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In order to understand the knowledge, attitude and practice (KAP) of vaccination against influenza, pneumonia, human papillomavirus (HPV), herpes zoster (HZ), COVID-19, and hepatitis B among staff of vaccination units in Shandong Province, a sample survey was conducted among 797 staffs of adult vaccination units in 12 counties (cities and districts) of Shandong Province from August to September 2022. The results showed that the respondents had the highest total score of knowledge and attitude for the COVID-19 vaccine, with the M ( Q 1 , Q 3 ) of 23 (20, 25) and 10 (10, 10), respectively, and had the lowest score of knowledge and attitude for the herpes zoster vaccine, with the M ( Q 1 , Q 3 ) of 19 (15, 22) and 8 (8, 10), respectively. The vaccine-related knowledge point"vaccine applicable population"had the highest score, with the M (Q 1 , Q 3 ) of 26 (23, 30). The "contraindications/adverse reactions" and "adverse reaction management" had the lowest score, with the M (Q 1 , Q 3 ) of 24 (20, 29) and 24 (20, 28), respectively. About 89.71% of respondents received one adult vaccine within two years at least. The principal driver for vaccination of 53.58% of recipients was their understanding of vaccines, which was"it was necessary to receive the vaccine". About 66.00% of respondents who had not received any adult vaccine in the past two years had insufficient awareness of the necessity of vaccination and believed that they were in good health and did not need to receive it. In summary, the staff of adult vaccination units in Shandong Province have a poor understanding of the herpes zoster vaccine in terms of vaccines and a relatively poor understanding of"contraindications/adverse reaction and management"in adult vaccination knowledge points.

Objective: To investigate the characteristics and trends of spontaneous subarachnoid hemorrhage (SAH) in Shandong province. Methods: In this study, SAH incidence data of residents from 2012 to 2021 were collected from the chronic disease monitoring information management system of Shandong province, including the basic information of outpatient, emergency or inpatient cases and out-of-hospital deaths (name, gender, ID number, address, etc.) and disease diagnosis information (disease diagnosis, date of onset, date of diagnosis, etc.). The crude incidence rate and age-standardized incidence rate were used as indicators to describe the incidence of SAH in different gender, age groups and regions (urban and rural areas). Joinpoint regression was used to analyze the variation of incidence rate and age by year. The rate difference decomposition method was used to estimate the contribution of population aging to the increase of SAH incidence. Global and local spatial autocorrelation analysis was performed using DeoDa 1.12 software. Results: From 2012 to 2021, a total of 11 629 cases of SAH were reported from 19 provincial monitoring sites in Shandong province. Among them, 54.11% (6 293 cases) were female and 91.87% (10 684 cases) were≥45 years old. The reported crude incidence rate increased from 5.26/100 000 to 9.50/100 000, with an average annual increase of 7.75% ( Z trend =7.30, P trend <0.001), and the standardized incidence rate also showed an upward trend ( Z trend =3.92, P trend =0.004). The crude incidence rate of women was higher than that of men in all years (all P values<0.05), and the standardized incidence rate of women was higher than that of men in all years except in 2012 and 2021 (all P values<0.05). In 2012, the crude incidence and standardized incidence of urban residents were lower than those in rural areas ( P <0.05); from 2013 to 2017, the urban incidence was higher than that in rural areas; and after 2018, the rural incidence exceeded the urban incidence again (all P values<0.05). The median age of onset of SAH increased from 61.9 years in 2012 to 67.2 years in 2021. The age of onset of SAH in men was lower than that in women in all years (all P <0.05), and there was no significant difference between urban and rural residents in most years ( P >0.05). The incidence of SAH increased with age ( P trend <0.001), with a low incidence reported in residents aged<45 years and a rapid increase in residents aged≥45 years. According to the seasonal decomposition, the incidence of SAH had three small peaks in January, March to May and October to November. From 2013 to 2021, the contribution of aging population to the increase of crude incidence of SAH increased from 27.86% to 43.68%. The global spatial autocorrelation analysis showed that the incidence of SAH was in an obvious spatial aggregation distribution (Moran's I >0, P <0.05). Local spatial autocorrelation analysis showed that the counties with high incidence were mainly concentrated in Dezhou City in northwest Shandong Province and Heze city in southwest Shandong province. Conclusions: The crude incidence rate of SAH in Shandong province is increasing, with spatial clustering and seasonal clustering. Residents aged 45 years and older, female residents, and rural residents are at high risk of developing SAH, so targeted prevention and control measures should be taken for high-incidence seasons, high-risk groups, and high-incidence clustered areas.

Objective: To analyze the trend of incidence and mortality of thyroid cancer and estimate its age-period-cohort effect in Shandong Province from 2012 to 2022. Methods: The Joinpoint regression was used to analyze the trend of incidence and mortality of thyroid cancer and calculate the average annual percentage change (AAPC) based on the data on thyroid cancer from 2012 to 2022. The age-period-cohort model was used to analyze the age-effect, time-effect and cohort-effect of thyroid cancer risk in the population aged over 20 years. Results: From 2012 to 2022, the incidence of thyroid cancer in Shandong province showed a significant upward trend, with an AAPC of 21.68% (95% CI : 19.14%-24.27%, P <0.001). The incidence of females was higher than that of males, and the incidence of urban areas was higher than that of rural areas. The trend of thyroid cancer mortality was relatively stable with an AAPC of -3.04% (95% CI :-8.81%-3.09%, P =0.323). The age effect of incidence increased with age before 60 years old and decreased with age after 60 years old. The incidence peaked in the age group of 55-59. The period effect increased with time. The cohort effect showed that the cohort born before 1957 had a downward trend over time, while the cohort born after 1957 had an upward trend. Conclusion: The incidence of thyroid cancer in Shandong shows a rising trend from 2012 to 2022. Age is an important factor affecting the risk of thyroid cancer. The mortality of thyroid cancer remains stable.

Objective: To study the complete genome characterization of Human Astrovirus (HAstV) in Shandong Province. Methods: Stool samples from acute flaccid paralysis (AFP) surveillance in Shandong Province from 2020 to 2022 were collected, and HAstV nucleic acid was examined by real-time quantitative PCR (qPCR). Next-generation sequencing (NGS) was conducted for the positive samples to obtain complete genome sequences and identify the genotype. Homology comparison and phylogenetic analysis were performed by using BioEdit and Mega software. Results: A total of 667 samples were examined by qPCR, of which 14 were HAstV-positive (2.1%), including HAstV-1 ( n =6), MLB1 ( n =6), MLB2 ( n =1), and VA2 ( n =1). The complete genome sequences were obtained from 11 samples. The six HAstV-1 sequences of this study had 98.2% to 99.9% nt similarities with each other and 87.6% to 98.6% with those from other regions. The four MLB1 sequences of this study had 99.1% to 99.9% nt similarities with each other and 92.2% to 99.4% with those from other regions. The VA2 sequence of this study had 96.0% to 96.3% nt similarities with those from other regions. Phylogenetic analysis based on ORF2 region showed that the local HAstV-1 sequences were most closely related to Japanese strains, and had distinct topology with phylogenies based on ORF1a and ORF1b regions. Conclusion: The complete genome sequences of 11 HAstV strains are obtained, and the VA2 complete genome is found.

Objective: To analyze the epidemiological characteristics and clinical features of pertussis cases reported in Shandong Province of China. Methods: Data on pertussis cases in Shandong Province from 2007 to 2022 were collected from China Information System for Disease Control and Prevention. At the same time, some case information was collected from the database of notifiable pertussis in Shandong Province from 2007 to 2022. The distribution characteristics and clinical features of pertussis were analyzed. A spatial distribution map of pertussis cases in Shandong Province was drawn. Results: A total of 26 122 pertussis cases were reported in Shandong Province during 2007-2022, with an annual incidence rate ranging from 0.11 to 5.77 cases per 100 000 people. Cases occurred throughout the whole year, with a seasonal peak occurring in spring and summer, especially in July and August. In recent years, reported cases were mainly distributed in the central and western regions of Shandong Province, with fewer cases in the eastern region. The hot spots of the disease shifted from Heze and Dezhou City in 2007-2013 to Jinan and Tai'an city in 2014-2022. The age range of onset was from 1 day to 93 years old. The proportion of cases with age≤1 year was the largest (41.81%, 10 922/26 122), and the proportion of cases aged 0-6 months decreased from 32.21% (67/208)-55.67% (157/282) within the period of 2007 to 2013 to 16.78% (883/5 263)-41.97% (444/1 058) within the period of 2014 to 2022, with a statistically significant trend ( χ ² trend=670.01, P <0.001). There were 13 682 male cases and 12 440 female cases, with a male-female ratio of 1.10∶1. The male-female ratio was 1.45∶1 (806∶556) from 2007 to 2013 and 1.08∶1 (12 876∶11 884) from 2014 to 2022. The proportion of women increased from 42.31% (88/208) in 2007 to 47.84% (2 518/5 263) in 2022, and with a significant trend ( χ ² trend=22.25, P <0.001). In pertussis cases, the proportions of scattered children, kindergarten children and students were 71.38% (18 645/26 122), 15.13% (3 951/26 122), and 11.60% (3 031/26 122), respectively. The top five clinical symptoms of pertussis cases were paroxysmal spasmodic cough (86.33%, 21 411 cases), flushing (39.61%, 9 824 cases), restless sleep (34.51%, 8 558 cases), fever (30.80%, 7 638 cases), and crowing (27.53%, 6 829 cases). Among 24 802 cases, there were 15 542 cases (62.66%) with a history of immunization against pertussis vaccine. Conclusion: From 2007 to 2022, the incidence rate of pertussis cases in Shandong Province shows an upward trend, with the majority being young children, and the clinical symptoms are relatively typical.

Objective: To investigate the operation of children's vaccination clinics in Shandong Province, simulate the efficiency of vaccination capacity utilization, and explore the feasibility of carrying out adult vaccination in children's vaccination clinics. Methods: Using the extreme hypothesis method to determine the maximum vaccination capacity of children's vaccination clinics. Based on on-site surveys, population, and vaccination rate data, simulation parameters were determined, and the simulation method was used to simulate the utilization efficiency of vaccination capacity in different scenarios of children's vaccination clinics. Results: There were 2 654 children's vaccination clinics by the end of 2021 in Shandong province. There was (6.93±4.02) staff per vaccination clinic, with an average opening day of (4.16±2.19) days per week. In the scenario of only vaccinating children, the utilization efficiency of vaccination capacity during the non-influenza vaccination season was only 30.74% and 14.07% in urban and rural vaccination clinics, respectively. During the influenza vaccination season, the utilization efficiency of the vaccination capacity of urban vaccination clinics reached 49.26% when the child influenza vaccination rate reached 20%. In the scenario of simultaneous vaccination of children and adults, the utilization efficiency of vaccination capacity during the non-influenza vaccination season was 41.48% and 18.52% in urban and rural vaccination clinics, respectively. During the influenza vaccination season, the utilization efficiency of vaccination capacity in urban vaccination clinics reached 51.47% when the influenza vaccination rate of the entire population reached 3%. The utilization efficiency of vaccination capacity in rural vaccination clinics reached 52.44% when the influenza vaccination rate of the entire population reached 20%. Conclusion: The accessibility of children's vaccination is good in Shandong province, and the utilization efficiency of vaccination capacity can meet the current vaccination needs of children and adults. The vaccination capacity in urban areas needs to be strengthened to meet the growing vaccination needs of children and adults in the future.

Objective: To understand the knowledge, attitude and behavior of adult residents on influenza, pneumococcus, human papillomavirus (HPV), herpes zoster (HZ), COVID-19, hepatitis B and rabies vaccination in Shandong Province. Methods: From August to September 2022, a multi-stage stratified random sampling method was used to investigate community-dwelling residents aged 18 years old and above in 12 counties (cities and districts) of Shandong Province. A questionnaire survey was used to collect the basic information of the respondents, such as knowledge, attitude and vaccination behavior of influenza, pneumococcus, HPV, HZ, COVID-19, hepatitis B and rabies vaccine. Analysis of variance was used to compare the differences in the respondents' knowledge and attitude scores of different vaccines. The Chi-square test was conducted to compare the differences in vaccination reasons among different characteristics, and a logistic regression model was used to analyze the influencing factors of vaccination behavior. Results: The median age ( Q 1 , Q 3 ) of the 2 754 respondents was 39 (29, 57) years ranging from 18 to 94 years, with a number of 1 234 (44.81%) males. The average score of the respondents' understanding of various knowledge about adult vaccines was less than 4 points, with the highest score for understanding which diseases can be prevented by adult vaccines. The average score of consent and necessity for adult vaccines to prevent diseases was greater than 3.6 points. In terms of knowledge demand and trust in information channels, there was a high level of trust in the recommendations of vaccination outpatient staff and clinical doctors [with scores of (4.15±0.79) and (4.02±0.80), respectively]. The highest demand for information on vaccination safety knowledge was (4.18±0.84) points. In recent two years, 52.11% of the population had been vaccinated with other vaccines in addition to the COVID-19 vaccine and rabies vaccine, and 45.44% of the population felt it was necessary to be vaccinated through media publicity. Women, age growth, high education level, and high-income level were the promoting factors for adopting vaccination behavior. Conclusion: Adult residents in Shandong Province have a basic understanding and supportive attitude towards vaccination, but the vaccination behavior rate is still relatively low, with significant differences in sex, age, education level, and income level. It is necessary to further increase efforts in the breadth and depth of adult vaccination promotion and education, as well as promotion strategies targeting different populations.

Objective: To analyze the utilization of adult vaccination among people aged 18 and above in Shandong Province from 2018 to 2022. Methods: Data on vaccination units in 2022 and individual cases of vaccination information for people aged 18 and above were extracted from the Shandong Immunization Information System. A descriptive analysis was conducted on the distribution of adult vaccination units and adult vaccination varieties. The total vaccination amount and vaccination rate were calculated. Results: By the end of 2022, there were 3 948 vaccination units providing adult vaccination in Shandong Province, with 0.36 adult vaccination clinics per 10 000 people. Adult vaccination including RabV(rabies vaccine for human use), InfV(influenza vaccine), HPV(human papillomavirus), HepB(hepatitis B vaccine), PPV23(23-valent pneumococcal polysaccharide vaccine), MenACYW135(meningococcal polysaccharide vaccine group ACYW135), MMR(measles, mumps and rubella combined attenuated live vaccine), HEV(hepatitise E vaccine), RZV(recombinant zoster vaccine), TV(tetanus vaccine) and HF(haemorrhagic fever with renal syndrome vaccine) vaccines were administered, with a cumulative dose of 40.056 9 million and an average of 0.1 doses per person per year from 2018 to 2022. The top three vaccines were RabV, InfV and HPV, accounting for 31.48%, 22.57%, and 15.93% of the total vaccination amount, respectively. The annual vaccination dose for adults increased from 3.477 3 million in 2018 to 13.308 6 million in 2022, with an average annual growth rate of 56.55%. The cumulative 5-year doses of RabV and TV were 15.90 doses per 100 people and 0.21 doses per 100 people. The average annual vaccination rate of InfV was 2.28%. The cumulative full vaccination rates of HPV, HepB, PPV23 and RZV were 12.44%, 1.61%, 0.52% and 0.17%, respectively. The cumulative 5-year doses of RabV and TV were 29.19 doses per 100 people and 0.43 doses per 100 people in the age group of 20 to<30 years old. The vaccination rates of InfV and PPV23 were 9.08% and 1.27% in the age group of 70 to<80 years old. The vaccination rate of RZV was 0.11% in the age group of 50 to<60 years old. The HPV vaccination rate was 18.09% in the age group of 20 to<30 years old, and the HepB, MenACYW135, MMR and HEV vaccination rates were 6.21%, 9.55%, 2.65%, and 2.83% in the 18-19 age group, respectively. Conclusion: There are relatively few types of adult vaccination in Shandong Province, with narrow coverage and low vaccination rates.

Objective: To understand the setting of adult vaccination clinics and the situation of adult vaccination in Shandong province, and provide the date basis for the construction and development of adult vaccination clinics in Shandong province. Methods: Multi-stage stratified cluster random sampling was used to survey the settings, personnel allocation, operation status, and adult vaccination status of child-adult vaccination clinics and adult vaccination clinics. A random sampling survey was conducted for hydrophobia vaccination clinics in 12 counties (cities, districts) of Shandong province. The settings and vaccination status of different types of adult vaccination clinics were compared and analyzed using analysis of variance or χ 2 -test. Results: Among the investigated counties (cities, districts), the child-adult vaccination clinics, the adult vaccination clinics, and the hydrophobia vaccination clinics accounted for 59.51%, 7.97% and 32.52%, respectively. The construction model could be divided into three models: child-adult vaccination clinic model, child-adult and hydrophobia vaccination clinic model, child-adult, adult and hydrophobia vaccination clinic model. The child-adult vaccination clinics had been set up for a long time (≥3 years accounted for 94.33%) and were set up by public primary medical institutions (public institutions accounted for 93.81% and primary institutions accounted for 92.78%). Each vaccination clinic was equipped with full-time and part-time staff of (3.19±3.01) and (3.72±4.32). The adult vaccination clinics had been set up for a short time (≥3 years accounted for 94.33%) and were set up by public/private primary/secondary medical institutions in urban areas (urban areas accounted for 100%, primary institutions accounted for 69.23%, and private institutions accounted for 57.69%). Each vaccination clinic was equipped with full-time and part-time staff of (2.46±2.87) and (3.08±3.53). The coverage of influenza vaccine (InfV), human papillomavirus vaccine (HPV) and hepatitis B vaccine (Hep B) reached 100%, 98.45% and 97.42% in children-adult vaccination clinics, and 88.46%, 84.62% and 73.08% in adult vaccination clinics, respectively. The hydrophobia vaccination clinics only provided rabies vaccine for human use (RabV) and tetanus vaccine (TV) vaccination simultaneously. A total of 819.8 thousand doses of adult vaccines were administered in 2021. The adult inoculation doses of RabV, lnfV and HPV accounted for 42.60%, 27.47% and 17.54% of the total inoculation doses, respectively. The inoculation doses of InfV, HPV and RabV accounted for 49.33%, 21.97% and 13.80% of child-adult vaccination clinics, respectively. The inoculation doses of HPV, HepB and RabV accounted for 49.36%, 15.40% and 14.71% of adult vaccination clinics, respectively. The proportion of RabV reached 94.44% in the hydrophobia vaccination clinics alone. Conclusion: Adult vaccination is at the initial stage in Shandong province. The children's vaccination clinic is mainly responsible for adult vaccination. The variety of adult vaccines is relatively concentrated, and the adult vaccination rate is lower. The construction and publicity of adult vaccination should be further strengthened.

Predicting seizure recurrence risk is critical to the diagnosis and management of epilepsy. Routine electroencephalography (EEG) is a cornerstone of the estimation of seizure recurrence risk. However, EEG interpretation relies on the visual identification of interictal epileptiform discharges (IEDs) by neurologists, with limited sensitivity. Automated processing of EEG could increase its diagnostic yield and accessibility. The main objective was to develop a prediction model based on automated EEG processing to predict one-year seizure recurrence in patients undergoing routine EEG. We retrospectively selected a consecutive cohort of 517 patients undergoing routine EEG at our institution (training set) and a separate, temporally shifted cohort of 261 patients (testing set). We developed an automated processing pipeline to extract linear and non-linear features from the EEGs. We trained machine learning algorithms on multichannel EEG segments to predict one-year seizure recurrence. We evaluated the impact of IEDs and clinical confounders on performances and validated the performances on the testing set. The receiver operating characteristic area-under-the-curve for seizure recurrence after EEG in the testing set was 0.63 (95% CI 0.55-0.71). Predictions were still significantly above chance in EEGs with no IEDs. Our findings suggest that there are changes other than IEDs in the EEG signal embodying seizure propensity., (© 2023. Springer Nature Limited.)

During the global efforts to prevent and control the COVID-19 pandemic, extensive research and development of SARS-CoV-2 vaccines using various technical approaches have taken place. Among these, vaccines based on adenovirus vector have gained substantial knowledge and experience in effectively combating potential emerging infectious diseases, while also providing novel ideas and methodologies for vaccine research and development (R&D). This comprehensive review focuses on the adenovirus vector technology platform in vaccine R&D, emphasizing the importance of mucosal immunity induced by adenoviral vector-based vaccine for COVID-19 prevention. Furthermore, it analyzes the key technical challenges and obstacles encountered in the development of vaccines based on the adenovirus vector technology platform, with the aim of providing valuable insights and references for researchers and professionals in related fields.

This study followed up the immune memory after 3-dose revaccination among infants with non-and low-response following primary hepatitis B (HepB) vaccination. About 120 children without self-booster doses were finally included who had anti-HBs<10 mIU/ml (anti-HBs negative) at the time of follow-up, of whom 86 children completed blood sampling and anti-HBs testing. Before the challenge dose, all 86 children were negative for anti-HBs, and the GMC of anti-HBs was<10 mIU/ml. The seropositive conversion rate of anti-HBs was 100% and the GMC of anti-HBs was 886.11 (95% CI : 678.15-1 157.84) mIU/ml after the challenge dose. Compared with those with GMC<7 mIU/ml before the challenge dose, infants with GMC>7 mIU/ml had a higher anti-HBs level after the challenge dose. The β value (95% CI ) was 0.82 (0.18-1.46) ( P =0.012). Compared with those with GMC<1 000 mIU/ml at primary vaccination, infants with GMC≥1 000 mIU/ml had a higher anti-HBs level after the challenge dose. The β value (95% CI ) was 0.78 (0.18-1.38)( P =0.012). The results showed a stronger immune memory was found at 9 years after revaccination among infants with non-and low-response to HepB.

Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.

Objectives: The coxsackievirus A24 variant (CVA24v) has raised a remarkable concern because of its main etiological role in acute hemorrhagic conjunctivitis., Methods: We conducted a retrospective study to summarize CVA24v isolated from acute hemorrhagic conjunctivitis outbreaks and acute flaccid paralysis surveillance in Shandong province, China during 1988-2020. Phylogenetic and phylogeographic methods based on the VP1 coding region were used to determine the CVA24v origin, spatiotemporal dynamics, and evolution. Also, the positive selection sites in the VP1 gene were identified and exhibited in the tertiary structure., Results: The global CVA24vs were classified into eight genotypes (GⅠ-GⅧ). Here, 12 CVA24v isolates were detected, of which five strains were typed as two novel genotypes (GⅦ and GⅧ) and reported first in the world. The time to the most recent common ancestor of the global CVA24v was estimated around March 1965 and evolved with 5.573 × 10 -3 substitutions/site/year. Four residues under positive selection were detected, and residue 146T might be adapted in the CVA24v pandemic. Phylogeographic analysis indicated that China was the main source sink for CVA24v dispersion in a long-lasting global pattern., Conclusion: Our study updated the epidemiological characteristics of CVA24v and enabled a better understanding of the molecular mechanism underlying different genotypes. The results provided new insights into the CVA24v origin, spatiotemporal dynamics, and possibly, the determinants of viral tropism and pathogenicity., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In the context of the global pandemic of COVID-19, the epidemic intensity, epidemic characteristics and infection risk of influenza have presented new features. COVID-19 and influenza have simultaneously emerged in many regions of the world. COVID-19 and influenza are similar in terms of transmission mode, clinical symptoms and other aspects. There are also similarities in the mechanism of influenza virus and novel coronavirus on cells. At the same time, it is feasible and significant to do a good job in the prevention and control of COVID-19 and influenza. This paper discusses the relevant strategies and measures for the joint prevention and control of influenza and novel coronavirus from the aspects of influenza vaccination to prevent co-infection, simultaneous vaccination of influenza vaccine and novel coronavirus vaccine, etc., and puts forward corresponding thoughts and suggestions, in order to provide scientific support for the formulation of strategies on seasonal influenza vaccine and novel coronavirus vaccination.

Objective: Assess the 10-year Immune persistence and the predictors after primary vaccination hepatitis B vaccine (HepB) among normal and high-responder infants. Methods: A total of 1 838 Infants of 7-12 months old located in Jinan, Weifang, Yantai and Weihai of Shandong Province who were induced normal or high antibody response (anti-HBs titer ≥ 100 mIU/ml) after primary vaccination (three dose with 0-1-6 procedure) with 5 μg recombinant HepB among newborns were included in the study, in 2009. 3 ml of venous blood samples were collected at baseline survey (T 0 ) and antibodies against hepatitis B surface antigen (anti-HBs), antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (HBsAg) were detected using chemiluminescence microparticle immunoassay (CMIA) method. A self-designed questionnaire was used to collect information including the infant's age, sex, birth weight, premature birth, birth number, delivery location and mother's HBV infection status. In 2014 (followed up for 5 years) and in 2019 (followed up for 10 years) (T 1 ), 2 ml of venous blood samples were collected. Anti HBS and anti HBC were detected by CMIA method. Those with anti HBS<10 mIU/ml were detected by CMIA method. Multivariate unconditional logistic and linear regression models were used to analyze the influencing factors of anti-HBs positive rate and geometric mean concentration (GMC) at T 1 . Results: After 10 years follow-up, 73.94% of the subjects (1 359/1 835) finished the follow-up. 51.15% of the subjects, a total of 625 were boys. The positive rate of anti-HBs was 100% at T 0 and decreased to 53.44% (95% CI : 50.59%-56.26%) at T 1 . The average annual decline rate of anti-HBs positive rate from T 0 to T 1 was 6.07%. The GMC of anti-HBs decreased from 607.89 (95% CI : 579.01-642.62) mIU/ml to 16.44 (95% CI : 15.06-18.00) mIU/ml. The average annual decline rate of anti-HBs GMC in 10-year follow-up was 30.30%. Multivariate logistic analysis showed that the positive rate of anti-HBs at T 1 was lower in those who did not vaccinate the first dose in time ( OR =0.25, 95% CI :0.07-0.71). Compared with those with GMC<1 000 mIU/ml at T 0 , those with GMC ≥ 1 000 mIU/ml had a higher positive rate of anti-HBs at T 1 ( OR =2.29, 95% CI :1.76-2.97). Multivariate regression analysis showed that the GMC of anti-HBs at T 1 was lower in those who did not vaccinate the first dose in time (β=-0.50, 95% CI :-1.24-0.24). Compared with those with GMC<1 000 mIU/ml at T 0 , those with GMC ≥ 1 000 mIU/ml had a higher GMC of anti-HBs at T 1 (β=0.81, 95% CI : 0.62-1.05). Conclusion: Anti-HBs GMC decreased in 10 years after primary vaccination of 5 μg recombinant hepatitis B vaccine among normal and high-responders. The anti-HBs persistence was mainly associated with whether the first dose was vaccinated in time and the level of anti-HBs at the end of primary vaccination.

Influenza is an infectious respiratory disease caused by the influenza viruses. Older people, infants and people with underlying medical conditions could have a higher risk of severe influenza symptoms and complications. The co-infection of Coronavirus Diseases 2019 (COVID-19) with influenza viruses could lead to the complication of prevention, diagnosis, control, treatment, and recovery of COVID-19. Influenza vaccine and COVID-19 vaccine overlapped in target populations, vaccination time, and inoculation units. Although there was insufficient evidence on the immunogenicity and safety of co-administration of influenza vaccine and COVID-19 vaccine, World Health Organization and some countries recommended co-administration of inactivated influenza vaccine and COVID-19 vaccine. This review summarized domestic and international vaccination policies and research progress, and put forward corresponding suggestions in order to provide scientific support for the formulation of vaccination strategy on seasonal influenza vaccine and COVID-19 vaccine.

Objective: To understand the incidence and economic burden of herpes zoster among the aged in Laiwu district, Jinan city. Methods: Retrospective cohort study was conducted in 5 communities in Laiwu District, Jinan City from July to September, 2019. A total of 8 300 residents born before July 1, 1959 and aged ≥60 years old were included in the investigation. At the same time, an economic burden survey was carried out among 220 cases who developed herpes zoster after July 1, 2017. A questionnaire was used to collect information on incidence and economic burden of HZ, and comparisons were carried out about the incidence and economic burden of herpes zoster among older people with different characteristics. Results: The age of 8 300 subjects was (71.46±6.71) years old. Male and female accounted for 44.10% and 55.90%, respectively. The cumulative incidence of disease after the age of 60 was 73.61‰ among population aged ≥60 years old. The cumulative incidence was 28.03‰, 71.26‰, 86.09‰, 93.48‰ and 88.10‰ among population aged 60-64, 65-69, 70-74, 75-79 and ≥80 years old,respectively. The average annual incidence of HZ was 9.49‰ and annual incidence was 7.59‰, 7.23‰, 8.43‰, 10.24‰ and 13.98‰ in 2014-2018, respectively. HZ cost was (2 626±667) RMB per patient with a median cost of 715 RMB (interquartile range 303-2 358) on 220 cases who developed disease after July 1, 2017. The cost of outpatient cases was (1 329±1 835) RMB per patient with a median cost of 560 RMB (interquartile range 300-1 320), and the cost of inpatient cases was (14 303±16 571) RMB per patient with a median cost of 8 190 RMB (interquartile range 4 368-15 160). Conclusion: The incidence of HZ is high among population aged≥60 years old, which could cause heavy economic burden for them.

Objective: To investigate the economic burden of bacillus Calmette-Guérin (BCG) lymphadenitis in Shandong Province. Methods: From May 2011 to December 2019, 304 patients applying for the province-level compensation of BCG lymphadenitis was selected from Shandong Province in this study. The basic situation, vaccination, outpatient (inpatient) records, cost and relevant information of those patients were collected to calculate the direct economic burden (including direct medical costs and direct non-medical costs), indirect economic burden and total economic burden. Comparison of the difference of economic burden of cases with different characteristics was taken. Results: The M ( Q 1 , Q 3 ) of age of BCG lymphadenitis patients was 3 (2, 4) months, among which 239 cases (78.6%) were male, 71 cases (23.4%) had lymphadenopathy, and 227 cases (74.7%) underwent surgery.The number of outpatient only, inpatient only and outpatient then inpatient was 25.7% (78 cases), 7.2% (22 cases) and 67.1% (204 cases), respectively. The M ( Q 1 , Q 3 ) of direct, indirect and total economic burden of single case after discount was 9 910 (5 713, 16 074), 2 081 (1 547, 3 122) and 12 262 (7 694, 18 571) yuan, respectively.The direct medical expenses accounted for 89.4% of the direct economic burden, the direct economic burden accounted for 84.9% of the total economic burden, the total economic burden of 80.0% cases accounted for only about 20.0% of the compensation amount, and the total economic burden of only 2.3% cases accounted for more than 60.0% of the compensation amount.The direct, indirect and total economic burden of patients with inpatient only and outpatient then inpatient was higher than that of patients with outpatient only; the direct, indirect and total economic burden of patients with operation was higher than that of patients with non-operation; the direct and total economic burden of patients with unulcerated lymph node was higher than that of patients with ulcerated lymph node(all P values<0.05). Conclusion: The economic burden of BCG lymphadenitis cases in Shandong Province is influenced by the mode of diagnosis and treatment, with direct medical expenses as the predominant component.

Objective: To investigate the distribution characteristics and trends of mortality and spatial aggregation of gastric cancer in Shandong Province from 1970 to 2013. Methods: The mortality data of gastric cancer from 1970 to 1974, 1990 to 1992 and 2004 to 2005 were collected from the first, second and third retrospective sampling survey of causes of death in Shandong Province, respectively. The mortality data of gastric cancer from 2011 to 2013 were collected from the all-cause surveillance data of Shandong Province. The crude mortality rate and age-standardized mortality rate were used to describe the death level of gastric cancer. The age-standardized mortality rate of Shandong Province was calculated based on Segi's world standard population, and the age-standardized mortality rate of counties (cities and districts) was calculated based on the Chinese population in 1964.The factors influencing the difference of gastric cancer mortality in different periods were decomposed by using the method of differential decomposition of mortality, and the contributions of population and non-population factors in different periods were estimated.Using ArcGIS 10.2 software, the death level of gastric cancer in different counties (cities and districts) in Shandong province from 1970 to 1974 and 2011 to 2013 were visualized. DeoDa 1.12 software was used for global and local spatial autocorrelation analysis. Results: The crude death rate and age-standardized death rate of gastric cancer in Shandong province increased firstly and then decreased during 1970-2013, and the crude death rate of gastric cancer increased from 18.33/100 000 in 1970-1974 to 28.51/100 000 in 2011-2013. Segi's age-standardized mortality rate for gastric cancer decreased from 20.94 per 100 000 in 1970-1974 to 18.17 per 100 000 in 2011-2013.From 1990 to 1992, from 2004 to 2005 and from 2011 to 2013, the contribution value of non-population factors to the increase of crude gc mortality was 95.59%, 48.45% and -20.57%, respectively, showing a continuous downward trend. The Moran's I index of crude mortality of gastric cancer in Shandong province from 1970 to 1974 and from 2011 to 2013 were 0.77 and 0.57, respectively, and the Moran's I index of age-normalized mortality was 0.75 and 0.44, respectively. Local autocorrelation analysis showed that there were 31 and 19 high aged-mortality areas of gastric cancer in 1970-1974 and 2011-2013 respectively, and 7 overlapping counties (cities and districts), 6 of which were located in Jiaodong area. Conclusion: The crude mortality and age-standardized mortality of gastric cancer in Shandong province increased first and then decreased from 1970 to 2013, and the distribution of gastric cancer mortality had obvious spatial aggregation and changed with time.

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People's Hospital were also included and divided into the testing and validation cohorts. CD8 + T cells, CD4 + T cells, B cells, and M1 macrophages were associated with favourable outcome (all p <0.01), whereas Treg cells were strongly associated with poor outcome ( p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-β). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy., Competing Interests: 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., (Copyright © 2021 Ji, Yuan, Gao, Xu, Yang, Yang, Zhang, Yang, Li, Zhu, Cheng, Wu and Wang.)

Objective: To analyze the intensity and epidemiological characteristics of hepatitis B virus (HBV) reactivation among inactive HBsAg carriers (IHC) of rural areas in Ji'nan. Methods: In 2018 and 2020, follow-up investigations were conducted on IHC identified in the population physical examination in Zhangqiu district of Ji'nan. The results of the two follow-up visits were compared to analyze the incidence and distribution characteristics of HBV reactivation in IHC at the community level. Results: A total of 424 IHC completed two follow-up visits, and 47 cases of HBV reactivation were found, the cumulative reactivation rate was 11.08%, and the incidence density was 5.46/100 person-years. Multivariate analysis showed that gender, age, smoking, drinking , family history of liver disease and chronic diseases were not associated with HBV reactivation ( P >0.05), and baseline HBV DNA load was associated with reactivation ( P <0.05), in the HBV DNA level ≥1 000 IU/ml group, the reactivation rate could reach 18.92%. After reactivation, the mean level of ALT increased from baseline and the abnormal rate increased, liver function tended to be abnormal in reactivated patients. 4 (8.51%) reactivators had hepatitis, and 1 (2.13%) had jaundice hepatitis. Conclusions: The incidence of HBV reactivation was higher among IHC in rural communities in Ji'nan. Most of the reactivators were asymptomatic or mildly reactivated. Follow-up of inactive HBsAg patients should be strengthened and changes in ALT and HBV DNA levels should be closely monitored.

Objective: To evaluate the persistence of HBsAg-specific antibodies eight years after revaccination with hepatitis B vaccine (HepB) among adults who were non-responsive to primary immunization. Methods: From August to September 2009, rural communities in Zhangqiu district of Ji'nan city were selected as the study site. The subject's inclusion criteria were 18 to 49 years old, local resident population, without HBV infection history and HepB vaccination history, and good health status. Antibodies against hepatitis B surface antigen (anti-HBs) were detected in adults following the standard primary vaccination. Those who were non-responders (anti-HBs titer <10 mIU/ml) were revaccinated with three doses of HepB and included in the study. Blood samples were collected from all of them at one month (T 1 ), two years, four years, and eight years after revaccination. The three indexes of anti-HBs, hepatitis B surface antigen (HBsAg), together with antibody against hepatitis B core antigen (anti-HBc), were measured by chemiluminescence microparticle immunoassay (CMIA). Results: The proportion of subjects with anti-HBs titers ≥10 mIU/ml was 85.12% (549/645) at T 1 , 60.60% (283/467) at two years, 55.90% (199/356) at four years and 55.09% (222/403) at eight years after revaccination. The first two years' annual decline rates, three to four years and five to eight years, were 15.62%, 3.96%, and 0.36%. The GMC of anti-HBs was 153.92 mIU/ml at T 1 , 21.43 mIU/ml at two years, 15.02 mIU/ml at four years, and 13.68 mIU/ml at eight years. In the first two years, three to four years and five to eight years, the annual decline rate of GMC was 62.69%,16.28%, and 2.31%, respectively. Multivariable analysis showed that the titer of anti-HBs at T 1 was independently associated with the persistence of anti-HBs at eight years after revaccination. Compared with anti-HBs titer <100 mIU/ml , those whose anti-HBs titers were 100-mIU/ml and ≥1 000 mIU/ml at T 1 had a higher positive rate of anti-HBs ( OR =14.13, P <0.001; OR = 62.91, P <0.001) and a higher probability of anti-HBs titer ( β =1.88, P <0.001; β =3.24, P <0.001) at 8 years after revaccination. Nobody was found seroconversion of HBsAg, and the anti-HBc positive rate was 14.14% (57/403). Conclusions: Following revaccination with three doses of HepB in adults who were non-responsive to primary immunization, anti-HBs titers declined rapidly within the first four years. They then maintained a stable level after the fifth year. More than half still kept anti-HBs protective titer at eight years after revaccination. The immunity persistence was associated with anti-HBs titer at one month after revaccination.

Objective: To analyze the carriage characteristics of Neisseria meningitidis ( Nm ) among healthy population of epidemic cerebrospinal meningitis in Shandong province. Methods: From April 2008 to April 2020, a total of 16 848 healthy population were recruited from Lixia District of Jinan City, Gaomi City of Weifang City, Jiaxiang County of Jining City, Wendeng District of Weihai City, Tancheng County of Linyi City and Linyi County of Dezhou City for the investigation.Throat swab samples were collected, Nm was isolated, cultured and identified, and Nm carrying characteristics of healthy population with different characteristics were analyzed. Results: Among the 16 848 healthy population, male accounted for 51.86% (8 737). A total of 136 Nm strains were isolated, and the carriage rate was 0.81%. Among the 136 Nm strains, serogroup B (60.29%) and ungroupable strains (23.53%) were dominant. Analysis of the Nm carriage rate, that were higher in the healthy population of Linyi (1.39%) and Jinan (1.14%), higher in 13-16 years old (1.60%) and 17-19 years old (1.10%) healthy population, and higher in male (1.02%). Conclusion: The Nm carriage rate of healthy population is relatively low in Shandong Province, and the proportion of serogroup B and ungroupable Nm is relatively high.

Objective: Investigate and analyze the etiology and serological diagnosis capabilities of pertussis in medical institutions in Shandong Province in 2018. Methods: Using the census method, a questionnaire survey was conducted among 603 second and above level medical institutions in Shandong Province. The deadline for the survey was December 2018, and a total of 543 questionnaires have been recovered, and the validity rate of the questionnaires was 90%. Surveyed the pertussis etiology and serology test items (pertussis IgM and IgG, pertussis nucleic acid and pertussis bacterial culture) and the start time of each test item by questionnaire. The reported cases (confirmed cases and clinically diagnosed cases) between January 1, 2012 and December 31, 2018 were derived from the Chinese Disease Control and Prevention Information System according to the onset date. We used indicators such as fixed-base development speed, chain development speed, and chain growth speed for analysis. The chi test was used to analyze the differences in the composition ratio of medical institutions with detection ability in different levels and regions, and analyze the changes in the number of reported cases before and after the development of pertussis etiology and serology testing. Results: A total of 543 medical institutions accounted for 90.0% (543/603) of all secondary and above level medical institutions in the province, 356 secondary medical institutions (65.6%), and 187 tertiary medical institutions (34.4%). There were 10 medical institutions that carry out pertussis IgM, IgG and nucleic acid testing, accounting for 1.8% (10/543) of the surveyed medical institutions respectively. 2 medical institutions that carried out bacterial culture, accounting for 0.4% of the surveyed medical institutions (2/543). 20 medical institutions have carried out the above tests (8 secondary medical institutions and 12 tertiary medical institutions), accounting for 3.7% (20/543). The proportion of tertiary medical institutions with pertussis IgM, IgG detection and nucleic acid detection capabilities [6.42% (12/187)] was significantly higher than that of secondary medical institutions [2.25% (8/356)] ( χ ²=6.01, P =0.014). From 2012 to 2018, the fixed base ratio development speed of reported cases was 3 834.69% in Shandong Province, among which medical institutions with etiology and serological testing capabilities reached 4 533.33%. In 13 medical institutions, the average annual number of reported cases after pertussis etiology and serological testing were higher than that of reported cases before testing. Conclusion: The ability of pertussis etiology and serology diagnosis of secondary and above medical institutions in Shandong Province needs to be improved.

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). No potential conflicts of interest were reported.

Objective: To explore the spatial clustering and trend of liver cancer mortality in different counties of Shandong province from 1970 to 2013, and provide scientific basis for the development of liver cancer prevention and control plan. Methods: Cancer mortality data were obtained from Shandong Death Registration System and three national death cause surveys in China. Mortality rate and age adjusted mortality rate were used to describe the trend of liver cancer in different years. Difference decomposing method was applied to estimate the contribution of demographic and non-demographic factors to the change of mortality. Software ArcGIS 10.2 was used for spatial analysis, and software SaTScan 9.4 was used for spatial clustering analysis on liver cancer mortality. Results: From 2011 to 2013, the crude mortality rate of liver cancer (29.89/100 000) in Shandong increased by 208.00 % and 35.37 % respectively compared with that during 1970-1974 (9.72/100 000) and 1990-1992 (22.08/100 000) and was similar to that during 2004-2005 (30.44/100 000). While age standardized mortality rate (ASMR) increased first and then decreased. The ASMR during 2011-2013 (12.62/100 000) increased by 60.97 % compared with that during 1970-1974 and decreased by 22.38 % and 21.81 % compared with that during 1990-1992 and 2004-2005, respectively. According to the difference decomposition analysis on liver cancer mortality in different years, the contribution of population factors to the liver cancer mortality rate increased from 3.38 % during 1990-1992 to 29.36 % during 2004-2005 and 46.16 % during 2011-2013. However, the contribution of non-population factors to the increase of liver cancer mortality decreased. According to the spatial distribution of liver cancer mortality, the crude mortality rate of liver cancer in different counties were quite different, ranging from 9.33/100 000 to 65.33/100 000. Using the spatial scanning statistical software to analyze the spatial clustering of liver cancer mortality, multi areas with high mortality rate of liver cancer were found, and they were mainly distributed in Jiaodong peninsula from 2011 to 2013, covering 20 counties (cities, districts) in Qingdao, Yantai and Weihai. The risk of liver cancer mortality in this area was 1.54 times higher than that in other areas. The spatial clustering distribution of liver cancer mortality during 1970-1974 was significantly different from that during 2011-2013, the areas with high mortality rate during 1970-1974 were mainly distributed in central and western Shandong. Conclusions: There were significant temporal and spatial distribution changes in the mortality rate of liver cancer in Shandong from 1970 to 2013. According to these trends and their geographical and spatial distribution, we should further explore the risk factors of liver cancer, and formulate feasible and area specific prevention and control measures for liver cancer.

Plasma cells (PCs) are essential for protection from infection, and at the origin of incurable cancers. Current studies do not circumvent the limitations of removing PCs from their microenvironment and confound formation and maintenance. Also, the investigation of PC population dynamics has mostly relied on nucleotide analog incorporation that does not label quiescent cells, a property of most PCs. The main impediment is the lack of tools to perform specific genetic manipulation in vivo. Here we characterize a genetic tool (Jchain creERT2 ) in the mouse that permits first-ever specific genetic manipulation in PCs in vivo, across immunoglobulin isotypes. Using this tool, we found that splenic and bone marrow PC numbers remained constant over-time with the decay in genetically labeled PCs being compensated by unlabeled PCs, supporting homeostatic population turnover in these tissues. The Jchain creERT2 tool paves the way for an in-depth mechanistic understanding of PC biology and pathology in vivo, in their microenvironment., Competing Interests: AX, RB, DC No competing interests declared, (© 2020, Xu et al.)

Objective: To investigate cytomegalovirus detoxification and associated factors among preschool children in Yinan County, Shandong Province. Methods: Two kindergartens were selected from the county and township of Yinan respectively. A total of 250 children were investigated in October 2018. Case information was obtained through the child's guardian. Saliva samples of children and their mothers were collected for cytomegalovirus realtime-PCR detection.The status of CMV detoxification of children was explored and the associated factors were analyzed. Results: A total of 242 preschool children were investigated, and the detoxification rate of cytomegalovirus among them was 22.31% (54/242, 95% CI : 17.0%-27.6%). Logistic regression analysis showed that the rate of detoxification was higher in children whose mothers were cytomegalovirus detoxified ( OR= 12.39, 95% CI: 1.73-88.65)and whose school was located in the county ( OR= 3.58 , 95% CI :1.34-9.55). Conclusions: The detoxification rate of cytomegalovirus in preschool children is high, and there is mutual transmission between children and mothers. Women of childbearing age should pay attention to prevent congenital cytomegalovirus infection when they come into contact with children.

Objective: To understand the detection of group A rotavirus (RVA) in domestic sewage and its molecular epidemiological characteristics, and further explore the feasibility and necessity of RVA environmental surveillance. Methods: From 2016 to 2018, we collected domestic sewage samples monthly in Jinan city, and concentrated them via anion membrane adsorption-elution method. Then RNA extraction and RVA VP7 and VP4 coding region RT-PCR amplification were performed. After purification, TA cloning and sequencing, homology analysis and phylogenetic analysis were conducted on the obtained sequences. Results: RVA G gene was detected in 31 of the 36 sewage samples (86.1% detection rate); RVA P genotype was detected in 33 samples (91.7% detection rate). A total of 536 RVA sequences were obtained, of which 225 G-type sequences belonged to 6 genotypes, and the G9 accounted for 92.4% (208/225); 311 P-type sequences were obtained, which belonged to 4 genotypes. The dominant P[8] accounted for 50.1% (156/311), followed by P[4] with 41.8% (130/311). Phylogenetic analysis shows that there were multiple transmission chains circulating in the dominant genotypes G9 and P[8]. Conclusion: The genotype, homology, and phylogenetic characteristics of sequences obtained from domestic sewage in Jinan area were described, which further confirmeing that RVA environmental surveillance is not feasible but also necessary.

The selective N-monomethylation of primary anilines was realized by the use of the Me3N-BH3/N,N-dimethylformamide (DMF) system as the methyl source. This method also allows for the controllable introduction of N-CH2D, N-CHD2, and N-CD3 units with high levels of deuterium incorporation using Me3N-BH3/d7-DMF, Me3N-BD3/DMF and Me3N-BD3/d7-DMF systems, respectively.

Rotaviruses infection is one of the main causes of diarrhea among infants and children in the world, resulting in rotavirus gastroenteritis, which is very harmful and has caused a huge disease burden and no specific drug treatment. This paper reviews the rotavirus etiology, epidemiological characteristics, disease burden of rotavirus gastroenteritis and rotavirus vaccines. RV in group A is the main cause of acute gastroenteritis in infants, people at all ages are generally susceptible to RV, 3 to 24 months infants have the most severe symptoms of diarrhea, RVGE epidemic is seasonal and peaks in winter, increasing RV vaccination can reduce the incidence and mortality of rotavirus diarrhea in infants to reduce the burden of corresponding disease. This article focuses on RV vaccines currently in use and their effect on preventing RV infection, and put forward thoughts and suggestions on technical issues related to the application of RV vaccine in China. Provide support for improving the RV vaccine immunization strategy and Chinese-specific immunization strategy for eventually incorporating RV vaccine into the national child immunization program.

Objective: To understand the genotype distribution and molecular epidemiological characteristics of hepatitis E virus (HEV) isolated in Shandong Province, 2017. Methods: The cases of hepatitis E who were reported to the National Notifiable Disease Reporting System (NNDRS) from January to December 2017 in Shandong Province were chosen as the subjects in the study. Epidemiological information and blood samples were collected from 1 045 participants. Both anti-HEV IgM and anti-HEV IgG were detected using ELISA method. Viral nucleic acids were extracted only from those of anti-HEV IgM positive samples. Nested reverse transcription-polymerase chain reaction was carried out to amplify 644 bp nucleotide sequences within HEV open reading frame (ORF) 2 region. The sample sequences together with reference sequences from GenBank were subjected to phylogenetic analysis. Results: In total, 638 (61.1%) cases were detected positive for anti-HEV IgM. The average age of male was (57.9±12.2) years, and the anti-HEV IgM positive rate was 61.5% (496/807). The average age of female was (58.1±15.0) years, and the anti-HEV IgM positive rate was 59.7% (142/238). A total of 163 HEV strains were detected, and the positive rate was 25.6% (163/638). The positive rate of the eastern, central and western region was 23.0% (71/309), 33.6% (72/214) and 17.4% (20/115), respectively. Phylogenetic tree and homology analysis indicated that all isolates belonged to genotype Ⅳ, clustering into four different subgenotype (4a, 4b, 4d and 4h). Subgenotype 4d was predominant, accounting for 85.9% (140 strains), followed by 4b (7.4%, 12 strains), 4a (3.7%, 6 strains) and 4h (3.1%, 5 strains). The 4a, 4b, and 4h subgenotype were mainly detected in the eastern region, accounting for 3/5, 11/12, and 4/6, respectively. The 4d subgenotype was mainly in the middle region, accounting for 50.0% (70/140). The homology analysis showed that the 163 sequences shared 82.7% to 100.0% nucleotide sequence identity with each other. The 140 sequences of HEV 4d strains showed high similarity with swine-origin HEV（KF176351）, cattle-origin HEV（KU904278）and sheep-origin HEV（KU904267）isolated in Shandong Province, and the nucleotide homology was 93.1%-98.3%, 92.7%-97.9% and 92.7%-97.9%, respectively. Conclusion: HEV genotype Ⅳ(4d subgenotype) was dominant in Shandong province. A complicated interspecies transmission might be the main source of human HEV infection in Shandong Province, China.

Background: In consideration of the difficulty in diagnosing high heterogeneous glioma, valuable prognostic markers are urgent to be investigated. This study aimed to verify that connective tissue growth factor (CTGF) is associated with the clinical prognosis of glioma, also to analyze the effect of CTGF on the biological function., Methods: In this study, glioma and non-tumor tissue samples were obtained in 2012 to 2014 from the Department of Neurosurgery of Nanfang Hospital of Southern Medical University, Guangzhou, China. Based on messenger RNA (mRNA) data from the Cancer Genome Atlas (TCGA) and CCGA dataset, combined with related clinical information, we detected the expression of CTGF mRNA in glioma and assessed its effect on the prognosis of glioma patients. High expression of CTGF mRNA and protein in glioma were verified by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. The role of CTGF in the proliferation, migration, and invasion of gliomas were respectively identified by methylthiazoletetrazolium assay, Transwell and Boyden assay in vitro. The effect on glioma cell circle was assessed by flow cytometry. For higher expression of CTGF in glioblastoma (GBM), the biological function of CTGF in GBM was investigated by gene ontology (GO) analysis., Results: In depth analysis of TCGA data revealed that CTGF mRNA was highly expressed in glioma (GBM, n = 163; lowly proliferative glioma [LGG], n = 518; non-tumor brain tissue, n = 207; LGG, t = 2.410, GBM, t = 2.364, P < 0.05). CTGF mRNA and protein expression in glioma (86%) was significantly higher than that in non-tumor tissues (18%) verified by collected samples. Glioma patients with higher expression of CTGF showed an obviously poorer overall survival (35.4 and 27.0 months compared to 63.3 and 55.1 months in TCGA and Chinese Glioma Genome Atlas (CGGA) databases separately, CGGA: χ = 7.596, P = 0.0059; TCGA: χ = 10.46, P = 0.0012). Inhibiting CTGF expression could significantly suppress the proliferation, migration, and invasion of gliomas. CTGF higher expression had been observed in GBM, and GO analysis demonstrated that the function of CTGF in GBM was mainly associated with metabolism and energy pathways (P < 0.001)., Conclusions: CTGF is highly expressed in glioma, especially GBM, as an unfavorable and independent prognostic marker for glioma patients and facilitates the progress of glioma.

Objective: To analyze the etiology and epidemiological characteristics of gastroenteritis virus in foodborne diseases from three cities in Shandong. Methods: From January to December 2017, six sentinel hospitals in Jinan, Yantai and Linyi city of Shandong Province were selected as the research sites. Stool samples of 1 397 diarrhea patients were collected, as well as basic information and clinical symptoms. Duplex quantitative RT-PCR was used to detect Norovirus genogroupⅠ (Nov GⅠ) and genogroupⅡ (Nov GⅡ), Sapovirus (SAV) and Human astrovirus (HAstV), respectively, quantitative RT-PCR was used to detect group A Rotavirus (RVA), and quantitative PCR was used to detect Enteric adenovirus (EAdV). The specific gene of the virus were sequenced and typed. It was compared that the gastroenteritis virus rate in cases with different characteristics and the clinical symptoms difference between the virus positive and negative cases. Results: The median age ( P (25), P (75)) was 23 (1, 42) , mainly male, 57.48% with 803 cased and children under 5 years old, 36.36% with 508 cases. The positive rate of gastroenteritis virus was 33.93% (474 cases), and that of Jinan, Linyi and Yantai City were 32.03% (147/459), 41.54% (189/455) and 28.57% (138/483), respectively ( P< 0.001). Nov GⅡ had the highest positive rate, 16.54% (231 cases), which, mainly GⅡ.P16/GⅡ.2 (48.28%, 56/116), peaked in May (24.75%, 50/202) and June (19.59%, 38/194). In patients of gastroenteritis virus positive, 44.51% (211/474) had vomiting symptoms, higher than that of patients of gastroenteritis virus negative (34.13%, 315/923). The difference was statistically significant ( P< 0.001). Conclusion: In Shandong Province, the majority of gastroenteritis patients were male and children under 5 years old. Nov GⅡ possessed highest epidemic intensity, and peaked in spring and summer. Viral gastroenteritis had atypical clinical symptoms.

Objective To compare the values of dynamic enhanced magnetic resonance imaging(DCE-MRI),digital breast tomosynthesis(DBT),and digital mammography(DM)in the early detection and diagnosis of breast cancer.Methods We retrospectively analyzed the clinical and imaging data of 65 cases with early breast cancer confirmed by surgical pathology from June 2017 to December 2018.All patients underwent breast DCE-MRI,DM and DBT before surgery.The receiver operating characteristic(ROC)curves were drawn,with the pathological results as the gold standard,to evaluate the diagnostic performance of different examination methods.The areas under ROC curves(AUCs)were compared using Z test.The differences among DCE-MRI,DBT and DM in detecting early breast cancer were compared using chi-square test in terms of positive rates,accuracy,sensitivity,and specificity.Pearson correlation analysis was performed to assess the accuracy of these imaging methods in detecting the size of early breast cancer.Results The AUCs of DCE-MRI,DBT,and DM based on the BI-RADS classification for early diagnosis of breast cancer were 0.910,0.832,and 0.700,respectively( z =2.132, P =0.001);the sensitivity of DCE-MRI,DBT,and DM for early breast cancer was 92.3%,70.8%,and 52.5%,the specificity was 65.0%,85.0%,and 79.3%,and the accuracy was 83.1%,70.8%,and 50.8%,indicating that DCE-MRI( χ 2 =15.330, P =0.0001) and DBT( χ 2 =5.450, P =0.020) had significantly higher diagnostic accuracy than DM.The measurement results of DM,DBT,and DCE-MRI were positively correlated with the pathological measurements( r =0.781, r =0.847, r =0.946;all P <0.01). Conclusions DCE-MRI and DBT have higher positive rates and accuracies than DM in detecting early breast cancer.Medical institutions where DCE-MRI is still not available can use DBT to improve the early detection of breast cancer.

Construction and application of immunization information system is an important part of health information, which is very useful to improve the quality, efficiency and safety of vaccination. The background, system architecture, functions and applications, working conditions and characteristics of Shandong province Immunization Information System (IIS) are introduced in this article. It is expected to provide experiences for the development of immunization information system of other provinces.

Objective: To describe the mortality trend of major malignant tumors in Shandong province, from 1970 to 2013. Methods: Data related to cancer mortality were obtained from the Shandong Death Registration System and three nationwide retrospective cause-of-death surveys. Trends of overall mortality and major causes of death were described using the indicators as: mortality rates and age-standardized mortality rates, through comparing the three large-scale mortality surveys in Shandong province. Difference decomposing method was applied to estimate the contribution of demographic and non-demographic factors for the change of mortality. Results: From 1970 to 2013, the crude mortality rate of malignant tumors in Shandong was increasing. The age standard mortality rate was increasing and then decreasing. The composition of cancer deaths in the all-cause-deaths was seen increasing and then decreasing as well. Both demographic and non-demographic factors contributed to the increase of crude cancer mortality rate. With the gradual increase of the proportion of population, its role exceeded the non-demographic factors. The age-standardized mortality rate of malignant tumors in 2011-2013 was lower than that in 2004-2005. Lung cancer mortality rose from the fifth to the first place, with an increase of 6.81 times from 1970-1974 to 2011-2013. Ranking of gastric cancer mortality dropped from first to the third place, with esophageal cancer dropped from second to the fourth. After adjusted by China's standard population in 1964, the mortality rate of lung cancer was still rapidly increasing, but the age-standardized mortality rates of esophageal cancer was gradually decreasing. The crude and age-standardized mortality rates of cervical cancer showed a rapid downward trend, reduced 87.00% and 93.00% respectively from 1970-1974 to 2011-2013. Conclusions: Malignant tumors were still major threats to the residents of Shandong province. The changing trend of different malignant tumors presented an inconsistent nature which called for different intervention strategies be carried out, accordingly.

Objective: To estimate the immune memory at 12 years after hepatitis B vaccination and its risk factors among adults. Methods: The study was conducted in 20 villages of Qudi town in Jiyang county, Shandong province, China in 2003. Hepatitis B surface antigen (HBsAg), antibody against HBsAg (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were tested for all healthy residents aged 15-40 years in these villages. Those who had no history of hepatitis B vaccination and were negative for all three indicators were divided into two groups randomly. Hepatitis B vaccine (HepB) was administrated to them on 0-6 month schedule or 0-1-6 month schedule respectively. Blood samples were obtained at one month after the last dose for each receipt and were quantitatively detected for anti-HBs. Finally a total of 629 participants completed HepB vaccination and anti-HBs testing, including 288 of two-dose group and 341 of three-dose group respectively. In 2015, an additional dose of HepB (challenge dose) was administrated to those who were negative for anti-HBs at follow-up (anti-HBs <10 mIU/ml) to evaluate the immune memory. A total of 93 blood samples, including 50 of two-dose group and 43 of three-dose group respectively, were drawn at 14 days after the challenge dose and anti-HBs was quantitatively detected. The anti-HBs geometric mean concentrations (GMCs) after the challenge dose were compared between the two groups. Multivariate linear regression model was built to find the independent risk factors associated with immune memory response (anti-HBs GMC after the challenge dose). Results: The challenge dose of HepB and post-challenge anti-HBs detection were completed among 93 participants. Totally 92 (98.92%, 92/93) participants were found holding immune memory (anti-HBs after the challenge dose was ≥10 mIU/ml). The immune memory positive rates were 100% (50/50) and 97.67% (42/43) in the two-dose group and three-dose group respectively and the corresponding anti-HBs GMC after challenge dose were 2 684.30 (95 %CI : 1 721.71-4 185.08) mIU/ml and 3 527.48 (95 %CI : 2 145.15-5 800.58) mIU/ml ( P= 0.410). The anti-HBs GMC after the challenge dose were 1 908.33 (95 %CI : 1 190.01-3 060.27) mIU/ml, 4 004.20 (95 %CI : 2 257.90-7 101.12) mIU/ml and 8 682.16 (95 %CI : 5 813.94-12 965.36) mIU/ml among the participants whose anti-HBs titer was<4, 4-6 and 7-9 mIU/ml at follow-up, respectively ( P= 0.002). There was no correlation between immune schedule and anti-HBs GMC after the challenge dose; β (95 %CI ) was -0.07 (-0.34-0.20), P= 0.601. Conclusion: The immune memory after primary hepatitis B vaccination lasted for at least 12 years among adults. The immune memory response was independently associated with ant-HBs titer at follow-up, but might be similar between 0-6 month schedule and 0-1-6 month schedule.

Objectives: The hepatitis A vaccine (HepA) has been included in the national expanded program on immunization (EPI) in China since 2008. This study was performed to evaluate the change in dynamics of the seroepidemiology of hepatitis A virus (HAV) before and after the introduction of the program., Methods: The trends in seroepidemiology of anti-HAV antibodies were examined in Shandong Province, China, drawing on two population-based samples of persons aged 1-59 years, one obtained in the year 2006 (n = 6682) and the other in 2014 (n = 5095)., Results: A dramatic increase in seroprevalence of anti-HAV antibodies from 30.76% (95% confidence interval (CI) 26.24-35.28%) to 77.46% (95% CI 74.04-80.87%) among children aged 1.5-7 years (born after HepA was recommended for routine childhood immunization), as well as an increase from 35.32% (95% CI 29.31-41.33%) to 66.69% (95% CI 55.59-77.80%) in subjects aged 8-14 years, was observed in 2014 when compared with 2006. By contrast, a decline in seroprevalence among subjects aged 15-29 years, as seen particularly in those 20-29 years of age, from 85.72% (95% CI 80.29-91.14%) to 69.24% (95% CI 62.02-76.45%), was found in this study. There was no statistically significant difference in seroprevalence between 2006 and 2014 among the subjects older than 30 years of age., Conclusions: The national HepA routine immunization program has had a positive effect, leading to an increase in anti-HAV seroprevalence among children in Shandong Province, China. More attention should be paid to young adults in the province., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Organoboron compounds are highly valuable in synthetic chemistry. In particular, α-borylcarbonyl compounds have shown versatile synthetic applications, owing to fruitful chemistries of both the boryl and carbonyl moieties. However, the synthesis of these molecules still remains tedious and time-consuming. Here we report a straightforward and practical route to synthesize α-borylcarbonyl molecules based on a regioselective radical α-borylation of α,β-unsaturated carbonyl compounds. The reaction features unusual α-regioselectivity and high functional-group compatibility. Further synthetic applications of new α-borylated products were also demonstrated. DFT and kinetic studies implicated that the α-regioselectivity of β-aryl-α,β-unsaturated carbonyl compounds was determined by the thermodynamically more favorable radical α-addition step, whereas the formation of α-addition products from β-alkyl-α,β-unsaturated carbonyl compounds was driven by an energetically favored hydrogen atom transfer step. Given that α,β-unsaturated carbonyl compounds can be easily obtained in abundance and variety, this method enjoys great advantages in diverse and economical synthesis of valuable α-borylcarbonyl molecules.

Based on the data from Shandong Province death registration system in 2015, the mortality rate was adjusted by the results of underreporting rate investigation, and the probability of premature death of non-communicable diseases was calculated by life table method. A total of 728 287 deaths caused by four main non-communicable diseases (NCDs) including cardiovascular and cerebrovascular diseases, malignant tumor, diabetes, and chronic respiratory disease, accounting for 85.83% of the total death in 2015. The death of cardiovascular and cerebrovascular diseases and malignant tumor accounted for 50.90% and 25.69% respectively. The probability of premature death was 17.84%. The probability in males was higher than that in females (23.12% vs 12.25%). The highest probability of premature death in urban was cancer, but in rural was cardiovascular and cerebrovascular diseases. The probability increased from the East areas to the West. The highest probability reached at 21.50% in the Western underdeveloped areas, and the lowest probability was in Dongying City (14.84%) and Weihai City (14.94%) in the coastal areas.

Objective: To characterize the etiology and epidemiological characteristics of the acute meningitis and encephalitis syndrome (AMES) in Jinan city in 2013-2016. Methods: The epidemiological data, clinical diagnosis, serum and cerebrospinal fluid (CSF) specimens were collected from 3 577 AMES cases in 6 sentinel hospitals in Jinan city in 2013-2016. Samples of all cases were made sero-diagnosis for Immunoglobulin (Ig) M antibody to Japanese encephalitis virus (JEV) and negative cases of JEV for enterovirus (EV), mumps virus (MuV) and herpes simplex virus (HSV) by enzyme-linked immunosorbent assay (ELISA). Virus isolation and molecular identification were performed. Positive rates were analyzed by Chi-square test. Results: In 2013-2016, the positive rates of JEV, EV, MuV and HSV were 9.0% (322/3 577 cases), 22.1% (643/2 916 cases), 9.9% (289/2 916 cases), 26.9% (783/2 916), respectively. Of these, the positive rates of JEV were 32.9% (261/794), 1.2% (14/1 175), 1.0% (8/807) and 4.9% (39/801 cases); EV: 19.5% (91/466), 35.1% (342/974 cases), 15.5% (115/743) and 13.0% (95/733); MuV: 9.2% (43/466), 14.4% (140/974), 9.0% (67/743) and 5.3% (39/733). HSV: 35.4% (165/466), 38.5% (375/974), 25.7% (191/743) and 7.1% (52/733). There were significant differences in positive rates of 4 kinds of viruses in 2013-2016 ( P <0.001). A total of 81 EV strains belonging to 8 serotypes were isolated from 1 020 CSF specimens. The positive rates were 4.8% (6 cases), 13.1% (55 cases), 4.1% (7 cases) and 4.2% (13 cases) from 2013 to 2016. Coxsackievirus (CV) B5, echovirus (E) 6 and E30 accounted for 46% (37 isolates), 22% (18 isolates) and 21% (17 isolates) of all strains. Conclusion: The AMES cases in Jinan city in 2013-2016 were mainly caused by HSV, EV, MuV, JEV. CVB5, E6 and E30 were the dominant serotypes of EV associated with AMES cases in Jinan city.

Objective: To analyze epidemiological characteristics of acute bacterial meningitis (ABM) cases and the common pathogens infected in Jinan, Shandong Province. Methods: Epidemiological and clinical informations and cerebrospinal fluid (CSF) and blood specimens of acute meningitis/encephalitis syndrome (AMES) cases (total 3 918 cases) were collected in the six sentinel hospitals from 2013 to 2016. neisseria meningitidis (Nm) , streptococcus pneumoniae (Sp) and haemophilus influenza (Hi) were detected by the methods of real-time fluorescent quantitative polymerase chain reaction (Real-time PCR), bacterial culture and latex agglutination. χ(2) test was used to compare ABM cases with different feasures, and compare the difference of Nm, Sp and Hi cases in clinical and epidemiological characteristics. Results: A total of 479 cases were diagnosed as ABM from 2013 to 2016, 82 cases of which were laboratory confirmed, including 54 cases infected with Nm , 25 cases infected with Sp , and 3 cases infected with Hi . The disease course in different age groups of ABM cases has statistically difference (χ(2)=40.95, P< 0.001). The disease course of under 6 (63.6%, 161/253) and 7 to 17 (55.9%, 33/59) years old ABM cases mainly required 14-28 days, and over 18 years old cases mainly required less than 14 days (59.9%, 100/167). For Nm cases, there was a main onset period from October to March (75.9%, 41/54); on the disease course, under 6 (81.0%, 17/21) and 7 to 17 (16/18) years old cases mainly required less than 14 days, while over 18 years old cases mainly required 14-28 days (8/15), and there was a statistically difference in different age groups (χ(2)=8.44, P= 0.015). For Sp cases, the major onset period was from December to May (84.0%, 21/25); on the disease course, all of under 6 and 7 to 17 years old cases were required 14-28 days, while over 18 years old cases mainly required less than 14 days (9/17), and there was a statistically difference in different age groups (χ(2)=6.62, P= 0.037). 91.0% of the ABM cases (436/479) were healed or improvement, with the relatively higher ratio in under 6 (94.9%, 240/253) and 7 to 17 (98.3%, 58/59) years old groups, and poorer ratio in over 18 years old group (82.6%, 138/167), and the difference was significant in different age groups (χ(2)=22.77, P< 0.001). For Nm, Sp and Hi cases, the ratio of cases that were healed or improvement were 87.0% (47/54), 92.0% (23/25) and 3/3, respectively, and there were no death cases. Conclusion: ABM cases were found mostly in under 18 years old group in Jinan, Shandong Province, and the bigger age group had poor prognosis. Nm was the major pathogen causing ABM, followed by Sp and Hi . Distinguished differences of epidemiological characteristics were found on ABM cases suffered with different pathogens infected.