The rise in location-based service (LBS) applications has increased the need for indoor positioning. Various methods are available for indoor positioning, among which pedestrian dead reckoning (PDR) requires no infrastructure. However, with this method, cumulative error increases over time. Moreover, the robustness of the PDR positioning depends on different pedestrian activities, walking speeds and pedestrian characteristics. This paper proposes the adaptive PDR method to overcome these problems by recognizing various phone-carrying modes, including texting, calling and swinging, as well as different pedestrian activities, including ascending and descending stairs and walking. Different walking speeds are also distinguished. By detecting changes in speed during walking, PDR positioning remains accurate and robust despite speed variations. Each motion state is also studied separately based on gender. Using the proposed classification approach consisting of SVM and DTree algorithms, different motion states and walking speeds are identified with an overall accuracy of 97.03% for women and 97.67% for men. The step detection and step length estimation model parameters are also adjusted based on each walking speed, gender and motion state. The relative error values of distance estimation of the proposed method for texting, calling and swinging are 0.87%, 0.66% and 0.92% for women and 1.14%, 0.92% and 0.76% for men, respectively. Accelerometer, gyroscope and magnetometer data are integrated with a GDA filter for heading estimation. Furthermore, pressure sensor measurements are used to detect surface transmission between different floors of a building. Finally, for three phone-carrying modes, including texting, calling and swinging, the mean absolute positioning errors of the proposed method on a trajectory of 159.2 m in a multi-story building are, respectively, 1.28 m, 0.98 m and 1.29 m for women and 1.26 m, 1.17 m and 1.25 m for men. This indicates on average that men are 12 cm taller than women. Therefore, gender is a reasonable parameter for considering two height categories. In addition, pedestrians’ step lengths vary due to their walking speed, because acceleration data differs across walking speeds. In the long and complicated paths in buildings, the pedestrian moves at different speeds depending on different situations. Thus, the positioning error can be decreased by considering the different walking speeds. Hence, considering varying pedestrian characteristics as well as detecting various motion states and walking speeds can improve the robustness of PDR positioning.Indoor positioning systems have been studied as a means of guiding pedestrians around buildings, particularly in emergencies . A variePDR positioning is more adaptable when considering various phone-carrying modes, including texting, calling and swinging, as well as different pedestrian activities, including ascending and descending stairs and walking. This is because sensor data differ for different phone-carrying modes and pedestrian activities. The acceleration data also differ across walking speeds as walking can be classified as fast, medium and slow; thus, positioning accuracy is improved and adapted to changes in walking speed. This paper uses the DTree and SVM to identify various motion states and walking speeds. Using the proposed classification strategy, 15 combinations of five pedestrian activities and three phone-carrying modes are accurately distinguished.In addition to detecting different motion states and walking speeds, considering height and gender as effective parameters in estimating step length promotes distance estimation accuracy. By analyzing each motion state separately for women and men, PDR positioning is further adapted to diverse heights and genders, so the overall accuracy of positioning improves.After state detection, parameters of step counting and methods for step length estimation are separately adjusted for each pedestrian activity, phone-carrying mode, walking speed and gender to enhance the robustness and accuracy of PDR positioning.In this article, an adaptive PDR method is proposed to improve the robustness and accuracy of Three-dimensional positioning by adjusting its parameters based on different phone-carrying modes, pedestrian activities, walking speeds and individual characteristics. The proposed classification approach uses a combination of support vector machine (SVM) and decision tree (DTree) algorithms to recognize motion states. Additionally, the parameters of a step detection and step length estimation model are adjusted based on gender, the detected motion states and walking speeds. The main contributions of this research are as follows:The remainder of this paper is organized as follows: z-axis acceleration. Kim and Jang [Three-dimensional (3D) indoor positioning using the PDR method consists of various components such as step detection, step length estimation, heading determination and altitude determination. Several methods have been developed for step detection based on accelerometer sensors, such as threshold setting , peak deand Jang  utilizedand Jang . Moreoveand Jang . Movemenand Jang .Heading determination, which is a source of cumulative errors, plays a crucial role in the PDR method. Using only a gyroscope for heading determination causes a larger cumulative error. Besides, the cumulative error increases with time . Fusion Wang and Liu  used SVMWang and Ye  proposedGeng and Xia  proposedThe reviewed studies attempted to adjust the methods of step detection, step length estimation and heading determination based on motion states to improve the accuracy of the PDR. Few investigations, however, have adjusted the PDR components based on movement habits, walking speeds and user characteristics. Because the user moves at different speeds along a complex indoor path, using the PDR method without adjusting the parameters of its components based on various walking speeds causes errors in positioning. Moreover, according to the literature, detecting steps and estimating step length without considering users’ characteristics including gender, height and age led to significant positioning errors. In this paper, we improve the accuracy and robustness of the proposed method by adjusting PDR component parameters based on walking speeds, motion states and pedestrian characteristics, including gender and height.The proposed PDR system  includesi and i, respectively. The initial location is assumed to be known and can be determined by default or by QR codes in the building.According to (1), the PDR approach calculates the user’s location at each step based on his/her length, direction and location in the previous step .(1)Xi=XPositioning using the PDR method includes various components, such as movement state recognition, step detection, step length estimation and movement altitude estimation. Each of these components will be discussed as follows. Since smartphone-embedded inertial sensors are not very accurate, the raw sensor data are noisy. Before step detection and motion state recognition, a preprocessing process must be applied to eliminate the noise and errors. The low-pass filter, which uses a cut-off frequency of 5 Hz, softens and eliminates some high-frequency noises from the acceleration signals, allowing more accurate detection of pedestrian movements and reducing false step detection. In Smartphone magnetometers are easily affected by the magnetic fields of the local environment. There are two kinds of disturbances in the magnetometer data, hard iron disturbance and soft iron disturbance. Permanent magnet materials cause a hard iron disturbance, which affects the magnetometer’s values, similar to constant bias. Unlike hard-iron disturbances, soft-iron disturbances are caused by materials that influence or disturb but do not generate magnetic fields . The magVarious activities were considered in the proposed method to enhance the robustness of PDR positioning, such as walking, ascending and descending stairs. Further, walking was classified as fast, normal, or slow, based on speed. Moreover, three phone-carrying modes, texting, calling and swinging, were considered. Based on To recognize different motion states, 15 features were extracted from the accelerometer, gyroscope and barometer data. The features were the average (except for the barometer), standard deviation (STD), the difference between the maximum and the minimum, skewness and zero crossing rate. To evaluate the performance of the classification, 43 experimenters of different ages and heights participated in the data collection, including 24 women and 19 men. The mean age and height of the men were, respectively, 27.5 ± 5.1 years and 171.1 ± 5.5 cm, while those of the women were, respectively, 27.54 ± 5.6 years and 159.6 ± 6.7 cm. More details about the experimenters’ height and age are shown in The combination of 15 motion states including three phone-carrying modes  and five pedestrian activities  were considered as different motion states and the experimenters collected data in each state. After data collection, data segmentation was performed using a two-second sliding window with a 50% overlap and the sensor sampling frequency was 100 Hz. Each two-second sliding window is called an instance. Women and men had 6112 and 5336 instances in total, respectively. The instance number of each class is reported in A combination of DTree and SVM algorithms was adopted to detect the motion states, including different phone-carrying modes and pedestrian activities. Based on 5-fold cross-validation , Figure Using DTree and SVM algorithms, 15 combinations of phone-carrying modes and pedestrian activities were recognized. As shown in The recognition accuracy of the DTree algorithm based on 5-fold cross-validation is shown in The recognition performance of SVM based on 5-fold cross-validation is given in The peak detection method is used for step detection and its process is initiated by detecting the peak points in the accelerometer data. If the peak points are below the peak threshold or closer to the corresponding valley points than the peak valley threshold, they are eliminated. Additionally, peak points are removed if the time between them and the next peak point is less than the time threshold to prevent overcounting . The menBased on pedestrian activity and walking speed, threshold values were determined empirically to improve the accuracy of step detection. z-axis acceleration, was adopted to estimate step length [Weinberg’s model, which uses the quartic root of the difference between the maximum and minimum of p length . Forty pThe step length was calculated using the Weinberg model. To assess the performance of the step length estimation, four experimenters of different ages and heights participated, including two women and two men. The mean age and height of the men were respectively 25.5 ± 6 years and 175.1 ± 6.5 cm, while those of the women were respectively 25.5 ± 5.5 years and 161.5 ± 7.7 cm. In this section, gender and walking speeds are called effective parameters. Assuming that pedestrian activity is detected, for walking, the k values were selected based on effective parameters and step length was estimated based on the selected k; otherwise, for ascending and descending stairs, the step length was assumed 0.3 m regardless of the effective parameters. According to Algorithm 1. GDA algorithmInput: acc → measured acceleration, ω → measured angular velocity, mag → measured magnetometer,Output: 1.2.  If ( | ||3.   stability = 14.else then5.     stability = 06.end if7.F(8.If (stability) then9. F was used for heading estimation. The mathematical analysis of the gradient descent algorithm for heading estimation has been widely covered in the literature ,53; theryroscope . β was aq is q0 and its vector part is .According to (3), the heading was estimated based on Eulerian angles . In (3),h0 is the initial height in meters, R is the universal gas constant equal to 8.31432T0 is the temperature in Kelvin and P0 and tP are, respectively, the initial atmospheric pressure and the atmospheric pressure in Pascal at time t. Moreover, g is the magnitude of local gravity acceleration equal to 9.806 M is the average molar mass of air equal to 0.0289644According to (4), pressure sensor measurements were used for height estimation .(4)ht=hThe values of altitude estimation error were calculated based on differences between the estimated and the actual altitude values. The mean and standard divisions of altitude estimation error were 0.26 m and 0.19 m, respectively. The cumulative disturbance function (CDF) was used to further analyze the absolute estimation altitude errors. According to The experiments were conducted in the building of the School of Surveying and Geospatial Engineering at the University of Tehran (Iran). As shown in To evaluate the performance of the positioning, experimenters of different ages and heights, two women and two men, participated. The average age and height of the men were, respectively, 28 years and 174.1 cm and, respectively, 25 years and 164 cm for women. The experimenters moved along the designed path of 159.2 m using four smartphones . As shown in In this experiment, reference points were set at the ending and starting points of staircases and turning points, which are significant landmarks for estimating error positioning along the designed path. In this regard, we asked the experimenters to step over the reference point as precisely as possible. The positioning error is estimated by calculating the Euclidean distance between the estimated and actual coordinates of reference points. Furthermore, the estimated distance is the total length of the step lengths and the distance estimation error is the difference between the estimated distance and the actual distance. In this section, positioning with the PDR method based on the recognition of walking, ascending and descending stairs is called activity-based PDR. However, the proposed method recognizes walking speed in addition to activities. It also considers different genders in each activity and the walking speed.According to The cumulative error distribution curve of reference point estimation for the first woman is illustrated in According to The cumulative error distribution curve of reference point estimation for the first woman is illustrated in According to The cumulative error distribution curve of reference point estimation for the first woman is illustrated in According to This study used adaptive PDR positioning. Different pedestrian activities, phone-carrying modes and walking speeds were detected using a combination of SVM and DTree algorithms to promote the robustness of PDR positioning. Additionally, each motion state was investigated separately based on the experimenter’s gender. The proposed classification approach recognized various motion states and walking speeds with a recognition accuracy of 95% for women and 97% for men. After motion state detection, motion states, walking speeds and gender were utilized to adjust the parameters of step counting and step length estimation methods separately for each motion state and gender. The goal was to enhance the robustness of PDR positioning. Using the optimization parameters, the absolute distance estimation error for texting, calling and swinging modes were respectively 1.4 m, 1.06 m, 1.48 m for women, 1.83 m, 1.48 m and 1.22 m for men on a trajectory of 159.2 m. The average absolute positioning error values of the proposed method for three phone-carrying modes, including texting, calling and swinging, were 1.28 m, 0.98 m and 1.29 m for women and 1.26 m, 1.17 m and 1.25 m for men in a multi-story building on a trajectory of 159.2 m. The proposed method promoted step length estimation and position accuracy with robust PDR method, by utilizing embedded smartphone sensors. Future studies can consider other smartphone-carrying modes such as pockets and bags and more pedestrian activities such as running and lateral walking.


A significant increase in the prevalence of short sleep among children has been observed. Short sleep may be associated with unhealthy breakfast and snacking behaviors. The purpose of the current study was to explore the associations of short sleep with breakfast and snacking behaviors among children. Data were obtained from the 2010–2012 China National Nutrition and Health Surveillance (CNNHS). A total of 5254 children aged 6 to 17 years were included. Sleep duration was classified into three categories: moderate sleep, slightly short sleep, and severely short sleep. Breakfast behaviors included skipping breakfast, food diversity, intake of energy and macronutrients, and their proportion of daily total intake. Snack behaviors included snack consumption rate/frequency, types, intake of energy and macronutrients, and proportion of daily total intake. Multiple linear regression and multivariate logistic regression were used for analysis, with models adjusted for the potential effects of gender, age, region, and family income level. The bootstrapping method was used to calculate the 95% confidence intervals of the model statistics. Results showed that slightly short sleep ) and severely short sleep  was related to higher rates of skipping breakfast compared to moderate sleep. Severely short sleep was associated with higher energy , carbohydrate  and protein  intake at breakfast and breakfast accounted for a higher proportion of total daily energy , protein  and carbohydrate . Severely short sleep was associated with higher energy , protein , and fat  intake at snacks and snacks accounted for a higher proportion of total daily protein intake  and fat intake . Slightly short sleep was associated with higher energy  and carbohydrate  intake at snacks and snacks accounted for a higher proportion of total daily carbohydrate intake. Children with severely short sleep were more likely to choose sugar-sweetened beverages (SSBs) as snacks (16.5%) and intake them more frequently, at a daily consumption of 204.7 g and 26.7 g per night. Overall, short sleep was associated with unhealthy breakfast patterns and snack behaviors among children. Children with short sleep had higher intake of energy and macronutrients at breakfast and snacks compared with those with moderate sleep. Promoting adequate sleep among children may have a positive effect on developing healthy eating behaviors. Sleep is the foundation of early childhood development. Adequate sleep plays an important role in promoting the growth and development of children and strengthening the immune system. Sleep-related issues in children have received more attention in recent years. This is against the fact that reports and studies from many countries show that children are experiencing a decrease in sleep duration and higher rates of sleep deprivation ,2. In 20The significant association of short sleep with obesity , diabeteTo summarize, considering that adequate sleep during childhood plays an important role in the development and maintenance of healthy eating behaviors and the prevention of disease in adulthood, it is necessary to pay attention to the association of short sleep with breakfast and snacking behaviors. However, few studies are available on this, especially for Chinese children. Moreover, studies focusing on skipping breakfast and snack intake/frequency are predominant, with less attention paid to other breakfast and snacking behaviors. Therefore, the current study used the China National Nutrition and Health Surveillance (CNNHS) to explore the association of short sleep with breakfast and snacking behaviors.Data came from the CNNHS in 2010–2012. The target population was the resident population of the sampled households in 31 provinces, autonomous regions, and municipalities directly under the Central Government . For residents aged 6 years and above, a stratified multi-stage whole-group sampling method was employed to recruit subjects. China’s county-level administrative units were categorized by level and type of economic development into large cities, small and medium-sized cities, ordinary rural areas, and poor rural areas. Overall, 34 monitoring sites (districts/counties) were selected from large cities, 41 from small and medium-sized cities, 45 from ordinary rural areas, and 30 from poor rural areas. A total of 6 residential (village) committees were selected from each monitoring site, and 75 households were selected from each sampled committee by simple random sampling method. To ensure the required sample size for children aged 6 to 17 years, the sample area was appropriately supplemented with the number of children surveyed in this population.After excluding the children with missing basic personal information, or less than 1 day of dietary records, or daily energy intake less than 800 kcal (3345.6 KJ) or more than 5000 kcal  per day, 5254 children were eventually included in the current analysis. This study was approved by the ethics review committee of the National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention (No. 2013–018), and all participants and their guardians signed the informed consent.The dietary collection was conducted by trained investigators in household visits and consisted of a 3-day consecutive (2 weekdays and 1 weekend-day) 24-h dietary recall and household weighing method. Children were asked about their food intake during the past 24 h before each household visit, including the type and weight of each food item, cooking method, and eating occasion. The food pictures and models were used to facilitate a more accurate and complete recall. When children were unable to recall accurately, their guardians, the person who prepared the cuisine, or the person jointly eating the meal were interviewed to complete the dietary recall. The consumption of edible oils, salt, sugar, and other condiments was collected by the household weighing method.Sleep duration was collected by an interview-administrated questionnaire. All the children were asked the question “how long did you usually sleep per day last week?”. The children younger than 10 years old finished the question with the help of their guardians. Based on the National Sleep Foundation’s (NSF) recommendations, children aged 6–13 years with more than 11 h of sleep, 9 to 11 h, 7 h or more but less than 9 h, and less than 7 h were classified as long sleep, moderate sleep, slightly short sleep, and severely short sleep, respectively. Children aged 14 to 17 years with more than 10 h of sleep, 8 to 10 h, 6 h or more but less than 8 h, and less than 6 h were classified as a long sleep, moderate sleep, slightly short sleep, and severely short sleep, respectively. Only 30 children (0.5%) in the current study were classified as long sleep and were therefore deleted for further analysis.Breakfast patterns include the following four variables: (1) Skipping rate: a dichotomous variable, categorized into <3 times and 3 times during the 3-day dietary recall. (2) Food diversity: Chinese Dietary Guidelines classifies food types into four major categories: cereals and potatoes and mixed beans; animal foods; milk products, soybeans products and nuts; vegetables and fruits. Food types at breakfast including three or more of these four categories were considered as meeting the food diversity criteria and vice versa. (3) Energy and macronutrients intake. (4) The proportion of energy and macronutrient intake in breakfast to the total daily intake.According to the Chinese Dietary Guideline, the snack was defined as food consumed on any occasion other than traditional meals . Snack behaviors included the following three variables: (1) Frequency: divided into ≥1 time/day and <1 time/day. (2) Snack types: The types of snack consumption were ranked by consumption frequency and by the amount consumed, respectively, in a complete 24 h period and in the period between dinner and breakfast in the subsequent day. In the former ranking, the occurrence of a snack food item in the dietary record was counted as one occasion, regardless of the amount consumed, and the top 5 food items were summed up as the 5 most frequently consumed. The latter ranking refers to the top 5 food items with the highest amount of snack consumption by summing up the amount of consumption of each snack food item in the dietary records. (3) Energy and macronutrients supply ratio: the proportion of energy and macronutrients from snacks to total energy intake throughout the day and the proportion from snacks to total intake in the period between dinner and breakfast in the subsequent day.Age was divided into two groups (6–12 years and 13–17 years). Large cities and small and medium-sized cities were combined into urban areas, and ordinary rural areas and poor rural areas were combined into rural areas. Family income level was divided into four groups  according to the 2009 National Net Income Register of the National Bureau of Statistics.p < 0.05 was considered statistically significant. Continuous variables were expressed as means, and categorical variables were expressed as percentages. Multivariate logistic regression were used to analyze the association of sleep duration with breakfast pattern and snack behavior, where the independent variable was sleep duration , dependent variable was skipping breakfast , breakfast food diversity , snack consumption , snack consumption frequency , post-dinner snacks consumption , respectively, adjusting the potential influence of gender, age, region, and family income level. Multiple linear regression was used to analyze the association of sleep duration with energy and macronutrients intake of breakfast and snacks, where sleep duration was an independent variable , dependent variable was energy intake from breakfast, carbohydrate intake form breakfast, fat intake form breakfast, proportion of energy intake from breakfast to total daily intake, proportion of protein intake from breakfast to total daily intake, proportion of carbohydrate intake from breakfast to total daily intake, proportion of fat intake from breakfast to total daily intake, respectively, adjusting the potential influence of gender, age, region, and family income level. The same multiple linear regression was used to analyze the association of sleep duration with energy and macronutrients intake of breakfast and snack, and the proportion of energy and macronutrients intake from sacks to total daily intake.All data were collated and analyzed in the Statistical Analysis System(SAS) 9.4 software  and a two-sided The bootstrapping method allows for a fuller exploitation of the information carried by the original observed sample data as well as free from the reliance on distributional assumptions of traditional statistical methods, which was used to recalculate the confidence intervals of linear regression and logistic regression statistics in this study . This analysis was based on the use of R language.Of the 5254 children, 32.7% were slightly sleep-deprived and 5.4% severely sleep-deprived. Sleep duration varied by age, region, and family income level, with all differences statistically significant. The prevalence of severely sleep-deprived children was higher among the elderly, rural, and low-income families, at 12.7%, 6.6%, and 6.1%, respectively . The rate of skipping breakfast among children was 24.0%, and 61.0% of children met breakfast dietary diversity. Both the rate of skipping breakfast and the rate of breakfast dietary diversity varied among children with different sleep durations . AdjustiAs shown in As shown in As shown in OR = 1.14, 95% CI: 1.06, 1.23) in 6287 Spain children aged 6–9 years in 2011. Hart, C. N. et al. [β = −11.11, 95% CI: −19.44, −2.78, p = 0.0069) compared to short sleep (<9 h) in Spanish school-age children. However, most of these studies explored differences in whole-day food and nutrients intakes at different sleep durations. Limited data exists concerning the relationship between sleep and energy and macronutrients in a particular single eating occasion (such as breakfast and snacks). Nedeltcheva, A. V. et al. [p = 0.04), and the main contributor to this difference was snacks (p = 0.04) rather than meals (p = 0.49). Kant, A. K., & Graubard, B. I. [p < 0.0004), and relative to those with average sleep duration, a higher percentage of those with short sleep reported received ≥50% more energy (p = 0.002). The current study identified similar findings in children to those of Nedeltcheva, A. V. et al. [p < 0.05). A study of 1033 primary school children in grades 1 to 6 in Ecuador showed that children with enough sleep (≥ 9 h) were more likely to eat breakfast every day  [The current study revealed the associations of sleep duration with breakfast patterns and snack behaviors, most of them being considered unhealthy. Previous studies had suggested that short sleep might be related to the intake of food groups, energy, and macronutrients. Pérez-Farinós, N. et al.  found th. et al.  found thd, B. I.  analyzed. et al. , that is. et al.  investig1, 2.08) . In this1, 2.08)  suggeste1, 2.08) ,28. BreaOR = 1.12, 95%CI: 1.04, 1.20) based on a national cross-sectional survey of 14,274 Iranian children aged 6–18 years. In a cross-sectional study of 5873 children aged 9–11 years, Chaput, J. P. et al. [OR = 0.79, 95%CI: 0.71, 0.88). Short sleep as a risk factor of adverse changes to metabolic hormones in the body was associated with an increased appetite for sweet foods [The current study also found that children with severely short sleep had higher levels of SSBs intake, which is similar to some previous studies. Mozaffarian, N. et al.  found th. et al.  found thet foods . We alsoThere are certain limitations to this study. Firstly, the measurement of sleep is complex, as it includes not only sleep duration but also sleep onset, sleep midpoint, and sleep quality ,33, and Short sleep was associated with skipping breakfast, high energy, carbohydrate and protein intake at breakfast and snacks, and high SSBs intake levels.Ensuring adequate sleep for children is of great significance in promoting the development of healthy breakfast patterns and snack behaviors.


The coronavirus disease 2019 (COVID-19) disease is a multisystem disease and recent studies have shown an increase in reported thromboembolic complications as deep venous thrombosis, pulmonary embolism (PE), stroke, and less frequently mesenteric artery thrombosis. We present a case of a 75-year-old woman, COVID-19 positive with five days of evolution, who was admitted to the emergency room due to diffuse abdominal pain with several days of progression, along with diarrhea and biliary vomit. Abdominal computed tomography presented images of subtraction of the lumen of the upper mesenteric artery. With the reported clinical case the authors intend to clarify the importance of differential diagnosis in patients with a typical severe acute respiratory syndrome coronavirus 2 (SARS CoV2) infection presentation. The gastrointestinal symptoms of SARS CoV2 infection can mask a more severe condition, so a high index suspicion for abdominal thromboembolic events is required once this complication may threaten patient’s life. The coronavirus disease 2019 (COVID-19) has multiple forms of presentation. Although it mainly affects the respiratory system, in the form of pneumonia, it can target almost every system, such as the gastrointestinal , which bAlong with deep venous thrombosis, pulmonary embolism (PE), and stroke, acute mesenteric ischemia (AMI) has been reported in severe COVID-19 patients. AMI is a severe complication with a high mortality rate. The risk is increased in patients with advanced age, cardiac arrhythmias, cardiac valvular disease, infective endocarditis, recent myocardial infarction, ventricular aneurysm, aortic aneurysm or atherosclerosis, peripheral artery disease, and low cardiac output states .A 75-year-old woman, with a clinical frailty score of 7, COVID 19 positive with five days of evolution, was admitted to the emergency room (ER) due to abdominal pain with several days of evolution, initially localized in the hypogastric region, but widespread at admission, along with diarrhea and biliary vomit. The results of the analytical investigation are in Table 2 76 mmHg).As we can see, there was increased systemic inflammatory markers, elevated D-dimer, hyperlactacidemia, hypokalaemia, and increased liver and cholestasis enzymes. Bilirubin was normal and initially there was no hypoxemia  and comfort measures with morphine and ropivacaine (for five days).At day 10, a new abdominal pelvic CT was performed and re-permeabilization of the lumen of the superior mesenteric artery was observed, with no thrombi, along with a normal permeability of the celiac trunk and the inferior mesenteric artery. There was also dilation of several loops of the small intestine, filled with liquid, with a thin wall, without relevant highlight, aspects that were consistent with previous ischemia.Favorable evolution was verified, with improvement of the inflammatory parameters, as well as the clinical condition, so it was decided to perform a new laparotomy at day 16. New laparotomy findings consisted of small intestine gangrene and generalized enteric peritonitis, and it was decided to maintain the initial strategy. There was a clinical decline, with a worsening of the state of dependence and she was admitted to a palliative care unit.COVID-19 is a multisystem disease with multiple forms of presentation, and the gastrointestinal tract is one of the most affected system (17.6% of patients with SARS CoV2 infection [Another manifestation of COVID-19 is thromboembolic complications. Alongside deep venous thrombosis, PE, and stroke, mesenteric artery thrombosis should be considered. The virus rises the incidence of mesenteric ischemia from 0.09% to 0.2% in the normal population to 1.9% to 3.8% [In this case we have an old woman, hypocoagulated, with typical gastrointestinal symptoms of COVID-19. Given her hypocoagulation therapy, a thrombotic phenomenon of this extension would not be expected. For this matter, the authors enhance the need for a high-index suspicion in order to identify abdominal thromboembolic events, as this is a life-threatening situation. Also, this clinical case highlights that gastrointestinal symptoms of SARS CoV2 infection can mask a more severe condition.


Medication-related osteonecrosis of the jaw (MRONJ) is a complication caused by anti-resorptive agents and anti-angiogenesis drugs. Since we wanted to write a protocol for a randomized clinical trial (RCT), we reviewed the literature for the essential information needed to estimate the size of the active patient population and measure the effects of therapeutics. At the same time, we designed a questionnaire intended for clinicians to collect detailed information about their practices. Twelve essential criteria and seven additional items were identified and compiled from 43 selected articles. Some of these criteria were incorporated in the questionnaire coupled with data on clinical practices. Our review found extensive missing data and a lack of consensus. For example, the success rate often combined MRONJ stages, diseases, and drug treatments. The occurrence date and evaluation methods were not harmonized or quantitative enough. The primary and secondary endpoints, failure definition, and date coupled to bone measurements were not well established. This information is critical for writing a RCT protocol. With this review article, we aim to encourage authors to contribute all their findings in the field to bridge the current knowledge gap and provide a stronger database for the coming years. Osteonecrosis of the jaw is a site-specific, osseous pathology that has been reported in the literature since the 19th century. Management of osteonecrosis is based on the disease stage, size of the lesion(s), and the presence of contributing drug therapy and comorbidities . Its incThe literature contains many studies and clinical trials, systematic reviews, and meta-analyses on this topic ,12,13,14The effectiveness of the different management methods was evaluated in a systematic review and meta-analysis . Out of Human amniotic membrane (hAM) has been used for many years to treat various pathologies because of its regenerative, anti-fibrotic, anti-scarring, anti-microbial, anti-inflammatory, and analgesic properties . In addiWe have accumulated extensive experience on the use of hAM for bone repair and in oral surgery ,30,31,32This review identifies crucial missing data on MRONJ management. It suggests, thanks to a questionnaire, the information that should be included in future publications to facilitate the writing of research protocols, define the size of the active patient population, and allow measurable effects of therapeutics, especially in RCTs.The clinical research manager (FG) assisted by the methodologist (ALP) and two surgeons  compiled a list of 12 essential criteria to define the size of the active patient population and identify measurable effects of therapeutics: MRONJ grade classification tool; mucosal defect measurement; number of sites affected and number of sites treated; continuation of MRONJ-inducing drug; PRF application method; primary endpoint, evaluation method, and occurrence date; success rate by MRONJ grade; secondary endpoints, evaluation method, and occurrence date; criterion for defining failure; failure rate and occurrence date; bone re-exposure measurement; imaging tools.Literature reviews that were the most cited or considered the most relevant according to the participating clinicians  were evaluated by the clinical research manager (FG) and two surgeons . Additional, articles were added after manually screening the list of references of all publications selected by the search.Studies published in English and conducted on human subjects were included. Only studies on MRONJ management were considered. Prospective  and retrospective studies  and case series were included. Studies reporting only MRONJ epidemiology data (and not management of the disease) were excluded.The article selection and data collection were performed independently by three investigators . An article was evaluated in its entirety if it reported at least 5 of 12 essential criteria.Discrepancies between the three investigators were discussed to select the final articles. Tables were generated and used to collect the relevant information . Seven aTwo surgeons  assisted by the methodologist (ALP) and the clinical research manager (FG) developed a questionnaire based on the previously listed criteria and important information often missing in the literature and patient medical records.Eighteen relevant and highly cited reviews were identified ,46,47,48Data related to the 12 essential criteria and seven additional items are summarized in For the needs of our RCT, the questionnaire mainly focused on AAOMS stage 2 disease .The majority (39/43) of studies used the AAOMS definition of MRONJ to define the symptoms experienced by patients. Two studies used the Marx classification ,49 Tabl. One stuEven if the authors clearly defined the osteonecrosis, studies focused only on the patient’s clinical status at the time of inclusion, without giving specific information on lesion size, for example. Only three studies reported (as part of the primary outcome) the size of mucosal dehiscence, graded by size at the largest diameter or the maximum diameter of exposed bone, and the size before and after MRONJ treatment ,51,52 Fb Table . Howevern = 20), it was performed after consultation with the treating physician or the oncologist to ascertain whether it was possible to suspend BP and/or denosumab while treating the osteonecrosis (n = 7), it occurred between a few weeks and a maximum of 3 months before MRONJ treatment or a few weeks to a maximum of 3 months after MRONJ treatment [When a drug holiday was required   d (Table n = 8) . Again tn = 8) e.n = 28)  . Only twn = 28) f.Only five studies used the PRF technique to treat MRONJ ,47,50,72n = 39)  . Healing . Healinn = 39) g.Forty-one studies evaluated the primary outcome clinically, with no objective assessment of complete healing (such as X-ray or CT scan) . Only twAgain, as in clinical practice, in all these studies, the success of mucosal closure was associated with no MRONJ symptoms and no signs of residual infection, fistula, pain, or swelling.We found no consistency in the date on which the primary outcome was measured. In 15 studies, it varied between 1 month and 24 months . In six Out of 43 studies, only three focused on stage 2 MRONJ, and they reported a success rate of 0% to 100% ,53,54. TFour studies applied different osteonecrosis treatments depending on the stage ,69,76,77Only two studies analyzed the healing rate by stage; they showed that stage 1 or 2 cases have better healing than stage 3 ,66 Figuh.In four studies, the authors considered the disappearance of MRONJ symptoms  as secondary outcomes instead of the primary outcome ,65,67,78Interestingly, for Holzinger et al., the need for repeat surgery was a secondary endpoint . For MucOnly seven studies clearly defined the failure criterion, as in clinical practice, as either bone re-exposure, disease progression, or MRONJ recurrence ,63,72,75For Nisi and al., re-operation corresponded to failure . InteresIn the other studies, the authors did not specifically report their failure criterion but considered all the patients who did not meet the primary endpoint as failures .Again, as in clinical practice, failure depended on several criteria such as (i) the treatment indication for malignant disease or osteoporosis ,69, (ii)The failure rate was still not properly defined in the studies, and only 27 studies reported or calculated an approximative rate . Only twn = 7) [n = 11) [In our review, we found that the time point for evaluating secondary endpoints was not harmonized and occurred before (n = 7) ,76,78,79[n = 11) ,72,75,76n = 14) [In cases of bone re-exposure, the authors did not measure it and only specified whether it occurred (n = 14) ,75,76,80n = 24) used radiological examinations—orthopantomography (OPT), computed tomography (CT) scan, and cone beam computed tomography (CBCT)—to support the clinical diagnosis and to determine the size/extension of the lesion  or bone scintigraphy of the affected region as needed . One stuIn eight studies, radiological examinations supplemented the evaluation of bone healing but were not used as the primary outcome, which was mucosal healing ,60,68,70n = 29) or combination with denosumab (n = 12). In one study, a monoclonal antibody (mAb) was administrated to one patient, while the others received BPP [Only four of the selected studies were randomized ,47,65,78ived BPP . In anotived BPP .n = 9, and 1–2, n = 2). Only four studies focused on stage 2 (n = 3) [n = 1) [Six studies mixed all the MRONJ grades (0–3); 18 studies had three grades (1–3); and 11 studies had two grades  ,51,54 or [n = 1) . Further [n = 1) ,49.Very few patients per cohort had multiple lesions except for two studies ,51.n = 33), all grades of MRONJ were treated (n = 26). One study only addressed grades 2–3 [n = 1) [n = 4) [n = 1) [When specified  , grade 2 [n = 4) ,51,53,54 [n = 1) . When al [n = 1) ,69,76,77We identified important shortcomings in almost all MRONJ-related parameters as previously mentioned by Lorenzo-Pouso et al. . Here weMRONJ grade was mainly categorized according to the AAOMS classification, but some authors used Marx’s classification ,49 or thAs mentioned in the introduction, the MRONJ patient percentage sometimes combined (i) associated diseases (cancers and osteoporosis), (ii) the drug that contributed to MRONJ (anti-resorptive and anti-angiogenic drugs), (iii) the route of administration (IV and per os), (iv) MRONJ stage, and (v) mandibular/maxillary—multiple lesions ,53,83. HFor the diagnosis, associated clinical characteristics of the lesions, including site, and signs of secondary infection were often reported ,10,84. FOf the 43 studies, only 30 reported multisite lesions. Among these 30 studies, only 18 specified the number of patients suffering from multiple lesions. Only 14 studies specified the number of osteonecrosis sites, with the exact number (two or three sites) disclosed in only 9 studies. Furthermore, the precise location of the lesion(s)  was often not detailed, nor was the number of sites treated, except for two studies ,57. AddiThe role of a drug holiday is debated , and it In the management of MRONJ, it appears that 26 studies treated all grades and only five studies adapted the treatment to the grade. Consequently, it was unclear which groups were compared. For example, two treatments (innovative treatment versus standard surgery) could be compared in two groups of patients that mixed all stages ,74. OnlyIn the context of our RCT, we wanted to collect details on PRF application to assist us with hAM grafting; however, the literature does not describe it. We encourage authors to be more descriptive when using PRF.The clinical assessment of healing was often different between studies  and was p < 0.05), whereas no differences were found at 6 months and 1 year (p > 0.05) [No consensus was found on the exact date on which healing is determined. In our review, we found that the time point at which the primary endpoint was evaluated is not standardized and occurred before or at the end of follow-up. In a retrospective study, 6 months post-surgery, one in two patients healed with no improvement in the cure rate at 12 months . The aut > 0.05) . We beliIn the literature, due to the mixing of variable data , the healing rate percentage varies from 33% to 100% when a medical or surgical treatment or adjuvant therapy is used . InvestiThe criteria for defining failure, its measurement and date of occurrence, also varied between studies and were rarely quantitative ,56,75. HBone healing measurement methods also varied greatly among conventional radiographs , CT scan, CBCT, MRI, and functional imaging with bone scintigraphy and PET ,11,14. HClinicalTrials.gov website, which was mainly built for administrative purposes, as it is difficult for researchers and investigators to find relevant information [Recently, Gindraux et al. critiqued the ormation . HoweverBased on the findings of this review, the missing data identified in the literature and in patient medical records were incorporated in a questionnaire intended for practitioners to assist in the writing of our RCT protocol, defining the active patient population and measuring the effects of therapeutics. We hope this questionnaire will encourage authors to incorporate this important information in their future publications to add to our collective knowledge about MRONJ.Our multicenter RCT on the effectiveness of hAM in MRONJ will be conducted in five French hospitals (grant PHRCI-2020).During our search, we realized that no systematic review contained the information we were looking for. We chose to look for these data in publications that clinicians identified as most relevant. A systematic review of literature would have implied an analysis of more than 4000 PubMed references with low probability of finding an answer to our 12 focused questions.This review identified missing information or absence of consensus related to MRONJ grade classification, drug holiday, and PRF application methods. Additionally, it highlighted a lack of quantitative values sometimes coupled with heterogeneity in (i) patient percentage by MRONJ stage and healing rate, (ii) mucosal defect size, and number of affected sites and treated sites, (iii) primary and secondary endpoints, (iv) criterion for defining failure, its rate, and time of occurrence, (v) bone re-exposure, its measurement, and the use of imaging tools, and (vi) follow-up duration. Consequently, we developed a questionnaire to increase the likelihood this information will be included in future publications. Based on our findings, we have proposed some harmonized practices and encourage clinicians to establish a consensus.


Nodal Marginal Zone Lymphoma(NMZL) is an indolent lymphoma with a very low clinical incidence and is sometimes difficult to differentiate diagnostically from Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM). NMZL with elevated monoclonal immunoglobulin M (IgM) is even rarer. Nontraumatic chylothorax can be seen in aggressive lymphoma, which often happens with chest tightness and dyspnea as the primary clinical manifestation. We reported the first case of monoclonal IgM elevated NMZL complicated by atypical nontraumatic chylothorax. A 64-year-old male patient was first admitted to the Department of Respiratory Medicine with symptoms of chest tightness and shortness of breath. He was given several times thoracentesis to drain pleural effusion to improve pulmonary compression symptoms. The patient had a combination of elevated monoclonal IgM and atypical lymph node biopsy pathology. After two times lymph node biopsies and genetic testing, the patient was finally diagnosed with NMZL. Within a short time, he was admitted to the Department of Hematology due to the reappearance of massive pleural effusion, which indicated chylothorax. The patient repeatedly presented with left-sided pleural effusion, and the color went from red to yellow, and finally white. Only about half of the chylothorax cases present with typical clinical manifestations. We report this case intending to draw the attention of clinicians to hematologic malignancies with atypical nontraumatic chylothorax. Marginal zone lymphoma(MZL) is a group of B-cell lymphomas that originate from the marginal zone of the lymph node and can occur in the spleen, lymph nodes, and mucosal lymphoid tissue, accounting for approximately 10% of all non-Hodgkin’s lymphomas (NHL). The incidence of MZL is low, ranging from approximately 5%-15% in Western countries to 7.8% in China. MZL is highly heterogeneous and is classified by the WHO into three types: extranodal marginal zone lymphoma (EMZL), NMZL, and splenic marginal zone lymphoma (SMZL). EMZL is the most common type, accounting for approximately 70% of all MZL, and has a relatively good prognosis. SMZL accounts for approximately 20% of all MZL, while NMZL is the rarest type of MZL . The etiology of chylothorax may vary depending on the patient population admitted to the medical institution. However, malignancy is often the primary cause of nontraumatic chylothorax, whereas thoracic surgery is the primary cause of traumatic chylothorax . RetrospHerein, we reported our experience with the first case of monoclonal IgM elevated NMZL complicated by atypical nontraumatic chylothorax. The patient was first admitted to the Department of Respiratory Medicine with symptoms of chest tightness and shortness of breath. He was in critical condition and was given several times thoracentesis to drain pleural effusion to improve pulmonary compression symptoms. The color went from red to yellow, and finally white. A lymph node biopsy was performed to clarify the pathology. The patient had a combination of elevated monoclonal IgM and atypical pathology and was finally diagnosed with NMZL. Within a short time, he was admitted to the hospital several times due to the recurrence of massive pleural effusion. The patient was allergic to multiple drugs while on the first-line chemotherapy regimen and had quite acute side effects. The pleural effusion recurred and was eventually completely absorbed with the second-line GB chemotherapy regimen for four cycles. The patient did not undergo drug-related allergic reactions again. The patient eventually achieved CR and is currently in clinical follow-up.9/L, and platelets at 258×109/L. The color of the pleural effusion was red. A laboratory examination of the pleural effusion was as follows, monocytes at 96%, nucleated cell count at 2100×106/L, erythrocytes at 40-50/HF, ADA at 11.4U/L, glucose at 8.26mmol/L, and total protein at 47.8g/L. Biochemical showed an elevated globulin at 62.4g/L, albumin at 27.2g/L, lactate dehydrogenase(LDH) at 147.2U/L, β2 microglobulin at 4mg/L, and an elevated monoclonal IgM at 55.6g/L. A right supraclavicular lymph node biopsy was performed on day 5 of hospitalization. Combined with immunochemical staining and HE staining, histopathological revealed that this case is a B-cell lymphoma. Immunohistochemical results were as follows: LCA (+), CD20 (+), S100 (-), actin (-), SMA (-), Ki-67 (20% +), HMB45 (-), CD31 (+), κ (plasma cell +), λ (-), CD79α (+), CD5 (-), CD3 (background cell +), CD10 (-), CD21 (FDC +), CD23 (FDC+), CD38 (+), CD138 (+), CD43 (+), CyclinD1 (-), Bcl-2 (+), Bcl-6 (30% +), MUM1 (+), PAX5 (+), c-Myc (-), CD19 (+). Immunophenotyping was incomplete, and genetic testing was not done. Due to doubts about the immunohistochemical results and difficulties in distinguishing which subtype of B-cell lymphoma, the patient went to Ruijin Hospital, Shanghai Jiaotong University School of Medicine for an axillary lymph node biopsy in August 2021. An immunohistochemistry analysis were as follows: CD20 (+), CD79a (+), CD19 (+), CD22 (+), BCL-2 (+), IgD (+), CD23 (+), Ki67 (2% +), CD37 (50% +), CD10 (-), BCL-6 (-), C-myc (-), MUM-1 (-), Kappa (-), Lambda (-), CD30 (-), CD38 (-), CD3 (-), CD5 (-), CyclinD1 (-), PD-1 (-), CD138 (-), CD21 (+). Epstein-Barr virus-encoded small RNA in situ hybridization (EBER-ISH) was negative. The somatic mutation of MYD88L265P and CXCR4 were negative. Combined with the patient’s lymph node biopsies immunohistochemistry and clinical presentation, the patient was finally diagnosed with monoclonal IgM elevated NMZL. But the patient refused chemotherapy for personal reasons. In September 2021, the patient was transferred to the local hospital with a recurrence of chest tightness and shortness of breath. CT examination suggested a large amount of effusion in the left pleural cavity, and thoracentesis and drainage were performed again.In June 2021, a 64-year-old male patient was admitted to the Department of Respiratory Medicine of our hospital and complained of chest tightness and shortness of breath for more than 20 days. The chest CT showed that lymph nodes were partially enlarged in the right lower lung hilar, bilateral axillar, and retroperitoneal. In addition, there was a large amount of effusion in the left pleural cavity. Physical examination revealed multiple superficial lymph node enlargements throughout the body, breath sounds could not be heard on the left side, and did not reveal hepatomegaly or splenomegaly. Thoracentesis and drainage were performed in the Department of Respiratory Medicine. The patient’s chest tightness and shortness of breath improved significantly. The tuberculosis test was negative. The hemoglobin level was decreased at 95g/L, leukocytes at 8.84×10In October 2021, the patient was transferred to our hospital for further treatment. Flow cytometry of bone marrow showed that lymphocytes occupied about 12.7% of nuclear cells, of which CD19+ cells occupied about 6.2% of nuclear cells, expressing HLA-DR, CD19, CD20, cKappa, FMC-7, and CD38, and negative for CD5, CD10. There were no abnormalities in the chromosome examination. Referring to the 2014 Lugano staging, this patient was in stage IV group B. The patient chose chemotherapy of rituximab and lenalidomide. The patient developed a widespread rash with pruritus after taking lenalidomide and was considered to be allergic to it, which improved after discontinuation of the drug and anti-allergic treatment.The patient developed shortness of breath and facial swelling during hospitalization, and the ultrasound examination of the chest cavity indicated a large amount of pleural effusion on the left side again. Thoracentesis drainage was performed for the third time, and the the color of pleural effusion was yellow. A flow cytometric analysis of the pleural effusion indicated abnormal monoclonal B cells, which expressed HLA-DR, CD19, CD20, CD22, cKappa, and were negative for CD5, CD10, and FMC-7. The flow cytometry indicated that pleural effusion may be associated with invasion of the pleura. Because of the patient’s allergy to lenalidomide, the patient received the BR  chemotherapy regimen in November and December separately. The patient underwent chills, vomiting, and diarrhea during rituximab treatment and improved with symptomatic supportive treatment.6/L. The level of total protein was at 49.5 g/L, LDH at 110.2 U/L, and glucose at 7.25 mmol/L. The chyle test of pleural effusion was positive. The somatic mutation of MYD88L265P of pleural effusion was negative. Immunophenotyping of the pleural effusion suggested that lymphocytes occupied about 71.3% of the nucleated cells, with CD19+ cells occupying about 1% of the nucleated cells, expressing HLA-DR, CD19, CD20, CD22, and Kappa. Considering that the patient developed a severe allergic reaction to rituximab, we adjusted to GB  chemotherapy regimen in January 2022. One month later, the patient’s chest ultrasound showed a significant reduction of pleural effusion in the left side of the chest cavity. The patient received another two cycles of treatment. In April 2022, pleural effusion could not be detected by ultrasound. The patient performed GB chemotherapy for the fourth course. The patient did not experience drug-related allergies or reignition of pleural effusion. Most importantly, the globulin and IgM gradually decreased to normal. The patient is currently in follow-up and maintaining remission. The patient is currently on maintenance therapy with the GB regimen. No further pleural effusion was observed on repeat chest CT , t , t , and t  . HoweverThis patient repeatedly presented with pleural effusion, and the color of the pleural effusion went from red to yellow, and finally white. In patients with persistent or recurrent pleural effusions of unknown etiology, chylothorax should be considered if a pleural cavity aspiration or chest drainage reveals a milky, cloudy or bloody. Only about half of patients with chylothorax have a milky or milky white pleural effusion, so physicians need to be on high alert, especially in patients with a history of chest, neck, or abdominal surgery . PleuralThe patient underwent a second lymph node biopsy in August 2021, and pathological examination did not reveal diffuse growth of large B cells. After he was transferred to our center in October 2021, he underwent a bone marrow biopsy and re-evaluated his condition. Genetic examination of the patient did not detect TP53 mutation, NOTCH1 mutation, CDKN2A/B deletion, Bcl-2 overexpression, or MYC abnormal expression. Therefore, the transformation of NMZL into diffuse large B cell lymphoma(DLBCL) can be ruled out. However, close follow-up is still needed. The possibility of this kind of transformation should be vigilant if clinical symptoms such as enlargement of lymph nodes, cytopenia, B symptoms, elevated LDH, hypercalcemia, or new genetic abnormalities occur. New small molecules that modulate the pathways involved in the molecular pathogenesis of B-cell lymphoma, monospecific and bispecific monoclonal antibodies, drug-immunoconjugates, and cellular therapies are novel therapeutic options that are available for B-cell lymphoma . The finPatients with chylothorax tend to have difficulty breathing due to the mechanical compression of the pleural effusion. Other symptoms include feelings of heaviness in the chest, weakness, and weight loss . Fever aNMZL is a clinically rare subtype of MZL, and there are no previous clinical reports of NMZL combined with chylothorax. To the best of our knowledge, this is the first clinical report of monoclonal IgM elevated NMZL combined with chylothorax. A retrospective study has analyzed the clinical features of NHL combined with pleural effusion. A total of 430 patients were included in this study. The mean age was 58 years, 64% of the patients were male, 50% of the patients had pleural effusion at the time of NHL diagnosis, 62.5% of the pleural effusions occurred unilaterally, and 90% were exudate . There aNMZL is a clinically rare subtype of MZL, and there are no previous clinical reports of monoclonal IgM elevated NMZL combined with atypical chylothorax. The patient repeatedly presented with left-sided pleural effusion, and the color went from red to yellow, and finally white. Only about half of the chylothorax cases present with typical clinical manifestations. We report this case intending to draw the attention of clinicians to hematologic malignancies with atypical chylothorax.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by The First People’s Hospital of Yancheng. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.LW and QH conceived and designed the study, they contributed equally to this work and share the first authorship. JT, JF, YH, JD, YC, HX collected the clinical data. LW and YM wrote the paper. All authors contributed to the article and approved the submitted version.This work was supported by Yancheng Municipal Health Commission (Grant Number YK2020004).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The hydrogels based on natural polysaccharide offers high hydrophilicity and excellent biocompatibility while exhibiting soft physical properties related to texture and tissues, making them ideal candidates for food and biomedical applications. Herein, a new gel system composed of pectin and salecan (PS) was designed and prepared, and its structural and functional characteristics were further explored by scanning electron microscopy and rheological testing. Data fitting based on Herschel–Bulkley (HB) and Power-Law models enable in-depth comparisons and elucidations of the PS gels’ flow behavior. The cyclic strain time scanning test gave an interesting maximum strain recovery rate of about 70%; meanwhile, the creep data reported an adjustable creep compliance of 0.0146 to 0.1802. The comprehensive analysis of the structure and rheological exploration of the novel pectin-salecan hydrogels demonstrated their potential advantages over pectin and broader applicability in different food or biomedical fields. Hydrogels obtained from natural polysaccharides, which are non-toxic, degradable, and easy to assemble in various combinations, could imbibe a substantial quantity of water/liquid in their networks without dissolving ,2. This β-glucan (polysaccharide) fermented by the strain Agrobacterium sp. ZX09, which was discovered and industrialized in recent years with its newly registered CAS number 1439905-58-4. Although the traditional industry had proved that salecan is suitable for wastewater treatment (dye adsorption) [Although biological characteristics such as biological toxicity and metabolism are certainly important for applying gel materials ,6,7, rheorption) , with thorption) ,17,18. CThe present work aims to prepare a novel pectin-salecan composite gel and conduct detailed structural and rheological studies combining various key rheological parameters and model-fitting data to facilitate its application in different fields.Pectin was purchased from Anhui Yu Ning Pectin Co., LTD, China , and pure water was added to make 4% and 6% solutions, respectively; salecan  was dissolved in water  at room temperature to form a 2% solution. In the low-concentration pectin (4%) group, when salecan: pectin is mixed at 1:1, 2:1, and 1:2, samples PSA, PSB, and PSC are obtained; in the high-concentration pectin (6%) group, when salecan: pectin is mixed at 1:1, 2:1, and 1:2, the samples are labeled as PSD, PSE, and PSF, respectively. The samples PSG and PSH are 4% and 6% pure pectin gel control groups, respectively. As a typical process, the two precursor solutions are mixed in a certain proportion, and calcium ions, which were obtained from Adamas-beta Chemical Co. , are added . After the mixture was incubated in a 90 °C water bath for 20 min, it was then placed at room temperature to stand overnight to obtain the final product. In order to carry out a series of rheological studies, such as creep testing, the linear viscoelastic region  of the samples was determined in advance as a reference. Detailed instructions on the preparation of PS system hydrogels and further characterizations can be found in “Final gels’ product quality is influenced by the ratio of composite hydrogels. A two-concentration pectin (4% and 6%) mixture with salecan (2%) was also tested in order to investigate the compounding effect under different concentrations. As a control group, two neat pectin hydrogels (PSG and PSH) of corresponding concentrations were also prepared. The interior microstructure of lyophilized PSA, which could potentially affect its biological properties, was examined using an electron microscope to determine its morphology. As shown in With an increase in shear rate C,D, the 2) of pectin-salecan hydrogels obtained from both models. In this composite hydrogel system, although the fitting effect of both models is satisfactory, the HB model has a better degree of coincidence.There is evidence in the literature that the K value is influenced by viscosity and internal structure . It is cThe evaluation of the pectin-salecan gels system should also consider creep recovery. A logarithmic increase in stress is applied to gel samples during this experiment; once it has been maintained for a period of time, it will be terminated immediately. Through the analysis of factors derived from the experiment, it is possible to quantitatively determine the recovery efficiency of understudy substances. It can be seen in o) as the ratio of G’ to G” corresponding to the terminal creep measurement area. According to the data, PSB and PSE exhibited the highest values of Jo among all the pectin-salecan gels, suggesting that these two gels are more capable than other samples of restoring viscoelasticity. Pectin-salecan interactions and binding efficiency are superior in certain specific situations, which may explain this fact.It is usually possible to define the equilibrium creep compliance (JThixotropy reflects a special feature, that is, increasing the strain will greatly reduce the modulus of gels, and the modulus will quickly or gradually recover after the strain disappears. Cyclic strain time scanning is a general method to determine the thixotropy of samples by applying alternating large and small strains to gels. A new gel system, consisting of pectin and salecan, was prepared by ionic crosslinking and heating methods. By using a scanning electron microscope, we were able to observe the structural characteristics of PS gels. While the Herschel–Bulkley and Power-Law models were then utilized to analyze the PS gels’ flow behavior. The cyclic strain time scanning test gave an interesting maximum strain recovery rate of about 70%; meanwhile, the creep data reported adjustable creep compliance of 0.0146 to 0.1802. All the comprehensive structural and rheological explorations demonstrated their potential advantages over pectin and broader applicability in some advanced food formulations or biomedical fields.


Ischemic stroke is one of the world’s leading causes of death and disability. It has been established that gender differences in stroke outcomes prevail, and the immune response after stroke is an important factor affecting patient outcomes. However, gender disparities lead to different immune metabolic tendencies closely related to immune regulation after stroke. The present review provides a comprehensive overview of the role and mechanism of immune regulation based on sex differences in ischemic stroke pathology. Several CNS cells, such as glial cells, endothelial cells and even immune cells in the periphery, release mediators such as cytokines, chemokines, reactive oxygen species, and secondary messengers, which play important roles in regulating CNS function. However, the immune response, a combination of innate and adaptive immune responses, is involved in normal brain growth and certain pathological conditions, including dementia and stroke . InflammThe heterogeneity in immune responses to invading and autoantigens is linked to gender differences in autoimmune illnesses, infectious disease susceptibility, vaccine efficacy and age-associated diseases, including Alzheimer’s , 9. It h2The immune reaction in males and females is affected by the biological differences between the sexes, which determine how immune cells react to their respective environments, as shown in 2.1Current evidence indicates that estrogen plays a role in neutrophil apoptosis, chemotaxis and the development of neutrophil extracellular traps (NETs) . Female High doses of estrogen reportedly yield an immunoregulatory effect, boosting the humoral immune response to control the inflammatory response and promoting Th2 polarization and IL-4 secretion –32. In o+ T cells in addition to reducing the production of cytokines  and Th1 cells , macrophage inflammatory protein-1β, (MIP-1β) and RANTES by CD8ytokines . Many imytokines . Progesth1 cells –40. In ah1 cells , 42. Redh1 cells are some h1 cells .Combination therapy with estrogen and progesterone in a middle cerebral artery occlusion (MCAO) model has been shown to protect female rats against brain injury by decreasing the expression of cortical Iba1 and CD3, as well as by inhibiting the expression of IL-6 and chemokines  . It is w+ T cells while enhancing the NK cell response, elevating TNF-α, and decreasing IL-10  mice compared to ovariectomized XX mice, demonstrating the usefulness of the male sex chromosome complement. However, testosterone injection dampened the immunological response, suggesting a compensatory effect between the male chromosomal complement and testosterone , are more prevalent in males, while ‘surrogate’ Th2 cell activity and the secretion of IL-4 and IL-10 are more common in females , 78. MicReduced abundance of B cells throughout the body due to age and gender is associated with a loss of neurotrophic signals produced by B cells, an increase in the deleterious effects of B cell antibody production, and a decline in mental acuity . Besides3The pathogenesis of the ischemic brain is mediated by the immune response following a stroke. The neuronal cell death cascade begins with the release of inflammatory signals from immune cells triggered by brain damage. Glial cells and infiltrating leukocytes, including neutrophils, monocytes, and lymphocytes, make up the bulk of the immune system. The regulation of neuronal damage and wound healing after an ischemic stroke depends on glial cell activation and the production of proinflammatory and anti-inflammatory signals. White blood cells that have entered the damage site release inflammatory mediators, which worsen brain injury.3.13.1.1Microglia are macrophage-like cells in the CNS , making Depending on the activation signals they receive, microglia can either promote injury or repair , 99. DifAlthough both M1 proinflammatory and M2 anti-inflammatory microglia undergo physical changes, their molecular signaling routes and activities evolve differently . Current3.1.2Dendritic cells are professional antigen-presenting cells that express major histocompatibility complex(MHC) II and are essential for bridging the gap between the innate and adaptive arms of the immune system . By presAntigen presentation and antibody synthesis are functions of B cells, which are effector cells. The cerebrospinal fluid of human stroke survivors contains immunoglobulin , 108. Re3.1.3in situ phagocytosis  and selectin , which destroy infected cells by cytotoxic processes, while 40% are helper T cells (CD4+T cells), which release cytokines to modulate adaptive and innate immune responses , namely Th1, Th2, Th17 and induced T regulatory cells (iTregs)  . Maintai(iTregs) . By reco , which regulate IL-17 expression in γδ T cells  have been reported to be differentially expressed in females. Genes related to development, cell trafficking, and cellular mobility experienced male-specific changes in expression, suggestive of a more potent inflammatory response in men . The X c4.3in vitro and in vivo (Female hormones may play an important role in neuroprotection after ischemia , 222. In in vivo , 224. By in vivo .It is well-established that estrogen reduces apoptosis and oxidative stress in the brain , decreasLow concentrations of TNF aid in promoting injury repair, while high concentrations are neurotoxic , 242. Es5The role of sex differences in the incidence and prognosis of ischemic stroke is significant, and the immune regulation based on sex difference is one of the important reasons. However, the importance of gender factors varies at different ages, which is due to sex hormone levels, underlying disease differences and other factors. There is growing evidence that some risk factors, like hypertension and atrial fibrillation, tend to occur more frequently in older women, while others, like diabetes and smoking, disproportionately affect women. The disparity in stroke prevalence and outcome may also be influenced by sex-specific risk factors, such as the use of oral contraceptives and menopause. Evidence suggests that females are more likely than males to exhibit non-traditional acute stroke symptoms, making it more challenging for clinicians to correctly diagnose a stroke and potentially delaying the administration of thrombolytic intervention.in vitro as well as in animal models, leading to a slow progress in the study of mechanisms in this area. We expect more detailed studies to support the development of gender-specific stroke treatment options, including immunotherapy agents and specific inflammatory markers.More regrettably, there is still no gender-specific stroke treatment, even though gender differences are a valuable risk factor in many studies. Research on immune regulation based on sex difference presents great difficulties because it is difficult to simulate human ischemic stroke state PN and LL completed the manuscript and contributed equally to the article. YZ, ZS, BW, HL, and SZ collected and collated literature. SQ and YL designed this work. All authors contributed to the article and approved the submitted version.


Some studies indicate a different response to treatment between migraine patients with and without aura.To determine whether aura, or simple or complex aura subtypes, are clinical markers predicting response to preventive treatment.Conducted a retrospective cohort study at a headache clinic in a tertiary referral hospital. We included data from patients registered from 1 November 2014, to 30 June 2022, having migraine with or without aura, or with simple or complex aura, and who had received migraine preventive treatments with at least 3 months follow-up. The primary outcome was a response to preventive treatment defined as at least a 50% reduction from a baseline of monthly migraine or headache days (MMDs/MHDs). Secondary outcomes were improvement in quality of life and disability scores.For migraine patients with (45) and without (123) aura who took a migraine preventive with at least 3 months follow-up; except for median age, which was older for patients without aura, baseline sex, comorbidity, and migraine data were without significant difference including median history of migraine, chronic migraine subtype, chronic migraine with medication-overuse headache, median or mean MMDs/MHDs, number of preventive medications used, or migraine preventive medication inhibiting spreading depolarizations. Treatment outcomes at 3 and 6 months follow-up were not significantly different between migraine patients with and without aura, or with simple and complex aura, but tended to be greater in those with aura and those with complex aura. After adjustment for baseline comorbidity, migraine subtypes, aura subtypes, the number of preventives used, history of migraine, and MMDs/MHDs, we found no significant differences in 30% and 50% reduction from baseline of MMDs/MHDs in 3 or 6 months or most recent follow-up.Preventive treatment response tended to be associated with migraine aura subtypes. We found preventive treatment response tended to have more favorable outcomes in those with aura, especially those with complex aura. Migraine treatment consists of two approaches, treatment of acute attacks, and preventive treatment, which aims to reduce the frequency, severity, and duration of migraine attacks. The disorder can be categorized into two major subtypes: migraine with aura and migraine without aura. Because of the possibly different pathophysiology and etiology of migraine between the subtypes , treatmeThis retrospective cohort study was conducted at the Chulalongkorn Comprehensive Headache Center, King Chulalongkorn Memorial Hospital, a public general and tertiary referral hospital in Bangkok, Thailand, serving as a teaching hospital for the Faculty of Medicine, Chulalongkorn University. With an in-patient capacity of 1,435 beds, it is one of the largest hospitals in Thailand. The headache center has registered patients and created a case-record form for gathering patients’ demographic and socioeconomic data and headache information on every visit since 3 January 2007. The present study included data from all patients registered between 1 November 2014, and 30 June 2022, and was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 0644/65).We included patients with migraine according to the International Classification of Headache Disorders (ICHD), 2nd edition , ICHD, 3The inclusion criteria were as follows: age between 15 and 80 years; taking preventive treatment; at least 3 months follow-up. The exclusion criteria were as follows: other primary and secondary headaches, but not medication-overuse headaches. Patients in this study were categorized into two groups, with aura or without aura, and with simple or complex aura. Potential chronic migraine and probable medication-overuse headache from the 2nd edition of the ICHD, and chronic migraine with medication-overuse headache from the beta version and the 3rd edition of the ICHD were combined to form a group with chronic migraine and medication-overuse headache.The primary outcome was a reduction from the baseline of monthly migraine/headache days (MMDs/MHDs) at month 3 for migraine patients with and without aura. The secondary outcome was a reduction from the baseline of MMDs/MHDs at month 3 for migraine patients with simple and complex aura. Other secondary outcomes were as follows: at least 30 and 50% reduction from baseline of MMDs/MHDs at month 3; a reduction from baseline of MMDs/MHDs at month 6, and at most recent follow-up; at least 30 and 50% reduction from baseline of MMDs/MHDs at month 6, and at most recent follow-up; quality of life score measured by using the Thai version of the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1  changed t test to determine mean differences, and a Mann–Whitney U test to determine median differences. Multivariate analyses using log-binomial logistic regression were applied to adjust for treatment effect modifiers, including the number of preventive medications used at baseline, grouped into two categories: monotherapy and polytherapy; migraine subtypes, grouped into two categories: episodic and chronic migraine, or chronic migraine with medication-overuse headache; aura subtypes, grouped into two categories: simple or complex aura; and comorbidity, grouped into two categories, that is, with or without in a binary manner, to evaluate the treatment outcomes, including a 30% and 50% reduction of MMDs/MHDs at months 3, 6, and at most recent follow-up. The correlation between aura subtypes and the success of preventive treatment was applied using a contingency coefficient. A Bonferroni post hoc procedure was applied for a family-wise error rate due to multiple analyses. The sample size for migraine patients with aura and without aura was calculated with a minimum treatment response of 20% in the migraine patients without aura, an anticipated relative risk of 2.5, P < 0.05, and a power of 80%. The ratio of migraine patients with aura; to patients without aura, was 1:3. The sample size for migraine patients with aura was 39, and for migraine patients without aura was 117. We excluded cases where data was missing.Descriptive statistics were applied for data summary as follows: proportion or percentage for categorical data; mean and standard deviation for continuous data with normal distribution; or median and interquartile range for continuous data with non-normal distribution. Inferential statistics were applied as follows: we used a chi-square or Fisher exact test to compare dichotomous data between the two groups, an unpaired P = 0.79) between migraine patients with aura (9.3%) and without aura (10.0%) in the proportion of patients without indication for a migraine preventive medication, equal to 4 MMDs/MHDs or less.Between 1 November 2014, and 30 June 2022, 271 patients registered at our headache center. Of these 271 patients, 47 were diagnosed with secondary headaches or other primary headache disorders. Of the 224 patients with migraine, 54 (24.1%) had migraine with aura, and 170 (75.9%) had migraine without aura. Of the 54 migraine patients with aura, 49 had a simple aura, and 5 had a complex aura. The simple aura was as follows: simple visual aura for 41 (83.7%) and simple somatosensory aura accounted for 8 (16.3%) patients . The simFor migraine patients with and without aura who took a migraine preventive medication, except for the median age, which was older for migraine patients without aura, baseline sex, comorbidity, and migraine data were without significant differences, including the median history of migraine, chronic migraine subtype, chronic migraine with medication-overuse headache, median or mean MMDs/MHDs, median Thai-version MSQ version 2.1 score, median Thai-version MIDAS score, the number of preventive medications used, or migraine prevention inhibiting spreading depolarizations used . The comFor migraine patients with simple and complex aura who took a migraine preventive medication, baseline age, sex, comorbidity, and migraine data were without significant differences, including the median history of migraine, chronic migraine subtype, chronic migraine with medication-overuse headache, median or mean MMDs/MHDs, median Thai-version MSQ version 2.1 score, median Thai-version MIDAS score, the number of preventive medications used, or migraine prevention inhibiting spreading depolarizations used . HoweverDuring the treatment follow-up, 45 of the 48 migraine patients with aura, and 123 of the 142 migraine patients without aura had at least 3 months follow-up. Baseline age, sex, migraine data, and treatment outcomes for 3-month follow-up including a mean reduction from baseline of MMDs/MHDs, 30 and 50% reduction from baseline of MMDs/MHDs, mean improvement from baseline of Thai-version MSQ version 2.1, and mean reduction from baseline of Thai-version MIDAS score at 3, 6 months, and at most recent follow-up, were not significantly different between migraine patients with and without aura, but tended to be greater in those with migraine with aura . For theIn the present study, migraine aura was found in 54 patients (24.1%), which is consistent with the reported approximate range of from 15 to 33% of patients with migraine . Comorbipost hoc analysis comparing migraine patients with (n = 269) and without aura (n = 542) to determine the efficacy of topiramate in preventing migraine aura found migraine without aura decreased by 43.1% in the final 28 days of the open-label phase, in which migraine aura decreased by 54.1% in migraine patients with aura, and a 44.3% reduction in migraines in those without aura. However, in the double-blind phase, while migraine was increased with placebo as it was in the full study, the increase versus the frequency after topiramate treatment was not significant, presumably due to a lack of statistical power in the subgroup analysis. Likewise, the investigators found no significant change in aura frequency between the groups. They concluded topiramate reduces the frequency of aura in parallel with migraine frequency, similarly for migraine patients with and without aura (We found no significant differences in treatment outcomes between migraine patients with and without aura. The proportion of patients with a 30% reduction from baseline of MMDs/MHDs at 3 months follow-up tended to be higher in patients with aura (71.1%) than in patients without (65.9%) and the mean reduction from baseline of the Thai-version MIDAS score was 3.5 for those with migraine with aura and 1.0 for those without aura; however, the difference was not significant. At 6 months follow-up, there was a trend for improvement in the 30 and 50% reduction from baseline of MMDs/MHDs in patients with aura, of 78.6 and 64.3%, respectively, compared with patients without aura, namely 69.7 and 58.4%, respectively, and mean improvement from baseline of the Thai-version MSQ version 2.1 in patients with aura, with a mean score of 16.3 compared with 12.8 in patients without aura, and a similar trend was found for the most recent follow-up. Between aura subtypes, simple and complex aura, the mean reduction from baseline of MMDs/MHDs at 3, 6 months, and at most recent follow-up tended to be higher in patients with complex aura, at means of 15.8, 15.3, and 16.8 days, than in patients with simple aura, at means of 7.6, 7.7, and 9.9 days, respectively, and the proportion of patients with a 30 and 50% reduction from baseline of MMDs/MHDs at 3 months follow-up tended to be higher in patients with complex aura (100 and 75%) than in patients with simplex aura (68.3 and 58.5%); however, the difference was not significant. At 6 months follow-up, there was a trend to improvement in the 50% reduction from baseline of MMDs/MHDs in patients with complex aura, namely 75%, compared with patients with simple aura, at 62.5%, and mean improvement from baseline of the Thai-version MSQ version 2.1 score in patients with complex aura, with a mean score of 20.5 compared with 15.7 in patients with simple aura. We also adjusted for potential treatment effect modifiers, including chronic migraine subtype with/without medication-overuse headache , the numout aura .Limitations of the present study may include its single-site design and sample size. If a larger multicenter study or if a meta-analysis is used to investigate the relationship between preventive treatment response and migraine aura subtypes, trends seen in the present study may become significant. Consistent use of a structured interview following the Migraine Aura Complexity Score and a more careful assessment of headaches as migrainous may provide a better classification of migraine aura.Other limitations are as follows: we had recorded no data regarding the frequency of migraine aura and aura subtypes, and our inability to identify from patient records, migraine with comorbid tension-type headache or other primary headache disorders.We found preventive treatment response tended to have more favorable outcomes in those with aura, especially those with complex aura.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 Institutional Review Board of the Faculty of Medicine, Chulalongkorn University. Written informed consent for participation was specifically waived for this retrospective study in accordance with the national legislation and the institutional requirements.TA contributed substantially to the acquisition and analysis of data. Both authors contributed substantially to the concept and design of the study, to interpretation of data, drafted the manuscript and revised it critically for important intellectual content, approved the version submitted, its publication, and agree to be accountable for all aspects of the work.


RASSF1A) gene in cell-free DNA on the outcomes of patients with different types of cancer have been reported, the results are inconsistent.  Although the effects of methylation of the Ras association domain-containing protein 1 isoform A , which suggested there was a significant association between RASSF1A methylation and overall survival, and patients with an RASSF1A methylation status had a significantly increased risk of total death. Moreover, the Egger test result suggested there was no significant publication bias among the included studies.  Nine relevant publications involving a combined total of 1254 patients with different types of cancer were included in this study. The combined results of the random effects models yielded a hazard ratio of 1.73 (95% confidence interval: 1.31, 2.29; RASSF1A in cell-free DNA in cancer patients was observably associated with an increased risk of poor overall survival. The methylation of  DNA methylation, a form of epigenetic modification, plays an important role in many physiological and pathophysiological processes, including carcinogenesis –3. EpigeRASSF1A) gene, which encodes a member of the Ras association domain family, belongs to a class of genes that are often silenced by methylation rather than by mutation events. The RASSF1A protein is associated with the cell cycle, microtubule stabilization, and apoptosis [RASSF1A is usually expressed in most normal tissues, but it is downregulated or lost in some tumor cell lines and tissues [RASSF1A is associated with various types of tumors, including lung cancer and esophageal squamous carcinoma [RASSF1A methylation on the prognosis of patients with different types of cancer, the results are inconsistent across different studies [RASSF1A methylation in cfDNA and the prognosis of cancer patients.The Ras association domain-containing protein 1 isoform A  the study was of cohort type; and (4) the study reported hazard ratios (HRs) with 95% confidence intervals (95% CIs) of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), or relapse-free survival (RFS), adjusted by univariate or multivariable analysis.After the literature search, the retrieved articles were further screened according to certain inclusion and exclusion criteria. The inclusion criteria were as follows: (1) the study participants were adult patients with a histologically or pathologically confirmed cancer; (2) the study investigated the relationship between The exclusion criteria were as follows: (1) reviews, conference abstracts, commentaries, and other nonliterary research articles; (2) studies in which HRs (95% CIs) were not reported or could not be calculated according to the information in the article; and (3) repeated publications or multiple articles with the same data (only the one with the most complete research information was included).The data extraction according to the inclusion and exclusion criteria described above was performed by two reviewers. The following data were extracted: the first author name, year of publication, country in which the research was conducted, research type, basic characteristics of the object of study (sample size), patient gender, patient age, cancer type, sampling time, follow-up time, confounding factors, and research outcomes. After completing the data extraction, the two reviewers would exchange their extraction tables and discuss and resolve any inconsistencies.The methodological quality of the studies, which was evaluated on the basis of the selection, comparability, and exposure of the included subjects, was scored according to the Newcastle-Ottawa Scale  . StudiesRASSF1A methylation status and the prognosis of cancer patients, HRs and 95% CIs were used as effect size indicators for evaluating whether the difference in risk of death between the methylated and unmethylated groups was statistically significant. Cochran's Q test and the I2 test were used to test for heterogeneity [Q statistic of P < 0.05 or I2 > 50% indicates that there is significant heterogeneity between studies, and the random effects model should be used for the meta-analysis. Values of P ≥ 0.05 and I2 ≤ 50% suggest that heterogeneity is not significant, and the fixed effects model is used instead. In addition to the inclusion of all cancer patients for the meta-analysis, the effect of RASSF1A methylation on patient prognosis was also evaluated according to specific cancer types. Egger's test was used to assess whether there was significant publication bias in the included studies [To explore the association between the ogeneity . A Q sta studies . Additio studies .RASSF1A methylation status in cfDNA. Only three studies reported an HR (95% CI) with multifactor adjustment, whereas the remaining studies conducted single-factor analyses.As indicated in The results of the methodological quality evaluations are shown in RASSF1A methylation and OS for all the cancer patients, where it can be seen that there was significant statistical heterogeneity among the included studies. The combined results of the random effect models suggested a significant relationship between RASSF1A methylation and OS (P < 0.001). Therefore, cancer patients with RASSF1A methylated may have a significantly increased risk of a poor survival prognosis.Since only one article reported RFS, DFS, and PFS results, this meta-analysis only incorporated effect values on OS. RASSF1A methylation and OS in patients with GC, CRC, and BC specifically are illustrated in Figures P = 0.004) between RASSF1A methylation and GC prognosis (P < 0.001) between RASSF1A methylation and CRC prognosis , and the combined results were stable and not affected by any single study. Similarly, the sensitivity analysis of the CRC patients also suggested stable combined outcomes. However, the meta-analysis results for the GC patients were not stable because they became insignificant (P = 0.238) after the Karamitrousis [As shown in itrousis  study haP values of greater than 0.05 for the total, GC, and CRC studies, indicating the absence of any publication bias  rendered them unsuitable for sensitivity analysis or Egger's test.Egger's test, which was used to evaluate whether there was observable publication bias between the studies, yielded ion bias . The limRASSF1A, a well-known tumor suppressor gene, affects cancer development and progression. Its inactivation through mutation, loss of heterozygosity, or promoter methylation occurs in various cancer types. The effect of RASSF1A methylation on the prognosis of patients with specific types of cancer has been well reported, whereas there are no published studies on the association between RASSF1A methylation in cfDNA and prognosis for all cancer patients. Therefore, we conducted this meta-analysis and found significant correlations between RASSF1A methylation in cfDNA and cancer prognosis in general, especially in GC, CRC, and BC.RASSF1A methylation is considered to be one of the first cellular changes to occur during tumor progression, and the frequency of this epigenetic modification varies widely among solid tumors [RASSF1A has also been investigated. Hassan et al. found that methylation of RASSF1A was associated with poor prognosis in patients with neuroblastoma [RASSF1A methylation in lung cancer tissues was significantly associated with a lower OS [RASSF1A is often caused by hypermethylation of the promoter region, which allows the abnormal methylation of RASSF1A being more easily detected in a variety of cancers, including BC, lung cancer, and gastrointestinal cancer [RASSF1A promoter hypermethylation had poor prognoses [RASSF1A promoter methylation had significant lower PSF and OS [RASSF1A remains expressed in cancer, concentrations of RASSF1A protein above or below its optimal expression threshold can disrupt signal transduction and lead to malignant transformation [RASSF1A was also found to be significantly correlated with tumor size and histological grade of BC [RASSF1A promoter disrupts normal body signal transduction, leading to tumor recurrence, and metastasis and poorer clinical outcomes.d tumors , 28. Theblastoma . Sensitilower OS . These fl cancer . The sturognoses . CompareF and OS . Althougormation . Promotede of BC . TherefoRASSF1A in cfDNA, that can easily be detected in liquid biopsy samples or blood samples from cancer patients to predict their prognostic risks and clinical outcomes.Clinically, liquid biopsy or collection and analysis of easily accessible patient samples, such as blood, can contribute to the diagnosis of early tumors, as a less invasive diagnostic approach , 35. CfDTo illustrate the strengths of this meta-analysis, we not only included patients with various types of cancer for the combination of effect values but also grouped specific cancers for analysis, with the combination results showing good consistency. Furthermore, the evaluation of the methodological quality of the included studies showed that selection bias, measurement bias, and lost track bias were reasonably controlled , which suggested the studies were of medium and high quality. More importantly, no significant publication bias was found in this meta-analysis, and the combined results were highly reliable.RASSF1A methylation and disease progression and recurrence for comparison with the OS association.There were several limitations to our meta-analysis. First, although the statistical heterogeneity of the nine studies was relatively small, the clinical and methodological heterogeneity among them  should not be ignored. Second, the number of studies included in the meta-analysis was small, with less than five articles for each specific cancer type. Additionally, the incomplete literature information made it difficult for us to explore the influences of age, cancer stage, treatment methods, and other factors on the combined results through subgroup analysis. Third, because the meta-analysis results for GC and BC were unstable, more large-sample studies are needed to verify the findings. Finally, it is recommended that follow-up studies focus on the relationships between RASSF1A methylation in cfDNA was observably associated with an increased risk of total deaths for patients with GC, CRC, and BC. Therefore, more high-quality, large-sample, and prospective cohort studies are recommended to verify the stability of the results.In conclusion, this meta-analysis revealed that