with SZ and n = 493 with MDD). The age and sex distribution between the two groups differed significantly (see Results for further details).The study participants were drawn from a consecutive clinical sample of adult patients, aged 18–60 years, who presented at the Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine. The hospital's Ethical Committee approved the study, and it was performed according to the Declaration of Helsinki. Informed written consent was provided by patients prior to inclusion in the study. Only patients with SZ or MDD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), who completed the screening questionnaires, were included in the current analyses. The inclusion criteria were as follows. (1) Age 18–60 years. (2) Completed at least 6 years of education and able to understand the study. (3) Met the DSM-IV criteria for SZ or MDD based on the Structured Clinical Interview for DSM Disorders/Patient edition (SCID-I/P). (4) In a stable treatment condition, that defined as the dose or type of the medication with which the patient has reached psychopathological stability must be constant for at least 2 months prior to inclusion in the study. None of the patients had a history of stroke, brain trauma, central nervous system infection, or seizure. The final sample comprised 1,026 participants  , a self-A quantitative index of childhood maltreatment severity was assessed using the Chinese version of the Child Trauma Questionnaire Short Form (CTQ-SF) –21. The t-test or kappa test. Effect sizes were calculated using Cohen's d for mean comparisons. Because some variables do not satisfy the normal distribution, Spearman's correlation analysis was used for PD traits and CTE in the two groups. Lastly, stepwise regression was performed using SZ/MDD as dependent variables, and age, sex, family history, and subscales of PDQ-4+and CTQ-SF as independent variables. Statistical significance was indicated by p < 0.05.Statistical analyses were performed on IBM SPSS version 21.0 . One sample Kolmogorov-Smirnov Test was used to examine the data's normal distribution. Demographic characteristics, PD traits, and CTE data for SZ and MD groups were analyzed using frequency and descriptive analyses. Group differences were analyzed using the independent 2 = 0.347, p = 0.556), but significantly differed in age  and sex distribution . The MDD group endorsed more SCH, HIS, NAR, BOR, AVO, DEP, and OBS traits and more childhood emotional neglect than the SZ group (p < 0.05).A total of 1,026 outpatients participated in the study, including 533 (51.9%) with SZ and 493 (48.1%) with MDD. Detailed sociodemographic and clinical characteristics between the SZ and MDD groups are reported in Associations between all variables of interest (PDQ-4+ and CTQ-SF) were tested. Non-parametric Spearman correlation analysis yielded significant correlations between different types of PD traits  and diffIn patients with SZ, the PAR and SCHT PD traits were significantly associated with the EA type of CTE. In patients with MDD, the correlation between PD and CTE was more significant than that in patients with SZ .p < 0.001) and ANT (p < 0.001) were significantly related to SZ. In contrast, the BOR (p < 0.001), NAR (p = 0.006), AVO (p = 0.009) PD traits were significantly associated with MDD in this model. The CTE variables of SA (p = 0.004) and PN (p = 0.005) were significantly related to SZ, while EA (p = 0.017) and EN (p= 0.028) were significantly related MDD.As shown in The primary aim of the present study was to examine the difference and relationship between PD traits and CTE within two major psychiatric diagnostic groups, namely, SZ and MDD. We noted three key findings. First, patients with MDD reported more PD traits (7 in 10 PD domains) than those with SZ. Second, the correlation between PD traits and CTE was more obvious in the MDD group than in the SZ group. Third, SZ and MDD are associated with different PD traits and CTE. These findings indicated that a robust relationship exists between CTE and PD traits in patients with SZ and those with MDD, with different interactive patterns. To the best of our knowledge, this is the first study conducted in a large Chinese clinical sample to establish and compare the associations between CTE and PDs between SZ and MDD.In this study, patients with MDD reported increased PD traits compared to patients with SZ, even in Cluster A PD traits  that are marked by odd and eccentric behaviors. These results are in line with those of Zhang et al. , who fouEN reported by the participants were more frequent in the patients with MDD than those with SZ, as confirmed through a recent meta-analysis . SurprisInterestingly, significant associations were mainly between childhood abuse and cluster A PD traits in the SZ group. Moreover, all types of CTE and Cluster B  and Cluster A PD traits were significantly related in the MDD group. Previous evidence , 31 has Several limitations should be considered when interpreting our findings. The patients with SZ were significantly younger than those with MDD (by an average of ~1–2 years). Thus, there may be potential selection bias and memory information bias, as younger patients would be more likely to recall and report CTE than the elderly. Second, PD traits and CTE were assessed using a self-report, retrospective measure. Self-report measures assume reliable reporting, which may be a concern in our patient populations, especially in patients with SZ, who are more likely to have cognitive impairment –34. FurtOur results show that most PD traits and childhood emotional adversities were more prominent in patients with MDD. In contrast, childhood sexual and physical adversities are more prominent in patients with SZ. The history of CTE is significantly related to specific PD traits of the disease spectrum, such as SCH and SCHT PD traits in the psychotic spectrum, and BOR and NAR PD traits in the affective spectrum. Therefore, both CTE and PD traits have the potential to be premorbid risk factors that could be targeted for preventative interventions, including cognitive behavioral therapy .The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethical Committee of Shanghai Pudong New Area Mental Health Center. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.NZ collected the data and performed the statistical analyses. DS wrote the original manuscript. JH and QC designed and wrote the study protocol. QW offered many important suggestions on this study. All authors contributed to the article and approved the submitted version.This study was supported from Excellent Young Medical Talents Training of Health Commission of Pudong New Area (PWRq2020-49); Pudong New Area of Science and Technology Development Fund (PKJ2019-Y25); Shanghai Municipal Health Industry Clinical Research Project (2020Y194).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Head and neck cancers metastasize into the neck lymph nodes. The surgical removal of neck lymph nodes  is commonly performed before or after radiation therapy. The most common types of neck dissection include selective  and radical modified . Given the variability in surgical techniques, quality and prognostic markers for neck dissection are missing. Lymph node ratio  has been previously suggested as a quality and prognostic marker. Here, we assess the impact of prior irradiation on the lymph node yield (LNY) as well as the role of LNR in both selective and modified radical neck dissection. We found that previous irradiation to the neck leads to a reduced LNY; there is no change in LNR. LNR has a prognostic impact in modified radical neck dissection but not in selective neck dissection.Background: Lymph node metastases are associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Neck dissection (ND) is often performed prior to or after (chemo)radiation (CRT) and is an integral part of HNSCC treatment strategies. The impact of CRT delivered prior to ND on lymph node yield (LNY) and lymph node ratio (LNR) has not been comprehensively investigated. Material and methods: A retrospective cohort study was conducted from January 2014 to 30 June 2019 at the University Hospital of Bern, Switzerland. We included 252 patients with primary HNSCC who underwent NDs either before or after CRT. LNY and LNR were compared in patients undergoing ND prior to or after CRT. A total of 137 and 115 patients underwent modified radical ND (levels I to V) and selective ND, respectively. The impact of several features on survival and disease control was assessed. Results: Of the included patients, 170 were male and 82 were females. There were 141 primaries from the oral cavity, 55 from the oropharynx, and 28 from the larynx. ND specimens showed a pN0 stage in 105 patients and pN+ in 147. LNY, but LNR was not significantly higher in patients undergoing upfront ND than in those after CRT . Cox hazard ratio regression showed that an LNR ≥ 6.5% correlated with poor overall  and disease-free survival  in MRND. Conclusion: ND after CRT leads to significantly reduced LNY. An LNR ≥6.5% is an independent risk factor for decreased overall, disease-free, and distant metastasis-free survival for MRND. Lymph node metastases (LNMs) are common at the time of diagnosis in head and neck squamous cell carcinomas (HNSCCs), while the rate of occult LNMs is up to 20% in some subtypes of HNSCC ,2,3,4,5.Management strategies for the neck encompass primary radiotherapy/chemoradiation (CRT), neck dissection (ND), or combinations of these treatment modalities. Neck dissection can be performed upfront prior to CRT of the primary tumor +/− the neck or following failed primary CRT as surgical salvage treatment. The extent of ND is variable and depends on factors such as clinical involvement of neck LNs, site of the primary tumor, and prior therapy, among others . From a Given that surgical technique can vary from center to center, standard quality markers for ND that correlate with outcome have not been comprehensively explored in the setting of upfront and salvage ND. A number of recent studies analyzed the relevance of parameters such as total number of LNs removed or lymph node yield (LNY), and as well as lymph node ratio (LNR), which is defined as the ratio between metastatic and total LNs in a ND specimen. Moreover, the effect of CRT on LNY has not been assessed in large cohorts of patients with HNSCC undergoing ND. While the importance of LNY and LNR is established in human malignancies such as colorectal and breast cancer, no general consensus on a specific yield or ratio has been definitively established in head and neck squamous cell carcinoma (HNSCC) ,20,21,22The primary purpose of this study is to assess the influence of CRT on LNY/LNR as well as the impact of LNR in terms of survival and disease control in patients undergoing SND and MRND.Approval was obtained from our ethics committee . All patients included in this study were treated at Bern University Hospital , Bern, Switzerland. Patients’ data were stored anonymously in a database only accessible to the principal investigators of this study.The study cohort consisted of patients diagnosed with HNSCC who underwent ND with curative intent between 1 January 2014 and 30 June 2019 at the University Hospital and Cancer Institute of Bern, Switzerland. Patients’ details have been standardized in a specific database since 1 January 2014. All management approaches were discussed at a multidisciplinary tumor board. Inclusion criteria were (1) histologically-proven SCC of the oral cavity, oropharynx, larynx, or hypopharynx, as well as LNMs of a SCC of unknown primary (CUP); (2) management of neck with ND . Patients were excluded in the following cases: (1) histopathology other than SCC; (2) head and neck cancer affecting other sites than mentioned above; (3) ND and histopathological evaluation performed at external institutions; (4) previous ipsilateral ND; and (5) insufficient data.Patient demographics  and clinical data  were collected in a study-specific database. The process of data extraction was double-checked by two of the authors (S.C.S and L.N).Neck dissection specimens were either sent en bloc or divided into nodal levels by the surgeon. In case of en bloc resections, non-specified levels are classified as “non-defined”. The standard histopathological diagnosis at our institution has been previously reported .p-value approach. For all survival analyses, the date of ND was considered the beginning point. We used the unpaired t-test to compare clinical features, LNY and LNR prior to and after CRT. Survival curves were plotted using the Kaplan–Meier method and differences in survival were plotted using the log-rank test and Cox proportional hazard to obtain univariate and multivariate hazard ratios (HRs), respectively. For multivariate analyses and to avoid missing potentially relevant variables, we considered variables present in at least 10% of the patients and that had a p-value < 0.1 in the log-rank test analysis. Variables fulfilling these criteria were entered in the Cox’s proportional-hazards model. LNRs was included regardless of significance in both the SND and the MRND groups. Only variables with a p-value < 0.05 in the final model were considered to be significant independent risk factors. All tests were two-sided, and a p-value < 0.05 was deemed to denote significance.Statistical analysis was performed using the SPSS statistics software Version 25  and with GraphPad Prism 9 . Lymph node yield refers to the actual number of LNs removed. Lymph node ratio was defined as the number of LNMs divided by the total of LNs excised, regardless of the extent of the ND. The value was reported as a percentage. First, we considered all included NDs, and analyzed LNY and LNR per type of ND, per side, and per level. Modified radical neck dissections was defined as NDs of levels I to V with or without removal of other muscular, nervous, or vascular structures . Then, subgroup comparisons were performed between SND I and III (the most commonly performed) and MRND. For bilateral ND consisting of an SND on one side and an MRND on the other side, only the MRND side was evaluated. In cases of bilateral NDs with metastases in only one side of the neck, only the pathologically involved side was used for the analysis. In case of bilateral involvement or bilateral absence of metastases, the median value for both sides was used. The cutoff value of LNR was based on the minimum The study cohort consisted of 252 patients fulfilling the inclusion criteria, who underwent 169 unilateral ND and 83 bilateral ND for a total of 335 sides operated . Most paOne hundred and eighty-one were SNDs of different types and 154 were MRND. The vast majority of NDs took place prior to CRT (89.29% upfront vs. 10.71%). In the upfront neck dissection group, 56.89% were patients were cN+ vs. 51.85% in the post-irradiation group. The rate of occult metastases (cN0/pN+) was 25% in the pre-irradiation group and 23% in the post-irradiation group, while the concordance between cN+ and pN+ cases was higher in the pre-irradiation than in the post-irradiation group  .p < 0.0001), with a higher level of significance in MRND. The differences between upfront and salvage ND were significant for all nodal levels, except for level V, which is the level with the lowest LNY.We determined LNY and LNR in patients undergoing ND before and after CRT . LNY andp = 0.5788), but comparison of LNR in SND vs. MRND yielded a highly significant difference .In contrast to the LNY, we could not find a statistically significant difference in terms of LNR in upfront vs. salvage ND  and of 43 months (range 2–149 months) for surviving patients. Overall survival was 81.02%  at 2 years and 61.89%  at 5 years. Disease-free survival (DFS) was 78.82%  at 2 years and 72.60%  at 5 years. Regional recurrence free-survival at 2 years in 89.03%  and at 5 years in 84.94% . Distant-metastasis free-survival was obtained for an estimated 88.46%  at 2 years and for 87.26%  at 5 years.n = 73) and MRND (n = 137) because of their different indications. To ensure homogeneity in the SND group, we included only SND of level I to III. Their clinical and pathological features are shown in p-value.For the analysis of comparative survival outcomes, we separately evaluated SND  previous CRT is associated with a significant decrease of LNY in ND specimens and in all nodal levels except level V, (2) previous CRT does not affect LNR, and (3) a lymph node ratio ≥6.5% is an independent predictor of decreased OS, DFS and DMFS in patients undergoing MRND but not in those with SND I-III.The 300 lymph nodes contained within the fatty and connective tissue of the neck represent the first metastatic target of head and neck malignancies. As such, management of the neck is an integral part of HNSCC management ,23. In iCRT is both an alternative approach to ND and a complementary strategy. CRT leads to tissular changes including fibrosis and atrophy of soft tissues, including the lymph nodes. RT has been shown to destroy the LN parenchyma, changing its size and number . LNY hasOur study shows a significant decrease in nodal yield in ND after CRT, from a median nodal yield of 38 to 22 LNs, except in level V. In line with this, several studies have demonstrated a reduction in global LNY in patients with oral, oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal, and upper esophageal malignancies undergoing preoperative CRT ,31,32,33In their landmark study, Ebrahimi et al.  suggesteTherefore, we suggest that LNR is a more accurate surrogate for disease extent and may bear a better correlation with surgical outcomes, along with the standard TNM staging. LNRs varying between 1% and 20% have been reported to have a prognostic impact in HNSCC with a general consensus that higher LNRs are associated with a poorer outcome ,38,42. IDespite being a pertinent prognostic marker, LNR has also its limitations. Having LNY as the denominator, a higher yield will cause a decrease of LNR. For example, Marres et al.  showed aIn terms of prognosis, an SEER database analysis by Roberts et al. , higher We need to acknowledge a certain number of limitations in this study, primarily its retrospective design and the relatively small size of the subgroup of patients undergoing ND after CRT. Moreover, as discussed above, our study suffers the usual variability related to surgical technique and level of pathologist training. The fact that our study takes place in a single University Cancer Institute with standardized procedures reduces this variability. Given the limitations in using LNY mentioned, larger, multicentric, and prospective studies would be desirable.The major finding is that an LNR of 6.5% or superior is an independent predictor of survival for OS, DFS, and distant metastasis control for MRND but not for SND. In addition, chemoradiation decreases the nodal yield in all levels, except level V. Furthermore, LNR would be an easy feature to integrate in the UICC/AJCC cancer staging, helping in the prognostic stratification of patients.


Leukocyte telomere length (LTL) is an important biomarker of aging. The oxidative balance score (OBS) is used to assess the oxidative stress-related exposures of diet and lifestyle. This study is aimed at exploring if the OBS was associated with LTL.  3220 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. LTL was assayed from leukocyte DNA. Twenty dietary and lifestyle factors were selected to score the OBS. Survey-based multivariable linear regression was conducted to assess the association between the OBS and log-transformed LTL. p for trend < 0.01), and the multivariable-adjusted beta estimate (95% CI) of the continuous OBS was 0.0039 (0.0014–0.0065). There was also the gender difference in the correlations of the dietary OBS and the lifestyle OBS with log-transformed LTL.  The association between the OBS and log-transformed LTL was positive in females but not males. For females, compared with the lowest OBS category as a reference, the multivariable-adjusted beta estimate  for the highest OBS category was 0.0701 (0.0205–0.1197) ( There was a positive association between the OBS and LTL in females. This result suggested that diet and lifestyle might affect LTL by regulating oxidative balance. Telomeres are repetitive nucleoprotein regions located at the ends of eukaryotic chromosomes. Researches show that telomere plays an active role in cellular lifespan, genome stability, and chromosome integrity . Since tBeyond chronological age, oxidative stress (OS) is another critical factor that accounts for shorter leukocyte telomere length (LTL) , 9. TeloHowever, studies that evaluated the effects of individual antioxidant or prooxidant exposures on senescence have produced inconsistent results , 27–34. The oxidation balance score (OBS) is a comprehensive indicator that reflects the overall exposure balance of dietary and lifestyle prooxidants and antioxidants. Generally, a higher OBS indicates a predominance of antioxidants over prooxidants. There were many studies reporting the negative associations between OBS and aging-related diseases, including type 2 diabetes , osteoarHence, the purpose of the present study was to evaluate the association between the OBS and LTL in NHANES 1999-2002. Based on the available researches, we hypothesized that the OBS was positively associated with LTL.n = 4113), (2) they were ≥85 years old cause all individuals who were aged ≥85 were given the age of 85 by NHANES (n = 40), (3) they were pregnant (n = 223), (4) the dietary recall status was under the minimum criteria (n = 1), and (5) their energy intakes were implausible  (n = 230). Finally, a total of 3220 participants were included in the present study  is a nationally representative cross-sectional study conducted every two years by the National Center for Health Statistics (NCHS) to assess the health and nutrition status of adults and children in the United States. About 5000 random samples are selected each year using a multistage, stratified probability sampling design. Written informed consent was obtained from all participants in this survey, and details that might disclose the identity of the subjects under study were omitted. Although NHANES has been collecting national data for many decades, only two 2-year survey cycles include information on LTL, 1999–2000 and 2001–2002. Among 21004 participants in the NHANES 1999-2002, only 7827 participants had LTL measurements. And individuals were excluded if (1) they lost data for any of the OBS components or covariates (nt study .TL relative to standard reference DNA (T/S ratio) was measured using the quantitative polymerase chain reaction (PCR) method described in detail elsewhere , 45. DNA2). The weekly metabolic equivalent (MET) was calculated from the data of the individual-specific leisure-time activities over the past 30 days, and the data was from the household interview.Both diet and lifestyle contributed to the OBS. In the NHANES, dietary intake data was from 24-hour dietary recall interviews (24HR) which were conducted in the Mobile Examination Center. The types and amounts of foods and beverages consumed during the 24 hours before interviews were collected and recorded in the NHANES computer-assisted dietary interview system. Assessment of dietary intake of nutrients was based on the University of Texas Food Intake Analysis System and the U.S. Department of Agriculture Survey Nutrients Database. Additionally, the nutrient estimates did not include nutrients obtained from dietary supplements or medications. Lifestyle factors related to the OBS in this study were alcohol consumption, smoking, body mass index (BMI), and physical activity. The alcohol consumption information came from the 24HR. To evaluate both active and passive smoking, we used serum cotinine to reflect the smoking. It is a major metabolite of nicotine with a longer half-life than nicotine, could be used to measure the extent of tobacco use and to estimate the extent of exposure to environmental tobacco smoke, and was measured by isotope dilution-high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry . Trained examiners recorded the body measurements of all examinees in the MEC, and BMI was weight divided by height squared , C-reactive protein (CRP), and dietary energy intake. Among covariates, demographic records were taken from household interviews, data of dietary energy intake came from the 24HR, and CRP was quantified using latex-enhanced nephelometry on the Dade Behring Nephelometer II Analyzer System . We categorized ethnicity as non-Hispanic white, non-Hispanic black, Mexican American, and others. Education background was graded into less than 9th grade, 9-11th grade (includes 12th grade with no diploma), high school grade/general equivalent diploma, some college or associate degree, and college graduate or above. The poverty to income ratio is an index of poverty status that is total family income divided by the poverty threshold. It was graded into three categories based on the analysis guideline: ≤1.3, 1.3-3.5, and >3.5 .6 [12 [The overall OBS was calculated by summing the points assigned for each component; a higher OBS reflected a predominance of antioxidant exposure. Based on a priori information about the relationship between nutrients or lifestyle factors and OS, sixteen nutrients and four lifestyle factors were screened to calculate the OBS, with five prooxidants and fifteen antioxidants. Most components have been used to calculate OBS at previous , and six6 , vitamin6 [12 , magnesi6 [12 , and cop6 [12 . In addiThe OBS had combined the contributions of both diet and lifestyle. To investigate whether diet or lifestyle factors significantly contributed to the OBS-LTL association, respectively, we calculated a dietary OBS by excluding four lifestyle variables: cotinine, alcohol consumption, BMI, and physical activity from the OBS measures that have been described above and calculated a lifestyle OBS that only included these four variables .P25, P75), and the categorical variables were expressed as unweighted frequencies (weighted percentages). These means and frequencies were generalizable to the American adult population. To test the characteristic differences for variables in different OBS groups (quartiles), the Rau-Scott chi-squared test, the weighted univariate linear regression, and the Kruskal-Wallis test were used for categorical, normal continuous, and nonnormal continuous variables, respectively.Statistical analyses were performed following CDC analytical reporting guidelines for complex NHANES data analysis. We considered the masked variance and used the recommended weighting scheme. In the present study, the individual sample weights were founded on four years of Mobile Examination Center records, as recommended by NHANES. LTL was log-transformed to better approximate a normal distribution. The continuous variables were presented as weighted means ± standard deviations or median  were used to investigate the associations between the OBS and LTL. In general, the OBS was treated as a continuous variable in analyses. To verify the correlation between the OBS and LTL and observe the possibility of a nonlinear relationship between the OBS and LTL, the OBS was converted to a categorical variable by quartile and computed The statistical analyses included three main steps. Primarily, the characteristic distribution of data in each gender was described according to the quartile of OBS. Then, the multivariate linear regression models were used to estimate the association between LTL and OBS in males and females, and sensitivity analyses were used to evaluate the robustness of multivariate linear regression results; it was to analyze whether the results would be significantly affected if one component was removed from the total score at one time. Finally, the dietary OBS and the lifestyle OBS were explored if they were associated with LTL, respectively.All analyses were performed using the statistical software SAS version 9.4 . Alpha was set at <0.05 for statistical significance, and all analyses were two-sided.p < 0.01). Although there were significant differences in the LTL for OBS quartiles, log-transformed LTL had no significant trend from the low OBS quartile to the high OBS quartile in males.Among the 3220 individuals included in this study, 1697 were males and 1523 were females. Participants had a mean age of 44.5 years (range 20 to 84) in each gender. The baseline characteristics of males and females by quartiles of the OBS are summarized in Tables Supplementary Table p trend was 0.89 in males and was smaller than 0.01 in females. When treating the OBS as a continuous variable, the beta estimates (95% CIs) of the OBS in the full model were 0.0001 (-0.0020–0.0023) for males and 0.0039 (0.0014–0.0065) for females, compared with the corresponding results after each OBS component was removed from the score one at a time with the original OBS (examined as a continuous variable). Removing any single OBS component did not significantly affect the results of males or females (Supplementary Table 001 -0.000–0.0023 The results of multivariate linear regression analyses to assess the associations of the dietary and lifestyle OBS with log-transformed LTL are presented in In the present study, we explored the association between the OBS and LTL within a large, random, and national sample of American adults. The result showed that the association between the OBS and log-transformed LTL was positive and stable in females but not males. Furthermore, both the dietary OBS and the lifestyle OBS were positively associated with log-transformed LTL only in females as well.The association between the OBS and the LTL for females was stable and positive. Although there was no direct evidence, several groups had investigated the relations between OBS and aging-related diseases. For example, researchers found that a higher OBS was associated with a lower risk of cancers , 42, 53,There was a significant gender difference in the correlations between the OBS and LTL, which was partly consistent with previous researches. Similarly, a positive association between adherence to the Mediterranean diet and TL was observed in a meta-analysis with 13733 participants from 5 countries. However, no association was reported for males in this meta-analysis . BesidesThe levels of sex hormones may partly contribute to the gender difference. All estrogens have a free phenolic hydroxyl group on the A-ring, which has antioxidant properties and is the sole structural determinant for free radical scavenging . It is lThere were several strengths associated with the present study. First, the oxidation potential of both diet and lifestyle to LTL was rarely accessed in other studies. Second, a complex, multistage probability sampling design was used to select the sample representative of the civilian noninstitutionalized resident population, so the results were generalizable to all civilian noninstitutionalized resident adults of the United States. Third, this study controlled many confounding factors, including sociodemographic characteristics, dietary energy intake, and CRP. Fourth, the sensitivity analyses provide evidence that the key results of the present study were robust.The current study also has several limitations. First, the cross-sectional nature of the data makes it difficult to infer causation and strongly weakened the associations between cotinine and LTL in males which partly contributed to the gender difference. Second, the OBS was hard to include all OS-related dietary and lifestyle exposures; many components, such as flavonoids, were limited in the database; moreover, there may be some ambiguous OS-related dietary or lifestyle factors not included. However, the correlation between LTL and the present OBS was stable enough and unlikely to be significantly affected by the nonincluded components. Third, all prooxidants and antioxidants were assumed to linearly correlate with OS without considering the threshold effect of antioxidants. Evidence supported that some antioxidants may exert prooxidant activities in large doses or under certain conditions, such as carotenoids and copper , 70. As In conclusion, results from a nationally representative sample of American adults indicated that the OBS was positively associated with LTL in females. It revealed that a higher OBS, which indicated a predominance of antioxidant exposure over prooxidant exposure in diet and lifestyle, was associated with a longer LTL. This finding might suggest a protective effect of adherence to an antioxidative diet and lifestyle on the LTL of American females. These findings require further corroborations from future prospective studies.