This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment . A dysmature EEG background was also associated with lower cognitive , language , and motor  developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial  was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients  at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1,  TSC1 or TSC2, encoding the proteins hamartin and tuberin. Both proteins are key components of a TSC protein complex that regulates the state of activation of the Ras homolog enriched in brain GTPase and hence the mammalian target of rapamycin complex 1 (mTORC1) (Tuberous sclerosis complex (TSC) is an autosomal dominant disorder affecting ~1 in 5,800 individuals ((mTORC1) . OveractTSC2 mutation, young age at seizure onset, a high seizure burden, epileptic spasms, and drug-resistant epilepsy  are common. Epilepsy affects 80–90%, 6% of TSC infants develop seizures during the first month of life, and 60–70% develop epilepsy within the first year of life –7. Aboutepilepsy –16. SimiRecent studies have shown that early interventions can improve seizure control and can preserve neurodevelopment to some extent , 17. A sPrenatal or early postnatal diagnosis of TSC is currently possible, due to the visualisation of cardiac TSC related-lesions or cortical tubers . Since eIn this exploratory EEG study we investigated whether the first EEG, recorded in infants with TSC, and taken below the age of 4 months could be used to predict neurodevelopment and especially ASD risk at the age of 24 months. Our hypothesis was that early EEG characteristics, such as IED and background abnormalities can predict neurodevelopmental outcome. In addition to the visual analysis of the EEG, we used quantitative EEG methodology for assessment and quantification of EEG background abnormalities.This EEG study was part of the EPISTOP project. The EPISTOP project was a multicentre long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in TSC (NCT02098759). As part of this biomarker study, serial EEGs were collected during this project. A second aim of the EPISTOP study was to investigate the potential benefit of preventive treatment with vigabatrin after the appearance of IED on the EEG  and before seizure onset vs. conventional follow-up and treatment only after the onset of clinical or electrographic seizures.Patients were enrolled from November 2013 to August 2016 at 10 sites. Male or female infants of age ≤4 months with a definite diagnosis of TSC , but witTM software version 3·5 . For this EEG study, the first EEG after enrolment was analysed. All EEGs were analysed separately by three experienced clinical EEG readers. When there was disconcordance, consensus was reached after discussion between the three readers.The EEG was recorded for at least 1 h, including wake and sleep at least until stage two. The EEG was performed using a minimum of 19 electrodes according to the 10–20 system. A reduced array with nine electrodes was allowed in infants under 3 months of corrected age . The video-EEGs were anonymized, coded and uploaded to a secure central server at the University of Leuven in Belgium. EEG assessment was performed blinded to TSC gene mutation, clinical (with exception of the age of the patient) and outcome data and was done using BrainRTFor each EEG the presence or absence of IED and electrographic seizures was assessed. An electrographic seizure was defined as an ictal EEG pattern, without clinical correlate and with a duration of at least 10 s . BackgroThese dysmaturity features can also be analysed by a variety of quantitative approaches , 29–31. 1, δ2, θ, α β) to assess the persistence of slow waves.The power in the common EEG frequency bands (δQuantitative EEG features derived from the range EEG (rEEG) [an estimation of amplitude-integrated EEG (aEEG)]. Specifically, the difference in distance from the rEEG median from the upper or the lower margin, known as rEEG asymmetry, was used to measure the discontinuity of the signal.With maturation, the EEG background evolves from a discontinuous to a more continuous pattern, showing less regularity and more complexity. This complexity of the EEG signal was measured by means of entropy: the higher the complexity, the higher the entropy .The regularity of the EEG signal was assessed by means of the Hurst Exponent: the higher the regularity, the higher the Hurst exponent .Neurodevelopmental outcomes were studied at the age of 24 months. ASD risk was based on the Autism Diagnostic Observation Scale 2 (ADOS-2) score (Toddler Module), which is the gold standard for assessing and diagnosing ASD. If the ADOS-2 test could not be performed due to the child being non-verbal, having a non-verbal age equivalent below 12 months, or was not able to walk independently, Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) clinical criteria were applied. Non-verbal children with a total score of 0–9, 10–13, and >13 were classified as “no risk,” “mild/moderate risk,” and “high risk,” respectively. For verbal children the cut-off scores for the three risk categories were 0–7, 8–11, and >11. Cognitive, language and motor developmental quotients (DQ) were based on the Bayley Scales of Infant and Toddler Development III (BSID-III) results at the age of 24 months. Tests were performed by neuropsychologists certified through formal reliability training at each centre and sent to a central research team in Rome for analysis and classification.U-test, because of deviation from the normal distribution demonstrated by Q-Q plots and Kolmogorov-Smirnov test. Both univariable and multivariable linear models were used to assess the relation between EEG characteristics and the DQs on the cognitive, language and motor test of the BSID-III at 24 months. Since the DQs on the cognitive and language test were not normally distributed, the DQs were logarithmic and reciprocal transformed, respectively. Associations between discrete variables and ASD risk were analysed using univariable, and multivariable logistic regression analyses. The selection of non-EEG variables in multivariable models was based on literature search on predicting variables of neurodevelopmental outcome in infants with TSC and based on our univariable models including non-EEG variables .Continuous non-EEG characteristics between groups were assessed by Mann-Whitney ariables , 2, 4  using three-fold testing, which means that two thirds of patients were used to develop the model and one third to test its performance. The results were reported in terms of misclassification error [percentage of misdiagnosis E(%)] and area under the receiver operating curve (AUC).For this EEG study, 64 first EEGs of EPISTOP patients were available for in dept analysis . The medp-value = 0.027). The odds ratio (OR) was 4.1 (95% CI = [1.2 – 14.4]). In a multivariable logistic regression analysis including the treatment strategy  and the pathogenic TSC variant (TSC1 or TSC2) as covariables, an abnormal first EEG remained significantly associated with a higher probability of ASD at the age of 24 months )] ] ] (Nineteen infants (30%) were diagnosed with ASD traits at the age of 24 months . When we 15.5])] . The pos 16.1])] . In mult 52.9])] . The PPV 52.9])] .The quantitative analysis of EEG background confirmed the association of an early abnormal/dysmature EEG, and ASD traits at the age of 24 months. A dysmature EEG is characterised by less complexity, with less entropy and higher regularity. The boxplots in p-value = 0.029], language [median 59 (IQR [53 − 71]) vs. 71 (IQR [62 − 81.75]), p-value = 0.006], and motor (median 70 (IQR [55 − 79]) vs. 76 (IQR [67.50 − 89]), p-value = 0.042] DQs at 24 months compared to those with a normal EEG background. The cognitive [median 62·50 (IQR [55 − 80]) vs. 75  vs. 68 (IQR [62 − 79]), p-value = 0.001], and motor [median 67 (IQR [48.25 − 74.50]) vs. 76 (IQR [67 − 87]), p-value = 0.017] DQs were significantly different between the children with a dysmature and those with a mature EEG background at 24 months of age (TSC1 or TSC2) and the treatment strategy, the results were no longer significant. In these multivariable linear models, a TSC2 mutation was significantly associated with a lower cognitive and motor DQs at 24 months , 68 (IQR [59 − 77]), and 73 (IQR [67 − 85]), respectively . Childres of age . Using a4 months , 5, 6. O5 − 90.754 months , 4.The main finding of our study is that an abnormal first EEG in neonates and infants with TSC, and more specifically a dysmature EEG background was associated with a higher probability of ASD traits at the age of 24 months. The sensitivity of this finding was low (42%), but the specificity was high (86%). Hence, an infant with TSC and an EEG in the first weeks of life showing a mature background was less frequently diagnosed with ASD symptoms at 24 months. A dysmature EEG background was also associated with lower DQs on cognitive, language, and motor BSID-III test results. It is important to stress that the predictive value was not influenced by mutation status, or by preventive or standard anti-epileptic treatment during follow up. We were also able to confirm our qualitative findings with a more quantitative approach, which ultimately might become a more reliable biomarker of EEG background development and abnormalities. Our findings are of major clinical importance as an early abnormal EEG might trigger early diagnosis and management of ASD in TSC children.A, and AMPA receptor functions, which contributes to increased seizure susceptibility, epileptic synchronisation, altered synaptogenesis, and altered connectivity. The subsequent malformations of cortical development provide a neuroanatomical and functional substrate for the early appearance of seizures, and developmental, and psychiatric disorders seen in association with TSC  compared to our patients (average age of 1 month at enrolment) and did not assess the strength of association between EEG features and neurodevelopmental outcome . Wu et aRecent studies using quantitative EEG analysis also facilitate a better understanding of the neurobiological mechanisms of the altered brain maturation in patients with TSC and can help with the identification of infants requiring developmental interventions. Peters et al. found, using graph theory, in older children, adolescents and adults with ASD, with and without TSC, a decreased long- over short-range connectivity with local over-connection and decreased functional specialisation . DickinsBesides clinical and quantitative EEG features, other characteristics, such as the pathogenic TSC variant, the epilepsy course (including the development of refractory epilepsy or epileptic spasms), MRI features and early development, can help to identify young infants with TSC at risk of developmental comorbidities , 42–47.One of the limitations of our study is that no measure of parental education or parental intelligence was included to predict developmental outcome. Second, the diagnostic power of the neurodevelopmental assessments at 24 months of age is perhaps not optimal, particularly in terms of the stability of diagnostic classification. It is theoretically possible that children who were classified with no ASD risk at 24 months of age are still diagnosed with ASD later in life. A follow-up study of EPISTOP patients with neurodevelopmental assessments at the age of 6 years is planned. Third, our cohort was relatively small, consequently including interaction terms in the multivariable models was not possible. Finally, the validity of the reported models for quantitative EEG analysis should be further tested on an independent new dataset.To conclude, in a prospectively studied cohort of neonates and young infants with TSC, an abnormal early EEG, and more specifically a dysmature EEG background was associated with a higher probability of ASD traits at the age of 24 months. A dysmature EEG background was also associated with lower DQs on cognitive, language, and motor BSID-III test results. Our findings suggest that detection of early EEG abnormalities in TSC infants can assist in the prediction of neurodevelopmental outcomes, facilitating early diagnosis and intervention.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 Ethische Commissie UZ/KU Leuven. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.JD and LL contributed to study design. JV, KK, RM, PC, BW, KR, MF, PK, RN, AJ, KW, DD-P, MK-F, CH, CF, SS, BB, EA, DK, FJ, and SJ contributed to data collection. JD, ML, BV, JV, KL, SV, and LL contributed to data analysis. JD, ML, SV, and LL contributed to data interpretation and contributed to writing. JD contributed to literature search. All authors contributed to read and approved the submitted version.KW was employed by company Transition Technologies. The remaining 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.


This meta-analysis was performed to incorporate newly published, high-quality randomized controlled trials (RCTs) to determine the effects of cemented versus uncemented hemiarthroplasty for elderly patients with displaced fracture of the femoral neck.2 statistic was used to quantify heterogeneity.The following electronic databases were extensively searched from the inception of the database through December 2018: EMBASE, Medline, the Cochrane Library, and Web of Science. RCTs focusing on the outcomes of cemented and uncemented hemiarthroplasty were reviewed and screened for eligibility. We used the Cochrane Collaboration's Review Manager Software to perform meta-analyses. Two independent reviewers extracted the data and assessed the study quality and bias risk through the Cochrane Collaboration tool. Use fixed effect model or random effect model to pooled data. Cochran's Q statistic was used to evaluate heterogeneity, and IP < .00001), less pain , lower mortality 1-year  and fewer implant-related complications  than Uncemented hemiarthroplasty. However, there are still some limitations in our study, such as the uniformity of the surgery administration programme and rehabilitation scheme, and the small sample size of the included studies.Fifteen RCTs were enrolled (n = 3790)  . The meta-analysis showed that cemented hemiarthroplasty has a longer operating time  4.83–11.23; Cemented hemiarthroplasty for elderly patients with displaced fracture of femoral neck may acquire better functional results. Hemiarthroplasty is the most common treatment for displaced fractures of the femoral neck in the elderly individuals and is associated with better functional outcome and fewer reoperations than internal fixation. There are 2 different methods for hemiarthroplasty: fixation with bone cement or press-fit without cement.Femoral neck fracture is a common and costly health problem worldwide. With increases in the ageing population and average life expectancy, the frequency of these fractures is steadily increasing.–7 have suggested that cemented hemiarthroplasty can be achieved with less pain by providing an immediate strong interlock between the prosthesis and the periprosthetic bone tissue. Cement fixation can decrease postoperative complications related to late mobilization, such as pneumonia or urinary tract infection, compared with uncemented fixation. However, other studies favor uncemented prostheses as the operative time, blood loss and incidence of perioperative mortality are less. As there is still a dispute about which treatment is more suitable for elderly patients with displaced fracture of femoral neck, we need critical evidence to provide guidance for clinical treatment.Many studies, systematic reviews and meta-analysesUntil recently, few systematic reviews and meta-analyses comparing cemented hemiarthroplasty with uncemented hemiarthroplasty had been published. However, several new randomized controlled trials (RCTs) have been published in recent years. The purpose of this meta-analysis was to include newly published high-quality RCTs to compare the clinical outcome of cemented and uncemented hemiarthroplasty for the treatment for elderly patients with displaced fracture of femoral neck in order to provide the best clinical evidence to provide guidance for clinical treatment.22.1The following electronic databases were extensively searched independently by 2 investigators from the inception of the database through December 2018: EMBASE, Medline, the Cochrane Library, and Web of Science. The search strategy was created with the assistance of a librarian using a combination of terms including hemiarthroplasty, femoral neck fracture, hip, hip fracture, bone cement, bone cements, cemented, uncemented, cementless, RCT, prospective, meta, review, and random. We limited searches to RCTs, systematic reviews, and meta-analyses and imposed no language or other limitations. Manual searches of relevant trials, reviews, and related articles were also performed. When possible, authors were contacted to obtain missing information.2.2To be included in this analysis, trials had to fulfil the following inclusion criteria:(1)RCTs and(2)studies comparing the outcome of cemented and uncemented hemiarthroplasty; The exclusion criteria included the following:(3)patients with a previous fracture of the same hip or with a pathological fracture;(4)case reports, editorials, experimental studies, conference articles, non-English studies, and other studies that failed to report the outcome of interest;(5)repeated studies and data; and(6)Articles that did not report any treatment results in the cemented or uncemented groups; 2 authors independently assessed the articles for compliance with the inclusion criteria, and disagreement was followed by discussion until consensus was reached.2.3After removing duplicates, the titles and abstracts were scanned by 2 independent investigators according to predefined selection criteria and potentially relevant RCTs were selected. Hard copies of all relevant articles were retrieved and read in full for further identification. The relevant data were extracted by adapting a predetermined standardized procedure, which involved first authors, year of publication, country, participant demographic characteristics, and treatment regime for each group. Disagreements regarding studies to be included and data abstraction were resolved by consensus or discussion with a 3rd author.2.4The Cochrane collaboration's tool for assessing the risk of bias was used to evaluate the methodological quality of the included trials. This tool focuses on the internal validity of the trial and assesses the risk of possible bias in different phases of the trial. The items in the tool are as follows: random sequence generation, allocation concealment, blinding of outcome assessment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other bias. Each item was classified according to a high, low, or unclear risk of bias that is represented as high (H), low (L), and unclear (U), respectively. All of the assessments were conducted by 2 independent reviewers . Any controversies were settled by consensus or discussion with a 3rd author (WHB).2.5All data were extracted independently by 2 reviewers. The following data were extracted: mortality, blood loss, operation time, length of hospital stay, residual pain, reoperation rate, complications, and functional outcomes. When only the survival curve was available, mortality was estimated. A consensus method was used to resolve disagreements, and a 3rd reviewer was consulted when disagreements persisted. To understand the baseline of each included study, we extracted data from trials that included the following information: number of patients enrolled, characteristics of participants, male/female ratio, and follow-up time.2.62 distribution test and Higgins I2 index. They were synthesized results was done by pooling the data and using a fixed effects model meta-analysis. However, if the I2 indicated moderate or high heterogeneity , a random effect model was selected for analysis. As defined by Higgins et al, heterogeneity was tested by Cochran's Q. If essential, subgroup analysis was conducted to identify and explain the heterogeneity, stratifying the data according to different time periods. When only the median, the minimum, the maximum, or the 25th and 75th percentiles were available, the sample mean and standard deviation were estimatedThe Cochrane Collaboration Review Manager Software Package (Rev Man Version 5.3) was used to perform the meta-analyses. The overall effect size of each anesthetic was calculated as the weighted average of the inverse variance for the study-specific estimates. For dichotomous variables, odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated, and the weighted mean difference (WMD) was used to estimate numerical variables. Heterogeneity was evaluated with the χ2.7As all analyses were conducted with data from previously published studies, ethical approval was not necessary.33.1,11 We only used chose the most recent study. Consequently, 15 studies–25 were analyzed in the meta-analysis. All selected studies in our meta-analysis were published between 1977 and 2018 and included 2052 patients: 1015 in the uncemented hemiarthroplasty group and 1037 in the cemented hemiarthroplasty group. The average reported age of the patients ranged from 70 to 85.3 years. Every patient in the included study had a fracture of the femoral neck, and the included study compared the outcomes of cemented and uncemented hemiarthroplasty. More detailed characteristics of the eligible trials are shown in Table Figure 3.2,17–23,25 and 1 study randomized patients based on the patient's hospital number (odd or even), which has a high risk of bias. In total, there were 9 RCTs–21,23,25 with adequate concealment of allocation. The participants and personnel were blinded in 8 studies.–19,23,25 Outcome assessors were blinded in 3 studies,19,20 while 3 studies,16,21 did not have a blind evaluation of the outcomes. The other 9 studies described the blinding procedures unclearly. A more detailed description of the risk of bias and methodological quality of the eligible studies is illustrated in Figures Overall, the methodological quality of all eligible trials indicated a low risk of bias. Based on the Cochrane Collaboration's recommendations, detailed methods for the random sequence generation were reported in 10 RCTs,3.3,21,23,24 compared the length of hospital stay in this meta-analysis. However, there was no significant difference the between cement group and the non-cement group in these studies. . The forest plot is illustrated in Figure Eight studies3.4,15–21,23 reported the operation time. The random-effects meta-analysis of all 9 trials showed an increased time of surgery for cemented hemiarthroplasty in comparison with uncemented hemiarthroplasty, with a pooled WMD of 8.03 (95% CI 4.83–11.23). The results were statistically significant (P < .00001). Evidence showed that the heterogeneity was high  and the results are presented in Figure  was excluded and the results are presented in Figure P < .00001; fixed-effects model) with low heterogeneity .A total of 9 trials3.5–19,22,23 In total, 25 patients from the cemented group of 627 patients and 37 patients from the uncemented group of 585 patients underwent revision surgery. In 1 trial, no patients underwent revision surgery. The fixed-effects meta-analysis of the 7 trials showed that there was no significant difference in the reoperation rate between the cemented group and the uncemented group. The odds ratio of reoperation for any reason was 0.60 , and there was no heterogeneity . The forest plot is illustrated in Figure Seven studies included data on the reoperation rates reported in those studies.3.6,17,19,23 reported residual pain. Five studies–13,19,23 showed no significant difference between the cemented groups and uncemented groups. However, the random-effects meta-analysis of all 8 trials revealed that the cemented groups were associated with less pain  compared with the uncemented groups. . The results are presented in Figure Overall 8 studies3.7,18–20,23 All 6 studies reported intraoperative blood loss and 2 studies,20 reported postoperative blood loss. The random-effects meta-analysis showed no significant difference in intraoperative blood loss between the 2 groups, with a pooled WMD of 22.41 . The forest plot is presented in Figure 2 value was 80%. To compare the difference and evaluate the sensitivity of the meta-analyses, a sensitivity analysis was performed to evaluate the stability of the meta-analysis. When 2 studies,20 were excluded from the meta-analysis, the I2 dropped to 56% and the sensitivity analysis is consistent with our previous analysis . The sensitivity analysis are illustrated in Figure P = .99) and no heterogeneity . The forest plot is presented in Figure Data regarding blood loss were reported in 6 studies.3.8–21,23,25 reported mortality at different times. There were no significant differences in short term postoperative mortality between the 2 groups . Additionally, no significant differences were detected between the 2 groups for mortality at 2 years  or 4 years . However, fixed-effect meta-analysis of 8 trials showed that the mortality at 1 year in the cemented group was lower than that in the uncemented group. . Forest plots for mortality at different times are presented in Figure Twelve studies3.9,21,24 reported the HHS at different times, such as at 3 months, 6 months, 1 year or 5 years. The random-effect meta-analysis of 3 trials showed no significant difference in HHS at 3 months , 6 months , or 1 year . However, Langslet et al showed that the HHS at 5 years in the cemented group was lower than that in the uncemented group . Forest plots for HHS at different times are presented in Figure Three studies3.10P < .00001), with small heterogeneity . However, there was no significant difference between the cemented group and uncemented group in terms of cardiovascular complications , local complications  and general complications . The forest plot is presented in Figure Eleven studies reported complications. Our findings show that significantly fewer implant-related complications occurred in the cemented group than in the uncemented group . Finally, we compared the incidence of complications between the 2 groups. In total, 9 of the included studies reported implant-related complications and the pooled results showed that cemented hemiarthroplasty has a lower risk of implant-related complications compared with uncemented hemiarthroplasty with small heterogeneity. Jameson et al reported that the uncemented group had more intraoperative and postoperative prosthesis loosening, periprosthetic fractures, and dislocation. Previous studies,33–36 also concluded that cemented stems have fewer implant-related complications than cementless stems. Therefore, surgeons should pay attention to these possible implant-related complications before surgery. We also found no significant difference between the cemented group and the uncemented group in term of local complications and general complications. This suggests that cement has little, if not no, effect on local complications and general complications. It is worth considering that there is no difference in the rate of cardiovascular complications between the 2 groups. Some previous studies,37,38 reported that the cement prosthesis may increase the risk of hypoxemia and transient hypotension, cardiovascular accidents, and pulmonary embolism. Therefore, high-quality evidence and well-designed RCTs are still necessary.Our study showed that there were no significant differences in the length of hospital stay between the 2 groups, which was consistent with 2 previous meta-analyses.Compared with previous meta-analyses, there are some advantages to our study. First, we used an exhaustive search strategy and more strict inclusion criteria. A total of 15 newly published, high-quality RCTs were strictly included in this study to provide more effective evidence. Second, our study analyzed clinical outcomes including the length of hospital stay, operation time, reoperation rate, residual pain, blood loss, mortality, HHS, and complications. Mortality was further stratified into short-term postoperative mortality and mortality at 1 year, mortality at 2 years, and mortality at 4 years postoperatively. Complication were also divided into 4 subgroups: implant-related complications, cardiovascular complications, local complications, and general complication. It can reduce the potential bias risk from pooling all kinds of mortality and complications. Third, the HHS was used as to evaluate hip function to reduce the deviation of descriptive analysis.–41 The variety of methods used to assess the functional results in the included studies, made it difficult to carry out a quantitative synthesis of the functional results. Due to certain features of the surgery techniques, it is impossible to blind orthopedic surgeons. Consequently, caution should be taken when interpreting the estimates of this meta-analysis. Finally, our evidence showed considerable statistical heterogeneity for several outcomes across the trials; however, the regression analysis and sensitivity analysis suggested that the results were stable.However, our research still has some limitations. The limitations of this meta-analysis involve the restrictions on the publication language, the uniformity of the surgery administration programme and rehabilitation scheme, and the small sample size of the included studies. The distorting effects of location bias and publication bias on systematic reviews and meta-analyses are well documented.5Cemented hemiarthroplasty for elderly patients with displaced fracture of femoral neck may acquire better functional results.Data curation: Binfeng Liu, Ang Li.Formal analysis: Jialin Wang, Hongbo Wang, Xiaoyu Lian.Investigation: Gongwei Zhai, Haohao Ma, Bo Zhang.Methodology: Binfeng Liu, Ang Li.Project administration: Jialin Wang.Resources: Yanzheng Gao, Liyun Liu.Software: Liyun Liu.Validation: Binfeng Liu.Writing – original draft: Binfeng Liu.Writing – review & editing: Yanzheng Gao.


Siniperca chuatsi, the growth-related genes and underlying relevant mechanisms are poorly understood, especially for difference of body sizes and compensatory growth performance. Muscle from 3-month old individuals of different sizes was used for transcriptome analysis. Results showed that 8,942 different expression genes (DEGs) were identified after calculating the RPKM. The DEGs involved in GH-IGF pathways, protein synthesis, ribosome synthesis and energy metabolisms, which were expressed significantly higher in small individuals (S) than large fish (L). In repletion feeding and compensatory growth experiments, eight more significant DEGs were used for further research . When food was plentiful, eight genes participated in and promoted growth and muscle synthesis, respectively. Starvation can be shown to inhibit the expression of Mhc, Mlc and troponin, and high expression of GHR2, IGFR1, and 4ebp inhibited growth. Fasting promoted the metabolic actions of GHR2, IGFR1, and 4ebp rather than the growth-promoting actions. MyoD can sense and regulate the hunger, which also worked with Mhc and Mlc to accelerate the compensatory growth of S. chuatsi. This study is helpful to understand the regulation mechanisms of muscle growth-related genes. The elected genes will contribute to the selective breeding in future as candidate genes.How organisms display many different biochemical, physiological processes through genes expression and regulatory mechanisms affecting muscle growth is a central issue in growth and development. In  Muscle growth is regulated by the gene expression nets of muscle cell proliferation and protein metabolism . In vertBody size is an obvious and vital characteristic of fish, which is controlled by cell number and cell size , and thiTranscriptome and RNA-sequencing (RNA-seq) have been applied to a substantial amount of fish biology studies, including zebrafish , channelSiniperca chuatsi is an important commercial fresh water fish in China. At present, the research on S. chuatsi mainly focuses on aquaculture, disease and immunity, nevertheless the growth-related genes and mechanisms are not well-understood   .All of the above experimental fish were anesthetized with tricaine methanesulfonate  and sacrificed via decapitation for subsequent sampling, and white muscle was removed immediately. The tissues were frozen in liquid nitrogen quickly, and stored at −80°C until use. Furthermore, each experiment was performed with three independent biological replicates.TM 2000.For RNA-seq, total RNA was extracted from white muscle in Family A with E.Z.N.A. total RNA kit II and detected with the concentration and quality. To acquire the entire transcriptome information, and to find out the growth-related DEGs, the muscle samples of family A were mixed with equal amount and then were divided into two RNA pools. PolyA mRNA was isolated by Beads with Oligo (dT) after total RNA was collected and interrupted to short fragments. Random hexamer-primer was used to synthesize the first-strand cDNA using the Qiaquick PCR Purification Kit (Qiagen). The second-strand cDNA was synthesized using buffer, dNTPs, RNaseH and DNA polymerase I, respectively (Invitrogen). Subsequently, short fragments were purified, enriched for end reparation and adding polyA, connected with sequencing adapters. After that, the suitable fragments were selected using agarose gel electrophoresis for the PCR amplification as templates. At last, the two cDNA library could be sequenced in BGI-Shenzhen using Illumina HiSeqClean reads were screened from raw reads gained from sequencing machines by removing adaptors, unknown nucleotides larger than 5% and low quality reads  which would negatively affect following bioinformatics analysis. Firstly, program-Trinity combines reads with certain length of overlap to form longer fragments without N, which are called contigs. Then, these contigs were taken into further process of sequence cluster with sequence clustering software to form longer sequences without N, which are defined as unigenes.The unigenes sequences were firstly aligned with a series of public databases, such as the non-redundant protein database, the Cluster of Orthologous Groups (COG) of protein database, the Kyoto Encyclopedia of Genes and GenBank non-redundant (NR) database and Swiss-Prot database, using BLASTx  and BLAST , respectively. According to the Nr annotation information, the obtained unigene was enriched with Gene Ontology (GO) by Blast2GO program. And then unigenes were classified into different GO functional cluster using WEGO software. GO has three ontologies: molecular function, cellular component and biological process. The basic unit of GO is GO-term, and every GO-term belongs to a type of ontology.P-value which corresponds to differential gene expression test in multiple tests. FDR ≤ 0.001 and the absolute value of log2Ratio ≥ 1 is used as the threshold to judge the significance of gene expression difference.The genes expression was calculated by the numbers of reads that mapped to the reference sequence and every gene. All genes expression levels were calculated by using the formula RPKM method and the RPKM of genes can be used for comparing between different samples. Different expression genes were carried out GO function analysis to understand its function. False discovery rate (FDR) was used to determine the threshold of ®RT reagent Kit with gDNA Eraser . The specific primers for the RT-PCR were designed based on selected growth-related genes using the Primer Premier5.0. Corresponding primers were designed to vertify the results , and the kits were SYBR® Premix Ex TaqTM II (Tli RNaseH Plus) , with 384-well plates. In each reaction system, there were 10 ul including the first-strand cDNA, 250 nM primers, and 5 μl SYBR Green PCR Master Mix . Each reaction was repeated three times. And the relative expression levels were calculated by the 2–ΔCt method.cDNA was synthesized from muscle in B and C families with PrimeScript results . 6 DEGs S. chuatsi in a pond were randomly selected from each group and sampled following anesthesia with MS-222 (100 mg/L). Sampling time points 0, 1, 2, and 3 represented S. chuatsi that had been fasted for 0, 1, 2, and 3 weeks, respectively. Sampling time points 4, 5, and 6 represented the fish that were re-fed continuously for 1, 2, and 3 weeks after starvation, respectively. The fish were fed twice a day and weighed every week, and weights were used to calculated The Specific growth rate (SGR). SGR means ((In W 2 -W 1)/(T 2 -T 1) × 100), where W 2 is the weight at the end of the growth interval and W 1 is the weight at the beginning of the growth interval, while T 2 -T 1 represents the duration (days) of the growing interval. The white muscle samples collected from S. chuatsi was rapidly frozen in liquid nitrogen and stored at −80°C and samples were used for real-time PCR analysis.Since transcriptome results represented gene expression at a certain time, change of gene expression over time cannot be known. So we researched the change of gene expression and its mechanism in compensatory growth experiments. A total of 80 experimental fish from one family  were randomly divided into control and experimental groups that each included four repeated subgroups, and they were provided live fish as bait. Each subgroup contained 20 in a separate tank. The water temperature was maintained at 25–26°C, and the compensatory growth experiment lasted for 6 weeks. During an initial 3 weeks of fasting, food was withheld from the experimental group, while that of the control group was maintained at a normal level. After this, both the experimental group and the control group were fed continuously during the following 3 weeks. Seven sampling time points (0–6) were set throughout the experiment. At each sampling time point, six P < 0.05).SPSS version 18.0 was used for the analyses in the study, Tukey’s test was applied to compare the significant differences of the expression of the growth-related genes. The level of significance for all statistical tests was set at 5% , ubiquitin mediated proteolysis  and RNA transport , respectively . The resThe muscle growth-related genes screened in RNA-Seq were studied in different family and period to identify the expression and regulatory mechanisms. In two periods of two families, the expression of MyoD in L was just above S, but Myf6 was just the opposite. For the expression of IGFR1 and 4ebp in S fish was higher. Along with the increased growth time (5-month old), the expression of Mhc and Mlc in S was significantly higher than that in L (P < 0.01) that in the control group. The elevated SGR that characterizes compensatory growth subsequently declined back to low level during the 2 weeks of realimentation, but the SGR of experimental groups was higher than (P > 0.05) that in the control group , suggesting IGFR1 played a more essential role for S over L in muscle, such as participating in and promoting the growth of muscle. Interestingly, prolonged fasting results in significantly reduced IGF-1 mRNA in the liver and muscle of numerous fish species  is controlled by the metabolic pathway regulated by IGFR1, and PKB can mediate the AKT/mTOR/p70S6K pathway to facilitate protein synthesis and cell growth . MeanwhiP < 0.05), and transcriptome results also showed that the growth rate of small fish was high, suggesting that Mhc can promote the growth of S through its high expression. In larval stage of S. chuatsi, the high expression of Mlc regulates muscle formation and early development , GHR2, IGRF1 and 4ebp were different. GHR2 was expressed stably to promote growth  of GHR2, IGFR1, and 4ebp rather than the growth-promoting actions. MyoD can sense and regulate the hunger, which also worked with Mhc and Mlc to accelerate the compensatory growth of https://doi.org/10.5061/dryad.wh70rxwjx.The original contributions presented in the study are publicly available. This data can be found in the DRYAD database: The animal study was reviewed and approved by Institutional Animal Care and Ethics Committee of Sun Yat-sen University.GL conceived the study. GL and XL designed the experiments and drafted the work or revised it critically for important content. XL, SZ, HL, and SB collected the samples. XL did the experiments. XL, SZ, and DG prepared the figures and tables. YZ, GW, XC, XZ, SL, YS, and HY made other contributions. The manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. All authors contributed to the article 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.


Various biomaterials are currently used for bone regeneration, with autogenous bone being considered the gold standard material because of its osteogenic, osteoconductive, and osteoinductive properties. In recent years, the use of autogenous dentin as a graft material has been described. This split-mouth clinical trial assesses the efficacy of autogenous dentin for the regeneration of periodontal defects caused by bone loss associated with impacted lower third molar extraction. Fifteen patients underwent bilateral extraction surgery (30 third molars) using dentin as a graft material on the test side, and leaving the control side to heal spontaneously, comparing the evolution of the defects by evaluating probing depth at three and six months post-operatively. Bone density and alveolar bone crest maintenance were also evaluated six months after surgery, and pain, inflammation, mouth opening capacity on the second and seventh days after surgery. Probing depth, radiographic bone density, and alveolar bone crest maintenance showed significant differences between the test and control sides. Autogenous dentin was found to be an effective biomaterial for bone regeneration after impacted lower third molar extraction. Impacted lower third molar (LTM) extraction surgery, whether prophylactic or therapeutic, is a very common procedure in the field of oral and maxillofacial surgery . The freNumerous authors ,6,7 suppDifferent biomaterials have been used to stimulate or improve bone gain at these post-extraction sites. Nevertheless, autogenous bone continues to be considered the material of choice for bone regeneration, as it is the only option that fulfills the criteria of osteogenesis, osteoconduction, and osteoinduction ,9. NeverIn recent years, dentin has been investigated as a possible biomaterial for bone regeneration. In 2010, Kim et al.  describeHuman dentin is composed of 70% organic content with four types of calcium phosphate , which provide dentin with its osteoconductive properties. The hydroxyapatite in dentin is in the form of calcium phosphate with low crystal content, which makes it easily degradable by osteoclast activity . It is cFollowing the study published by Kim et al. , other rIn 2015, a unique clinical case report described the use of autogenous dentin for alveolar preservation of an upper right third molar socket, observing bone formation in the grafted area in periapical radiographs and micro-computerized tomography over a one-year follow-up (micro-CT) [A systematic review by Gual-Vaqués et al.  highlighTherefore, the aim of this clinical trial was to use autogenous dentin to reduce the probing depth (PD) and improve clinical insertion levels in cases of impacted third molar extractions, comparing the clinical and radiographic results with the conventional surgical approach.This randomized, split-mouth clinical trial was conducted at the Oral Surgery Service of the Faculty of Dentistry at the Complutense University of Madrid (UCM). The study followed Declaration of Helsinki principals for research involving human subjects, and all patients provided their informed consent to take part. The study protocol was approved on 25 May 2018, by the Scientific Committee for Clinical Trials at the San Carlos Hospital, Madrid (Spain) (Reg. N° 18/203-E); patients were recruited over a period of 12 months after approval was granted.A total of 15 patients were selected who were attending the Oral Surgery Service at the UCM Faculty of Dentistry presenting indications for bilateral lower third molar extraction. The main researcher (L.S.L.) assessed the patients, who were provided with full information about the purpose of the trial, the procedures involved, and the possible risks and benefits associated with the treatment. Patients then signed an informed consent form before the start of the trial. A medical and dental history was created for each patient including a panoramic radiograph. In cases presenting a close relationship between LTM and inferior alveolar nerve (IAN), a cone beam computerized tomography scan (CBCT) was taken. Inclusion and exclusion criteria were as follows: Patients of either sex aged between 18 and 25 years.Indications for bilateral extraction of impacted LTMs.Presence of lower second molars.Patients in good health (ASA I or II).Patients able to understand and carry out instructions given by the researchers.Pregnant or lactating women.Patients in treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).Patients with periodontal diseases.The trial included 15 patients (N = 15), who were intervened bilaterally (30 impacted LTMs). On the test side after LTM extraction, dentin from the extracted LTM was used as a graft material. On the control side, the alveolus was left to heal in the conventional way by forming blood coagulate.In order to determine sample size, a pilot study was performed, based on the primary outcome parameter (probing depth). This study was carried out at the Oral Surgery Service of Complutense University of Madrid, enrolling 5 patients , with a split-mouth design, obtaining a mean reduction on probing depth of 2.4 ± 1.09 mm and 1 ± 0.66 mm, in test and control side, respectively. Using G Power 3.1 , considering an alpha-type error of 5% and a beta-type error of 5%, the estimation resulted in 10 patients per group. Patients’ number was ampliated to 15, to prevent possible dropouts of patients during the follow-up.A single clinician (L.S.-L.) performed all surgeries bilaterally. Randomization was performed by another researcher (J.M.M.-G.), using opaque envelopes whose content stipulated group assignation of the extraction sites (as test side or control side).As the test group required longer surgical time than the control group  the patients could not be blinded.®, Normon SL, Madrid, Spain).All interventions were performed by the same surgeon (L.S.-L.). Local anesthetic was administered consisting of 4% articaine and 1:100,000 adrenaline for the inferior alveolar, lingual, and buccal nerves  and compressed with gauze , while the clinician prepared the graft material. The extracted tooth, whether complete or split by odontosection, was cleaned with sterile gauze to remove traces of soft tissue and then dried with compressed air. Afterwards, the tooth was placed in a dentin grinding device  and ground for 3 s following the manufacturer’s instructions. When ground, it was sieved for 20 s to obtain a particle size of 300–1200 µm. The material obtained was mixed with 0.5 molar sodium hydroxide and 20% ethanol for 12 min in a sterile flask to eliminate any organic remains, bacteria, or toxins present in the dentin. Lastly, the particles were submerged in saline for 3 min, removing excess saline with a sterile pipette.On the test side, after inspecting and washing the socket, the site was compressed with gauze soaked in 0.12% chlorhexidine  was placed over the graft before suturing the wound with 4/0 silk   .After surgery, patients were prescribed an anti-inflammatory (25 mg Dexketoprofen every 8 h for 4 days) and a rescue analgesic (650 mg Paracetamol every 8 h) to be taken in case of pain. Antibiotics were just administered in cases of post-operative infection.The test side and control side were treated separately with an interval of 4 weeks between the two interventions.At the first visit, the main researcher (L.S.-L.) recorded the following variables: age; sex; medical and dental history; location and position of the LTMs; the close or otherwise relation with the inferior alveolar nerve observed in a panoramic radiograph .Pre-operative PD on the distal aspect of the lower second molar measured at three points: Disto-vestibular (DV), disto-medial (DM), and disto-lingual (DL) ; gingivaRadiographic exploration was performed with a panoramic radiograph, and just in cases showing a close relation between an LTM and the inferior alveolar nerve, a pre-operative CBCT was taken.Facial measurements were taken with silk thread measuring trago-pogonion distance, external labial commissure to the tragus, and from the gonion to the external canthus of the eye, following Amin and Laskins’ modified criteria for evaluating post-operative inflammation .®, Eibar, Spain), measuring a straight line from upper incisor edge to lower incisor edge to subsequently evaluate reductions in post-operative mouth open capacity.Mouth opening capacity was measured with an analogue caliper , and the surgical difficulty index according to the modified Parant scale .A periapical radiograph was taken to check adequate graft material placement in the socket , in compAll patients were examined by the same researcher who had performed surgery (L.S.L.). Pain level, inflammation, mouth opening capacity, probing depth, and bone density were recorded to evaluate differences in relation to the use or non-use of the graft material.Inflammation was evaluated by measuring facial patterns 48 h and 1 week after surgery. Mouth opening capacity was measured at the same times with an analogue caliper.Pain was evaluated using a visual analogue scale (VAS) scored as 1–10, 1 representing minimal pain and 10 maximum pain, every day for 7 days after extraction surgery. The number of rescue analgesics taken  during the 7 days after surgery was recorded.Probing depth was measured 3 and 6 months after surgery at the DV, DM and DL points on the distal aspect of the second molar as shown in Bone density, the degree of corticalization, and crestal bone height maintenance were measured 6 months after surgery on CBCT sagittal slices in all patients , using tBone density was measured in Hounsfield units (HU) .The degree of corticalization was classified as complete , incomplete, or absent .Distance from the IAN to the bone crest was measured at the distal aspect of the lower second molar, at the center of the third molar alveolus .Data were entered on a spreadsheet  at the end of the trial and analyzed with statistical software  by a statistician independent from the trial.This split-mouth trial compared the use or non-use of autogenous dentin grafts, whose effects were evaluated by evaluating probing depth, radiographic bone density, alveolar crest maintenance, and degree of corticalization. Pain, inflammation and mouth opening capacity were also compared.Descriptive statistics were calculated for all variables . Qualitative variables were analyzed with the chi-squared test. Quantitative variables  were analyzed with Student’s T-test and the Mann-Whitney test.p < 0.05).For all results, a 95% confidence interval was registered  and 11 (73.34%) women. The trial’s follow-up took place six months after LTM extraction; all patients completed the follow-up period.All the LTMs were extracted successfully. Autogenous dentin was placed in 15 alveoli as a graft material, while the other 15 alveoli healed spontaneously (blood coagulate). Information about LTM position and situation, intraoperative difficulty, and surgical time are shown in p = 0.038).Comparing reductions in PD between the test and control groups from the start of the trial to the end of the six-month follow-up, test group DV surfaces obtained a mean reduction of 1.53 mm compared with 0.27 mm in the control group  with stap < 0.001).On the DM surface, the test group underwent a reduction of 2.8 mm, compared with 0.07 mm in the control group  with stap = 0.109).The DL surface obtained a reduction of 2.33 mm in the test group compared with 1.4 mm in the control group  but withIn this way, the overall evolution of PD underwent a significant reduction in the test group compared with the control group. This reduction was mainly produced during the first three months after surgery, as shown in p < 0.001).Evaluated by CBCT scans taken six months after surgery, bone density (Hounsfield units: HU) was greater in the test group compared with the control group, as shown in In the test group, 20% of patients presented an absence of corticalization compared with 0% in the control group; 60% presented incomplete corticalization in the test group compared with 40% in the control group; and 20% presented complete corticalization in the test group compared to 60% in the control group. However, the Student’s t-test did not find statistically significant differences between the groups.p = 0.038). Therefore, the study group showed crestal bone height gain compared to crestal bone loss in the control group  compared with the control group (12.38 min). Nevertheless, no significant differences were found between the groups for the variables pain, inflammation, and mouth opening capacity.Pain, measured with a VAS, was similar in the test and control groups, with a mean of 5.33 in both groups at the time of surgery, falling to 4.33 vs. 4.27 on the third day after surgery, and 1.40 vs. 1.33 on the seventh day .As for the numbers of rescue analgesics taken, no significant differences were found between the test and control groups, with a mean number of 1.27 vs. 0.87 on the day of surgery, 1 vs. 0.73 on the third day, and 0.20 in both groups on the seventh day after surgery .Lastly, inflammation and mouth opening capacity were similar in both groups, with no significant difference between test and control groups. Almost-complete mouth opening capacity was achieved within one week of surgery, and complete capacity was restored within one month.Regarding intra-operative complications, one vestibular mucosal tear occurred during mucoperiosteal detachment in the control group.®, Laboratorios Kin, Barcelona, Spain), which closed the wound.As for post-operative complications, the same patient suffered a delayed abscess one month later, which was treated with antibiotics (Amoxicilin 750 mg three times a day for a week). A second patient in the control group presented a hematoma in the lower genian region during the post-operative period. A third patient suffered wound dehiscence two weeks after extraction, treated by applying 0.2% chlorhexidine gel  ,31 and oTo date, no other trial has been published that has used autogenous dentin as a graft material to resolve the periodontal defects on the distal aspect of the second molar derived from LTM extraction with post-operative clinical and CBCT monitoring. The present results displayed a significant reduction in probing depth on the test side with dentin graft compared with the control side without grafting during the first three months after surgery, a finding that agrees with a trial conducted by Inocencio-Faria et al.  in whichRegarding the preparation of autogenous dentin for grafting, the present trial used the LTM without removing the enamel, following other authors such as Kabir et al.  or Minet®) was placed over the autogenous dentin graft to prevent soft tissue invagination, following the method described by Ge et al. [In the present trial, a fibrin sponge (Gelatampe et al.  who compSome authors have reported a relation between surgical time and post-operative pain and inflammation . AlthougKabir et al.  employedDel Canto-Diáz et al.  publisheThe use of autogenous dentin was found to reduce PD and improve insertion levels in periodontal defects after LTM extraction in comparison with non-grafted control sites, showing similar behavior to the other biomaterials investigated to date. Moreover, the dentin grafts obtained higher HU values and bone crest height values in comparison with the control group, while no significant differences between the groups were found for the parameters pain, inflammation, mouth opening capacity or degree of corticalization.It would be useful to conduct additional studies that compare autologous dentin with other biomaterials to determine which exhibits the most favorable behavior in terms of PD in this type of defect.Bone regeneration techniques are recommendable in cases of impacted LTM extraction, because when pathological PDs are produced, manual or ultrasonic debridement is insufficient to restore parameters compatible with health.Autogenous dentin is a promising graft material for the regeneration of periodontal defects after impacted LTM extraction, as it reduced PD and improved clinical insertion levels in comparison with the conventional surgical approach.


Psoriasis is a chronic recurrent dermatological disease that patents always suffer from different comorbidities. Chinese herbal medicine (CHM) has been commonly used in the treatment of psoriasis for a long history. Previous systematic reviews (SRs)/meta-analyses (MAs) have shown that CHM may benefit patients with psoriasis. This overview aims to summarize the evidence from published SRs/MAs for clinical application and to provide several directions for future researches.Nine electronic databases  will be searched from their inceptions to September 2020 without language restrictions. At least 2 reviewers will independently conduct the study selection, data extraction, and quality assessment. The methodological quality, risk of bias, reporting quality, and evidence quality will be respectively evaluated by the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2), the Risk of Bias in Systematic Reviews, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.The results of this overview will be submitted to a peer-reviewed journal for publication.We expect to compile current evidence from published SRs/MAs of CHM for patients with psoriasis in an accessible and useful document.This study is a protocol for an overview of SRs/MAs that did not involve individual data. Thus, ethical approval is not required.DOI 10.17605/OSF.IO/VC654 Thus, they often report the poor quality of life.–4 In adults, the incidence of psoriasis ranged from 30.3 per 100,000 person-years in Taiwan to 321.0 per 100,000 person-years in Italy, and the prevalence varied from 0.14% in east Asia to 1.99% in Australasia, indicating that the incidence and prevalence of psoriasis have increased in recent years. Due to the heavy disease burden and high prevalence, psoriasis has become a major health problem, which means that more attention should be paid to the management of psoriasis.Psoriasis, a common chronic skin disease, is characterized by erythematous, pruritic plaques covered with silvery scales and is considered a multisystemic disease that patients often suffer from many different disorders, including hypertension, type 2 diabetes, coronary heart disease, and so on.,7 Because of the various side-effects and high costs, widespread treatment dissatisfaction was found in patients who used conventional systemic therapy or biologic for a long time. Thus, patients often select complementary therapy as an alternative option or as an add-on treatment.With a high rate of recurrence, the pathological mechanism of psoriasis is not yet clear but is thought to result from a confounding combination of genes and the environment. The 5 therapies were recommended by the international guidelines that consist of topical therapy, phototherapy, conventional systemic therapy, small molecule inhibitor, and biologic.–10 However, some systematic reviews (SRs)/meta-analyses (MAs) reported that the evidence supporting the effectiveness of CHM is insufficient.,12 Besides, no critically designed overview has been performed to assess the reporting and methodological quality of the published SRs/MAs so far. Therefore, this overview aims to evaluate the SRs/MAs of CHM for psoriasis and to summarize the evidence for clinical application. Moreover, we expect that our overview will provide several directions for future research.Chinese herbal medicine (CHM) is an important component of complementary therapies that have been applied to treat psoriasis for many years in China. Plenty of previous systematic reviews and meta-analyses had been conducted to evaluate the efficacy and safety of CHM, and they showed that both oral and external CHM may benefit the patients with psoriasis.22.1The protocol of this overview has been registered on OSF (registration number: DOI 10.17605/OSF.IO/VC654). This overview of systematic reviews will be reported according to the Preferred Reporting Items for Overviews of Systematic Reviews including the harms checklist (PRIO-harms).2.22.2.1The SRs/MAs of randomized controlled trials (RCTs) that evaluate the efficacy of CHM for the treatment of psoriasis will be included. Reviews with the most recent and comprehensive studies will be included if the same or similar original studies exist.2.2.2Participants should be diagnosed as psoriasis by any international or domestic diagnostic criteria. There will be no restrictions on gender, age, ethnicity, duration, and stage of the disease.2.2.3Reviews will include an experimental group that is treated with any internal or external therapies of CHM or CHM combined with other therapies, regardless of the dosage form . The control group treated with comfort therapy  or other therapies  will be included.2.2.4The primary outcome is the total effective rate measured by the psoriasis area and severity index (PASI) score decline rate. Secondary outcomes include the mean change of PASI, quality of life assessed by the dermatology life quality index or 36-item short form health survey (SF-36), the itching index assessed by itching evaluation scale, traditional Chinese medicine (TCM) syndrome score, adverse events, and the recurrent rate.2.3Duplicated publications, non-RCT SRs/MAs, network meta-analysis, conference abstracts, comments, overviews, protocols, SRs/MAs whose data cannot be extracted, and SRs/MAs whose objects are diagnosed as psoriasis with arthritis or other comorbidities  will be excluded. Studies on the nonmajor intervention of CHM  in the experiment group or studies on CHM as an intervention in the control group will be also excluded.2.4Five international electronic databases  and 4 Chinese electronic databases , China National Knowledge Infrastructure (CNKI), VIP Journals Database, Wanfang Databases) will be searched from their inceptions to September 2020 without language restrictions. The search terms will be used as follows: psoriasis, psoriases, traditional Chinese medicine, Chinese medicine, patent medicine, proprietary medicine, Chinese herbal drugs, Chinese material medica, Chinese herbal bath, systematic review, meta-analysis. The search strategy in Medline is listed in Table 2.5All the retrieved articles will be imported into the EndNote X9 software and the duplicate publications will be excluded. Two authors will independently scan the titles and abstracts of the searched articles for potentially relevant SRs/MAs. Full-text articles will be downloaded for further assessment according to the inclusion and exclusion criteria. Any disagreement will be resolved by discussion or consultation with the third author if a consensus is not reached. The flow diagram of the study selection process is presented in Figure 2.6Two authors will independently perform the data extraction following a predefined data collection form by using Excel 2017 and cross-checked each other's extracted data to avoid mis-entry. Discrepancies will be judged by the third author. The primary trials will be accessed if the information in SRs/MAs is unclear. The following data from the included SRs/MAs will be extracted: the first author, country, title, publication year, the number of included studies, sample size, diagnostic criteria, details of interventions in treatment and control groups, outcome measures, quality assessment methods, and main conclusions. The corresponding authors of the included SRs/MAs or original studies will be contacted to obtain missing data.2.7Two qualified authors who are trained in the Chinese Cochrane Center will independently conduct the quality assessment of included SRs/MAs and cross-check the results after evaluation. Any disagreement will be resolved by team discussion.2.7.1 a popular instrument for appraising SRs will be applied to assess the methodological quality of included SRs/MAs. AMSTAR 2 contains 16 items, and 7 of them are critical domains , which can critically affect the validity of the review and its conclusions. Each item is judged as “yes,” “partial yes,” and “no.” The tool divides overall confidence of the review results into 4 levels: high, moderate, low, and critically low.Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2),2.7.2 will be applied to assess the risk of bias of included SRs/MAs. ROBIS is completed in 3 phases: Phase 1 evaluates the relevance between target question and proposed question; Phase 2 identifies concerns with the SR process through 4 domains: “study eligibility criteria,” “identification and selection of studies,” “data collection and study appraisal,” and “synthesis and findings”; Phase 3 judges the overall risk of bias in the interpretation of results in SRs and whether this considered limitations identified in any of the phase 2 domains. Answers to the signal questions are categorized as “yes,” “probably yes,” “no,” “probably no,” or “no information.” The risk of bias is judged as “high,” “low,” or “unclear.”The Risk of Bias in Systematic Reviews (ROBIS)2.7.3 which can be useful for critical appraisal of published SRs/MAs, will be applied to assess the reporting quality of included SRs/MAs. The PRISMA statement consists of a 27-item checklist and a 4-phase flow diagram, including 7 aspects of SRs/MAs . Each item is described with “yes” when the content of the item is reported adequately, “partially reported” when the content is reported inadequately, or “no” when none content is reported.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA),2.7.4 will be applied to assess the quality evidence of included SRs/MAs. Although evidence based on RCTs begins as high-quality evidence, the quality of evidence can also be decreased by 5 elements that include limitations in study quality, the inconsistency of results, uncertainty about the directness of evidence, imprecise or sparse data, and high risk of reporting bias. The grade of evidence is categorized into 4 levels: high, moderate, low, and very low.The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system2.8A narrative description of characteristics in the included SRs/MAs will be shown in the table. The results of SRs/MAs will be summarized as the risk ratio or odds ratio for the dichotomous data, and as the standard mean difference or weighted mean difference for the continuous data with 95% confidence intervals. If the data is unsuitable for pooling due to the substantial heterogeneity, the narrative synthesis will be conducted. The results of AMSTAR 2, ROBIS, PRISMA, and the GRADE will be presented in tabulation and figures.3,19 To the best of our knowledge, this study will be the first overview to assess the published SRs/MAs of CHM for psoriasis. What we expect is that the results of this overview will give patients and doctors more information about the credibility of current evidence to make decisions, and will provide some directions for future research.CHM has been widely used in the treatment of psoriasis for a long history. Growing evidence indicates that CHM may have considerable therapeutic effects on psoriasis. However, the reporting and methodological quality of SRs/MAs have not been evaluated, which is an indispensable step before the treatment recommendations were presented.Conceptualization: Jie Zhang.Data curation: Jie Zhang, Qianying Yu, Li Peng, Wenxia Lin, Ying He.Formal analysis: Jie Zhang, Qianying Yu.Funding acquisition: Jing Guo, Mingling Chen.Investigation: Yuesi Qin, Jing Guo, Min Xiao.Methodology: Jie Zhang, Qianying Yu, Li Peng.Supervision: Mingling Chen, Min Xiao, Jing Guo.Writing – original draft: Jie Zhang.Writing – review & editing: Mingling Chen, Jing Guo, Min Xiao.


Streptococcus (GAS) infections (IGASIs) in infants. We described initial clinical and laboratory features and outcomes of <3-month-old infants hospitalized for an IGASI between 2007 and 2016 in France. Patients were identified from the French National Reference Centre for streptococci. IGASI was defined by the isolation of GAS from blood cultures or from other usually sterile sites. Data collection was performed by assessing the patients' hospitalization reports. Twenty-six patients  were included. Among 19 cases with available data, 14 (73.7%) were household contacts of a GAS infection, reaching 8/9 (88.9%) in neonates. The diagnoses were bacteremia , pleural effusion or pneumonia , meningitis with brain abscess , and septic arthritis . Fever , hemodynamic disorders , respiratory disorders , thrombocytopenia , and neutropenia  were frequently observed. The main emm-genotype was emm-1 . Thirteen (50.0%) infants have been admitted to the intensive care unit, and two (7.7%) died. Respiratory disorders, high C-reactive protein level, and the need for transfusion were significantly associated with severity. IGASI remains uncommon in <3-month-old children but leads to a high morbidity. Whether an antibiotic prophylaxis for contact neonates of a patient with GAS infection decreases the risk of infection remains to be determined.Few data are available on invasive group A  Streptococcus (GAS) is associated to various clinical presentations in children—from benign to severe invasive infections. In different countries, GAS was involved in 3–5% of bloodstream infections in children .The records of the CNR-Strep were retrospectively queried to identify all the neonates and infants <90 days of life who were declared to have an IGASI between January 1, 2007, and December 31, 2016.Then, each center was contacted and asked to send the hospitalization report to the first author, who collected the initial clinical and laboratory data and the clinical outcome  on a standardized anonymized paper case report form. Patients or their parents were not contacted to obtain additional or missing data. Severe IGASIs were defined as the presence of at least one of the following criteria: respiratory distress requiring mechanical ventilation, hemodynamic disorders requiring fluid resuscitation, or use of vasopressive amines, seizures, or hospitalization in the intensive care unit.emm genotyping were detected in the CNR-Strep using polymerase chain reaction, as previously described .We compared the severe and non-severe infection groups for each characteristic found in at least five patients. Fisher's exact test and Mann–Whitney The study has been approved by the Robert-Debré ethical committee (number 2016/318). As the data were obtained retrospectively with no involvement of the patients or their parents, no written informed consent was required by the ethical committee, in accordance with the local legislation. An information letter was sent to the parents. Data collection was approved by the French National Data Protection Commission (number 2002616v0).Thirty-seven infants younger than 90 days old were initially identified from 25 cities and 12 regions, but medical records were not retrieved for 11 patients. The characteristics of the 26 included patients , from 18 cities and 10 regions, are shown in p = 0.3].History about household contacts with GAS infection was available in only 19 cases. Out of these, 14 (73.7%) had a positive history: 7/19 (36.8%) were exposed to a maternal infection , among whom four mothers were hospitalized for toxic shock syndrome and two died; 5/19 (26.3%) of the household contacts had pharyngitis/tonsillitis; and 2/19 (10.5%) had a cutaneous infection. Among the nine neonates, a positive history of household contacts was more common than in the 10 infants more than 28 days old  and aminoglycosides [n = 19/26 (73.1%)]. Five out of the six children, who were not treated with a third-generation cephalosporin, received amoxicillin. Other drugs were more rarely prescribed and were always used in addition to another antibiotic: clindamycin (n = 3), vancomycin (n = 2), fosfomycin (n = 1), rifampin (n = 1), and imipenem (n = 1). Complications and outcomes of the 26 patients are presented in Treatments are reported in p < 0.05) compared to the other patients  and the completeness of the French CNR-Strep, which has been estimated to an average rate of 28%, we could estimate the incidence of IGASI in <3-month-old children at 1.6/100,000 infants per year.Although uncommon, our study has confirmed that IGASIs are frequently associated with clinical severity in <3-month-old infants. We found that bacteremia with no focal sign and pleuro-pneumonia were the most common clinical presentations, accounting for almost 90% of cases. Clinical characteristics were similar to those published in a previous review . In this population, the theoretical number needed to treat to prevent one secondary case using antibiotic prophylaxis was 50 compared to 271 for the overall population (Our study has several limitations. Data collection was retrospective, and only 26 patients have been included despite a 10-year period in the whole country. Moreover, we could not describe the characteristics of 11 patients identified by the CNR-Strep due to the impossibility to obtain the medical records. Thus, our results may not be generalizable.In conclusion, IGASI in <3-month-old infants remains uncommon, but 50% of patients are severely ill. The very high proportion of GAS infection in the household of these neonates suggests a need to assess whether a systematic prophylaxis and close follow-up allow avoiding these severe infections.The datasets generated for this study are available on request to the corresponding author.ZG conceptualized and designed the study, collected data, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. PB, CPl, SB, CPo, VB, AFr, and AFa conceptualized and designed the study and critically reviewed the manuscript for important intellectual content. RB conceptualized and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.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.


Mesenteric cysts are rare benign abdominal tumors, and they can appear anywhere in the mesentery of the gastrointestinal tract, from the duodenum to the rectum. They are generally asymptomatic and may present as an incidental finding. The diagnosis is confirmed by the laparotomy findings and the results of the histopathological examination. Complete surgical (open or laparoscopic) enucleation of the cyst is the treatment of choice. We present a case of a female patient who presented with abdominal pain and a giant palpable abdominal mass. The patient underwent a surgical exploration which showed a giant mesenteric cyst. A complete surgical enucleation of the cyst was successfully performed without the need of bowel resection. The histopathological examination of the cyst was compatible with the diagnosis of chylous mesenteric cyst. Mesenteric cysts are rare benign pathologic entities with an incidence of 1 : 100.000 in adults and 1 : 20.000 in pediatric hospital admissions , while aA 34-year-old woman presented with abdominal pain of 4-day duration. Her past medical history was clear, and a cesarean section was reported from her surgical history. On physical examination, a giant palpable mass was discovered on her right upper abdomen. Her vital signs were stable, and the laboratory tests were normal. An ultrasound of the abdomen showed a well-defined 15, 2 × 10 cm cystic mass, with a probable diagnosis of enteric duplication cyst. A CT scan of the abdomen was performed and revealed a giant cyst measuring 15, 9 × 14, 4 × 11, 2 cm with a thin wall and in contact with the right kidney and the uterus . The difThe histopathological examination showed a unilocular cyst with a smooth internal surface and a wall thickness 0,1–0,8 cm. The cyst wall was composed of vascular, connective, and fatty tissue with a small amount of smooth muscle fibers. Τhe stroma showed focal edema, focal mild lymphoplasmacytic infiltrates, and a few neutrophil polymorphonuclear cells. Focal lining of mesothelial type cells was recognized . These fMesenteric cysts are rare benign pathologic entities with an incidence of 1 : 100.000 in adults and 1 : 20.000 in pediatric hospital admissions .Mesenteric cysts may appear anywhere in the mesentery of the gastrointestinal tract, from the duodenum to the rectum. In a review of 162 cases by Kurtz et al., 60% of the mesenteric cysts occurred in the small bowel mesentery (most frequently in the ileum), 24% in the large bowel mesentery , 14,5% in the retroperitoneum, and 1,5% were undefined [According to the histopathological findings, mesenteric cysts are classified in six groups: cysts of lymphatic origin (simple lymphatic cysts and lymphangiomas), mesothelial origin , enteric origin (enteric duplication cysts and enteric cysts), urogenital origin, mature cystic teratomas (dermoid cysts), and nonpancreatic pseudocysts (traumatic and infectious origin) . The finBased on their etiology, Beahrs et al. classified mesenteric cysts in four groups: embryonic and developmental cysts , traumatic or acquired cysts, neoplastic cysts , and last infective and degenerative cysts  . The preMesenteric cysts can be single or multiple and unilocular or multilocular, and based on their content, they are described as serous, chylous, hemorrhagic, chylolymphatic, or infected , 9. In tMesenteric cysts usually appear in the fifth decade, and they show female predominance . They arMany approaches have been described for the management of mesenteric cysts, such as marsupialization, sclerotherapy, drainage, enucleation, percutaneous aspiration, and en bloc resection of the cyst with the involved adjacent organs . Due to high recurrence and infection rates related to marsupialization, drainage, and aspiration, complete surgical (open or laparoscopic) enucleation of the cyst is the treatment of choice , 10. In Mesenteric cysts are rare benign abdominal tumors. Preoperative diagnosis is difficult due to their noncharacteristic clinical presentation. The diagnosis is proven after surgical exploration and the results of the histopathological findings. Complete surgical enucleation of the cyst, open or laparoscopic, is the gold standard approach for the management of a giant chylous cyst.


The aim of this study was to describe the relative frequency and the main demographic and clinic-radiographic features related to patients diagnosed with Simple bone cyst (SBC) in an Oral Diagnosis Service in Southeast Brazil and present a review and discussion of international literature on this topic. SBC cases from our service encompassing the period between 1978 and 2017 were selected. In addition, a literature search was performed in the Pubmed/MEDLINE online electronic database published between 1951 and 2019. A total of 2,459 cystic lesions were documented in our service, thus 60 patients were diagnosed with the SBC representing 2.4% of all jaw cystic. Most of cases were asymptomatic. Multiple SBC lesions were seen in two patients (3.4%) and association with cemento-osseous dysplasia was seen in one female patient (1.7%). A total of 793 cases were enrolled in this literature review.  The SBC is an asymptomatic lesion often discovered in routine image exams in young patients. The unilocular, well defined margin with scalloped appearance is characteristic and helps the definition of diagnosis. This review suggests a different epidemiologic trend concerning to the sex and it confirms the posterior region of mandible as the more frequent location. The conservative treatment with limited exploration and curettage remains as the gold-standard treatment. Key words:Simple bone cyst, idiopathic bone cavity, traumatic bone cyst, conservative treatment. Simple bone cyst (SBC) is defined as an intraosseous cavity of unknown etiology, that is devoid of an epithelial lining, and is either empty or filled with fluid ,2. Many In the facial skeleton, SBC is most commonly observed in body mandible, during the second/third decade of life, with no gender predilection . It is oThe typical radiographic appearance of SBC is a radiolucent and unilocular lesion expanding between the roots of teeth ,12, withFew well documented series of SBC patients are available in the international literature ,16-18. Tet al. . All cases originally reported as SBC were retrieved and revised according to the fourth World Health Organization (WHO) Classification of Head and Neck Tumours. Data concerning gender, age, skin color, number and anatomic location of the lesion, history of trauma, symptomatology, association with other bone diseases, radiographic characteristics, treatment, and outcomes were recovered from medical and dental files, histopathological exam requests, and available radiographic exams. Regarding anatomic distribution, each lesion was classified according to its epicentre into anterior, premolar or posterior regions of the maxilla or mandible, as well as the angle or ramus of the mandible. For patients with a concise follow-up, treatment results were evaluated according to the radiographic criteria of Capanna A literature search was performed in the Pubmed/MEDLINE online electronic database, looking for case series (n = 5 cases or higher) published between 1951 and October 2019 with the terms “simple bone cyst”, “traumatic bone cyst”, “idiopathic bone cavity”, “hemorrhagic bone cyst”, or “unicameral bone cyst” combined with “mandible”, “mandibular”, “jaw” or “maxillofacial”. No restriction of language was made. Case series associated with literature review had only their own sample data collected. Two articles were excluded because a third one  and association with cemento-osseous dysplasia (COD) was seen in one female patient (1.7%).Radiographies from 51 cases were available for review, and their information are presented by The literature review enrolled twenty-nine articles -18,20-38SBC are uncommon lesions of maxillofacial region. They represented less than 14% of the bone lesions reported by a study conducted for a 15-year period in a Brazilian clinic  and 1.48In the past, the most widely accepted etiology hypothesis for SBC was related to traumatism without bone fracture in young patients, which could trigger an intramedullary hemorrhage with hematoma formation and finally development of cavity ,4. In thMoreover, other authors proposed that the trauma origin is not the most appropriate hypothesis to explain the SBC etiopathogenesis, since their cases were not related to trauma situations , while oThe majority of published series are from South America samples ,33,35-38About age predilections, SBC was more frequently diagnosed in young adults - in the second and third decade of life ,25-27,30Most of the retrieved paper, describes that SBC was most commonly found in mandible ,29-36,38Usually SBC patients, do not develop symptoms or evident clinical signs and the diagnosis is made often by routine radiographic examination ,3,10,38.Usually, the radiographic findings of SBC display unilocular radiolucent lesion with well-defined borders and scalloping contour among roots of involved teeth by lesion ,4. FourtThe presence of expansion of cortical margin is variable and can be analyzed either by physical or imaginological examination. The literature review presented a range 3.84% a 72.7% of bone expansion associated with SBC -25,34,35Displacement of teeth caused by SBC was not a common radiographic finding in our series, as well in the majority of reviewed studies, with only two articles ,28 reporPatients committed with multiple SBC lesions have also been reported by several authors in the literature ,28,29,33The SBC can also occur in synchronism with other lesions, mainly associated with COD ,24,29,34In all cases submitted to curettage , histopaThe treatment of choice for theses lesions consists in conservative surgical exploration of cavity and curettage, which it is essential to induce osseous neoformation and in the determination of the diagnosis . AggressIn conclusion, the SBC is an asymptomatic lesion often discovered in routine image exams in young patients. The unilocular, well defined margin with scalloped appearance is characteristic and helps the definition of diagnosis. This review suggests a different epidemiologic trend concerning to the sex, since female were more affected, and it confirms the posterior region as the more frequent location on the analyzed lesions. Finally, conservative treatment with limited exploration and curettage remains as the gold-standard treatment and should be performed with appropriate follow-up.


Sialadenoma papilliferum (SP) is an extremely rare benign neoplasm of salivary glands. To explore and define the clinicopathological features of SP, we retrospectively analyzed 89 cases previously reported and five new cases.The clinical features, histopathology, immunohistochemistry and molecular analysis of our cases were further performed and the related literatures were reviewed and analyzed.BRAF V600E mutation.Combining 89 cases from the literature with our cases, the hard palate was the most common locations for SP. However, two of our cases were rarely located in the esophageal mucosa. Among all cases, the male gender was more affected, with the average age and median age of 61.8 and 62 years, respectively. Conventional histomorphologically, SP was characterized by complex papillary structures with a biphasic growth pattern of exophytic squamous component and endophytic glandular component. The glandular structures were lined by a double layer of epithelium composed of flattened or cuboidal basal cells and a cuboidal or columnar luminal cells formed papillary infoldings into the ductal lumina. Immunohistochemically, the luminal epithelial configurations showed strong expression of CK7 along the luminal cell membrane, while the basal myoepithelia displayed strong nuclear p63 expression. In both the glandular and squamous tumour components showed BRAF V600E-positive immunostaining and BRAF V600E mutation. Additionly, adequate treatment for SP is surgical excision, with a favorable prognosis in patients.For the first time, we have comprehensively aggregated and analyzed 90 cases sialadenoma papilliferum from almost all previous publications, and further explored the clinicopathological features of SP; concordantly, this study demonstrated that SP shows a papillomatous growth pattern with exophytic and endophytic proliferation of ductal epithelium composed of double-layered cells harboring  Sialadenoma papilliferum (SP) is a rare benign neoplasm –3, estimWith Institutional Board Review approval, the Department of Pathology of the Affiliated Hospital of Jining Medical University and consultation archives from 2017 to 2019 were searched for cases of SP and analyzed for their clinicopathological features. In addition, all available hematoxylin and eosin-stained sections were reviewed and confirmed by two pathologists with expertise in head and neck tumour pathology. Apart from this, a thorough English language literature search was performed primarily through Google Scholar, PubMed, and the different editions of WHO classifications of salivary gland tumours using the keyword sialadenoma papilliferum, which included single case reports and short series of SP since 1969. Consequently, a total of 48 articles were remained for the literature analysis, and the following indexes were taken into account: patient gender, age at diagnosis, lesion occurrence site, lesion size, progression time, clinical diagnosis, clinical features, follow-up period, and recurrence. Also excluded from our study were cases with questionable histopathologic features or without available microscopic images.The immunohistochemical analysis was performed on paraffin-embedded sections using the EnVision two-step method. Primary antibodies used in the study were displayed as follows: CK7 , CK5/6 , p63 , CK8 , S-100 , and Ki-67 , Ready-to-use, Maixin Bio, Fujian, China. Anti-BRAF V600E  antibody was performed on Ventana BenchMark GX autostainer (Ventana) followed by the Optiview DAB Detection Kit (Ventana). Appropriate positive and negative controls were performed concomitant for all the markers tested.The unstained paraffin-embedded sections were collected for DNA extraction . And then DNA was amplified by polymerase chain reaction using primers for exon 15 of BRAF (HotStarTaq Master Mix kit (Qiagen), 5′-TCA TAA TGC TTG CTC TGA TAGGA-3′ (BRAF-Exon15-F), 5′-GGC CAA AAA TTT AAT CAG TGGA-3′(BRAF-Exon15-R)). The amplified products were purified using a QIAquick Spin Kit (Qiagen), and then purified products were sequenced with a BigDye Terminator v3.1 Cycle Sequencing Kit  on an ABI Prism 3700 instrument (Applied Biosystems). The confirmed assay was repeated for mutational specimens.There were five cases of SP from our hospital, including three males and two females, and age at diagnosis ranged from 50 to 78 years with an average age of 62 years. Four patients were found by accident in physical examination, only with slight local numbness but no obvious pain. In addition, one patient was treated for palatal tumours because of pain for 1 month. Two of the five cases occurred in the palate, one in nasal cavity and two in esophagus. All patients underwent tumour resection and were sent to the pathology department for pathological examination, with size of the mass ranging from 0.5 to 1.0 cm. Patients were followed for 6 to 22 months, and their prognosis was good without recurrence and worsening progression.Combining 94 cases from the literature with our cases, the hard palate was the most common location, accounting for 60%, and others included the junction of the hard and soft palate, soft palate, buccal mucosa, nasal cavity, upper lip, parotid glands, etc. Fig. . MoreoveThe tumour varied in sizes, from 0.2 to 3.0 cm in 70 cases known, with an average size of 0.81 cm, excluding two cases from the parotid gland (7.5 cm) and another two cases from the palate and left lower gingiva (4.0 cm). Gross observation showed that the cut surface of the lesion was slightly solid with grey-white to grey red colour, clear margins, and the papillary surface.Histologically, the tumours in our cases were characterized by biphasic differentiation, consisting of exophytic papillary structures covered by stratified squamous epithelium and endophytic glandular structures below the mucosa Fig. a. The suImmunohistochemical studies of our cases have shown that CK7 Fig. a and CK8BRAF mutation was confirmed in three of four cases, because of one case lacking sufficient tissue for testing (Fig. Molecular analysis revealed that ing Fig. .Fig. 5MOur patients were followed for 6 to 22 months, and their prognosis was good without recurrence and worsening. According to the literature review, conservative surgery was documented in 56 cases and treatment was not specified in 6 cases. And one case from the left lower gingiva with malignant transformation invading the mandible was treated by partial mandibular resection and cervical lymph node dissection. Another case from the parotid gland, considering the preservation of the facial nerve, only superficial parotidectomy was performed. In addition, the follow-up information of 37 cases was available, in which the length of follow-up period of the patients ranged from 1 month to 96 months, with an average length of 31 months. Three cases with malignant transformation of SP have been recognized, and only two recurrences were recorded, each at 36 months after initial treatment, which indicated a recurrence rate of 6.5%.SP is a subtype of intraductal papilloma, a rare benign tumour commonly found in older adults with hard palate, accounting for approximately 80%. It can also occur in the parotid gland, submandibular gland, nasopharynx and esophagus , 17–31. Histologically, SP is formed by mucosal surface epithelium and ductal epithelium of the salivary gland which proliferate outward and inward simultaneously, with the characteristics of biphasic proliferation of squamous and ductal epithelium , 44. GenImmunohistochemistry showed that CK7 and CK8 were strongly expressed in columnar luminal cells, and p63 was strongly positive in basal cells, but was negative in luminal cells from Table BRAF V600E mutations and one case has HRAS Q61R mutations, but except oncocytic SP. Notably, syringocystadenoma papilliferum of the skin, histologically analogous to SP, also exists BRAF and HRAS mutations, which suggests SP may be considered to be a salivary counterpart of syringocystadenoma papilliferum of the skin [The Histogenesis of SP is still not fully understood , 7, 44. the skin , 5, 44. the skin , 5, 44, the skin , 5. TherAlthough SP has been proposed as a distinct entity, it also needs to be differentiated from the following neoplasms. First of all, papillary squamous cell carcinoma, a papillary subtype of squamous cell carcinoma similar to the histopathological characteristics of SP, is characterized by an exophytic and papillary growth pattern. However, there is no glandular component with mucous cells in the lesion, and the squamous cell papilloma is mainly composed of the squamous epithelium, which manifests highly differentiated squamous cell carcinoma with keratinized beads structure, without downward extension of SP. Inverted ductal papilloma is another candidate for differential diagnosis, mainly composed of hyperplastic squamous epithelium under the mucosa that protrudes into connective tissue and connects with duct, but unlike SP with characteristic papillary surface configuration. Another antidiastole is highly differentiated mucoepidermoid carcinoma, which is rich in mucous cells, often forming a glandular cavity, and sometimes hyperplastic mucous cells form the papillary structure resembling that of SP, while mucoepidermoid carcinoma usually composed of epidermal-like cells, intermediate cells, mucus cells and other cell components . Wathin The current treatment of SP is conservative surgical resection , 45. In Although there have been a few reports of recurrence and malignant transformation, in which SP has reported that it can transformed into epithelial-muscle epithelial carcinoma, squamous cell carcinoma, and mucoepidermoid carcinoma, but malignant transformation is rare and not entirely convincing , 32, 47.Summarily, SP is a rare, benign and exophytic tumour of salivary gland neoplasm that commonly occurs in the hard palate in middle aged males with a painless and slow growing lesion. Characteristic of this tumour is its exophytic growth pattern, with multiple papillary surface fronds and deeper ductlike structures, which may be continuous with the surface epithelial component. In this study, we added another five cases of SP to the literature and discussed the clinicopathologic features of the 94 described cases of this unusual neoplasm. Although to identify the cell of origin of SP is difficult, we conclude that SP is a neoplastic lesion by immunophenotypic feature and molecular analysis, and virtually has no potentially malignant features mostly with good prognosis, which should be distinguished from other malignant tumours and avoided resultant overtreatment.