In-hospital mortality, prolonged length of stay (LOS), and 30-day readmission are common outcomes in the intensive care unit (ICU). Traditional scoring systems and machine learning models for predicting these outcomes usually ignore the characteristics of ICU data, which are time-series forms. We aimed to use time-series deep learning models with the selective combination of three widely used scoring systems to predict these outcomes.A retrospective cohort study was conducted on 40,083 patients in ICU from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. Three deep learning models, namely, recurrent neural network (RNN), gated recurrent unit (GRU), and long short-term memory (LSTM) with attention mechanisms, were trained for the prediction of in-hospital mortality, prolonged LOS, and 30-day readmission with variables collected during the initial 24 h after ICU admission or the last 24 h before discharge. The inclusion of variables was based on three widely used scoring systems, namely, APACHE II, SOFA, and SAPS II, and the predictors consisted of time-series vital signs, laboratory tests, medication, and procedures. The patients were randomly divided into a training set (80%) and a test set (20%), which were used for model development and model evaluation, respectively. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and Brier scores were used to evaluate model performance. Variable significance was identified through attention mechanisms.A total of 33 variables for 40,083 patients were enrolled for mortality and prolonged LOS prediction and 36,180 for readmission prediction. The rates of occurrence of the three outcomes were 9.74%, 27.54%, and 11.79%, respectively. In each of the three outcomes, the performance of RNN, GRU, and LSTM did not differ greatly. Mortality prediction models, prolonged LOS prediction models, and readmission prediction models achieved AUCs of 0.870 ± 0.001, 0.765 ± 0.003, and 0.635 ± 0.018, respectively. The top significant variables co-selected by the three deep learning models were Glasgow Coma Scale (GCS), age, blood urea nitrogen, and norepinephrine for mortality; GCS, invasive ventilation, and blood urea nitrogen for prolonged LOS; and blood urea nitrogen, GCS, and ethnicity for readmission.The prognostic prediction models established in our study achieved good performance in predicting common outcomes of patients in ICU, especially in mortality prediction. In addition, GCS and blood urea nitrogen were identified as the most important factors strongly associated with adverse ICU events. Patients in the intensive care unit (ICU) are usually critically ill, presenting a high mortality risk compared with other departments in the hospital . In addiHowever, traditional scoring systems, even some machine learning methods in predicting these outcomes, especially in stratifying the risk of readmission, have shown only modest results –10. AlthIn this study, we aimed to apply three time-series deep learning models for predicting three common ICU outcomes, namely, mortality, prolonged LOS, and readmission, of patients in ICU from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and identified predictors of high importance based on attention mechanisms to facilitate model interpretability.Patient information was extracted from the MIMIC-IV database  to conduA total of 40,083 patients were included in our study. Patients were excluded for the following reasons: (1) age ≤ 18 years or ≥ 90 years and (2) stay in the ICU for less than 24 h. In addition, we only included the first admission record if a patient was admitted to the ICU more than once, so the admission records and subject IDs corresponded.We extracted the following data from the MIMIC-IV database upon the initial 24 h of ICU admission and the last 24 h before discharge, and all of the variables were selected according to three conventional scoring systems [APACHE II , SOFA 2 and SAPShospital_expire_flag in the admissions table in the MIMIC-IV database. Another is the occurrence of prolonged LOS, a binary variable with a cutoff point of 75th percentile LOS of the study participants, which was 4 days in our study. Thus, patients with LOS for more than 4 days were labeled as 1, and those with LOS for less than 4 days were labeled as 0. Prolonged LOS information was calculated from the icustays table. The other outcome is readmission, which was defined as whether the patient was recorded as having full-cause readmission within 30 days after hospital discharge.Three primary outcomes were needed for prediction in our study. One is the occurrence of death in the hospital, which was defined as whether the patient died during hospitalization, and this information can be extracted from Data extracted from the initial 24 h after ICU admission were used to predict mortality and prolonged LOS, while data derived from the last 24 h before discharge were used to predict the risk of 30-day readmission.t-test or Wilcoxon rank-sum test according to their normality test results. Categorical variables are presented as counts and percentages and compared through the Chi-square test or Fisher’s exact test with significant p-values < 0.05.Continuous variables are presented as the means ± SDs or medians and interquartile ranges and are compared using Student’s According to recording frequencies, predictors can be classified into dynamic predictors and static predictors. Dynamic variables were those recorded more than once during ICU hospitalization, mostly consisting of vital signs and laboratory tests. Static variables, which included demographic information such as age, sex, and admission type, were all constant and did not change over time. The initial 24 h of ICU admission and the last 24 h before discharge were divided into a time-series of 24 steps, and all variables were obtained for each 1 h window to generate a complete dataset. For static variables, the same value of each patient was recorded 24 times. For dynamic variables, if a variable was recorded more than once in an hour, its mean value was used for aggregation, and then the last observation carried forward (LOCF) was conducted to impute missing values of time-series data. After the first missingness imputation, variables with missing rates of more than 30% were excluded. All categorical variables were one-hot encoded, so the final number of predictors was 33.All participants were randomly split into a training set (80%) and a test set (20%). The mean value of each continuous variable in the training set was used to impute the remaining missing values in both the training set and the test set. Three deep learning models, RNN, GRU, and LSTM, were used for model development in the training set, and model performance was evaluated in terms of AUC, sensitivity, specificity, and Brier score in the test set. Variable importance according to the attention mechanism was also produced from the test set.All data analysis procedures were conducted with SAS 9.4 and Python 3.7.Xt represents input variables of the present time step, while Ht–1 is the hidden layer of the previous time step, two of which co-determine the hidden layer Ht of the present time step, so Ht contains all information of both the previous time steps and the present time step.The mechanism of RNN to tackle time-series problems is that it includes a hidden layer, which incorporates information from all former steps, and with the extension of each time step, the hidden layer iteratively updates, and stores new memory. As shown in Zt) decides how much information to forget and how much information to keep and the reset gate (Rt) determines how much information on former steps to forget, as shown in Gated recurrent unit enriches the structure of RNN with gating systems (an update gate and a reset gate) to solve the problem of too much information kept in the hidden layer when time sequences are too long, in which the update gate (It), a forget gate (Ft), and an output gate (Ot) addition with a memory cell Ct. The three gates are all generated by Xt and Xt–1, and they separately decide how much present input information to keep, how much previous information to forget, and how much total information to output. The schematic diagram of an LSTM cell is shown in Long short-term memory is more complicated than GRU. It has three gates, an input gate (at = softmax(xtWt), and the sum of the weight of each time step was equal to 1 (|at| = 1), so the new input variable was represented as Xnew = A⊙X. As a result, we ignored the possibly different contributions of each time step but focused on the contribution of each variable. Through the aggregation of all time steps, the global contribution of each variable can be generated.Considering the complexity of the three deep learning models, especially LSTM, which has relatively more parameters, it would be very difficult to explain the contribution of each variable from these prediction models. Hence, an additional layer was added to each of the three models at the level of input variables; specifically, each variable of each time step  was given an attention weight, which can be represented as P < 0.001), comprised more women (P < 0.001) and more other or unknown ethnicity (P < 0.001), and were more likely to be admitted to the emergency room and transferred from the hospital (P < 0.001), had a longer LOS in the ICU (P < 0.001), and were more likely to be diagnosed with metastatic cancer (P < 0.001) and hematologic malignancy (P < 0.001). Patients with prolonged LOS were also comprised of more women (P < 0.015) and other or unknown ethnicity (P < 0.001), more transferred from the hospital (P < 0.001), and more were diagnosed with hematologic malignancy (P < 0.048), while fewer were diagnosed with metastatic cancer (P = 0.025). Patients who were readmitted were also older (P < 0.001), comprised of more white people and fewer other or unknown ethnicity (P < 0.001), more were transferred from the hospital (P < 0.001) and diagnosed with metastatic cancer (P < 0.001) and hematologic malignancy (P < 0.001). The diagnosis of AIDS showed similar results between both patients with and without in-hospital death (P = 0.777), prolonged LOS (P = 0.985), and readmission (P = 0.146).A total of 40,083 patients were included in our study for the prediction of mortality and prolonged LOS after excluding those who did not meet the selection criteria, and 36,180 of them were included to predict readmission, as shown in The receiver operating characteristic (ROC) curves of the three prediction models in predicting in-hospital mortality, prolonged LOS, and 30-day readmission are shown in The significance of the variables is shown in In this study, three time-series deep learning models were applied to predict in-hospital mortality, prolonged LOS, and 30-day readmission with conventional and easily available variables in ICU settings, and influential factors associated with the three outcomes were identified through attention mechanisms to enhance model interpretability.Our study focused on the outcome prediction of general patients without distinguishing their diseases, and the results showed in-hospital mortality of 9.74%, a prolonged LOS of 27.54%, and 30-day readmission of 11.79%, which were roughly consistent with previous studies , 30. ForThe results of the performances of the three deep learning modes  did not differ greatly in predicting outcomes, and this was inconsistent with what was obtained by Na’s study . For a sAttention mechanisms allowed us to identify important features used by three different models in prediction, and the influential variables of each outcome selected by different deep learning models also did not differ greatly. The GCS was identified as the top important factor for mortality, prolonged LOS, and readmission prediction, and the same results can also be extracted from other similar studies. For example, some studies have concluded that GCS is an independent mortality-related factor and has the most significant feature importance in some specific diseases , 39. ThiThere are several limitations to our study. First, we excluded some variables that may have predictive values because of high missingness rates, such as the mean arterial blood pressure and bilirubin, and the insurance variable, which may influence LOS, was also not included considering that more than half of the insurance type was labeled “Others.” Second, as a single-center study, the generalizability and representation of our conclusion still need to be demonstrated by other data sources. Third, the alternative variables may still be not comprehensive. For example, the diagnosis at ICU admission was not considered a predictor in our study, which may affect the application and generalization of this model in different patient groups. More variables that are easily available need to be explored to further improve model performance.Three time-series deep learning models were applied for the prediction of three common ICU outcomes, namely, mortality, prolonged LOS, and readmission. The prediction models reached good performance, especially in mortality prediction, which is of great value in clinical settings considering the conventional and easily available variables incorporated. Our results also indicate that GCS and blood urea nitrogen were highly associated with adverse outcomes of patients in ICU, and focusing on these variables can better assist clinical decisions.https://physionet.org/about/database/.All data analyzed in this study were obtained from the MIMIC-IV database, which can be found at Ethical review and informed consent were not required for this study as the study database, the MIMIC-IV database is publicly available, and all patient data are de-identified.YD designed the study and wrote the manuscript draft. BL and YJ critically revised the manuscript. SL assisted with the study protocol and data analysis. ZW contributed to manuscript editing and model explanation. YW helped with manuscript revision. All authors read and approved the final manuscript.


The characteristic morphological parameters (bony posterior fossa volume (bony-PFV), posterior fossa crowdness, cerebellar tonsillar hernia, and syringomyelia) and CSF dynamics parameters at the craniocervical junction (CVJ) in Chiari malformation type I (CMI) were measured. The potential association between these characteristic morphologies and CSF dynamics at CVJ was analyzed.A total of 46 cases of control subjects and 48 patients with CMI underwent computed tomography and phase-contrast magnetic resonance imaging. Seven morphovolumetric measures and four CSF dynamics at CVJ measures were performed. The CMI cohort was further divided into “syringomyelia” and “non-syringomyelia” subgroups. All the measured parameters were analyzed by the Pearson correlation.P < 0.001) in the CMI group. Otherwise, the PCF crowdedness index  and the peak velocity of CSF (P < 0.05) were significantly larger in the CMI cohort. The mean velocity (MV) was faster in patients with CMI with syringomyelia (P < 0.05). In the correlation analysis, the degree of cerebellar tonsillar hernia was correlated with PCF CI , MV , and the net flow of CSF . The Vaquero index was well correlated with the bony-PFV , MV , and the net flow of CSF .Compared with the control, the posterior cranial fossa (PCF) area, bony-PFV, and CSF net flow were significantly smaller (The bony-PFV in patients with CMI was smaller, and the MV was faster in CMI with syringomyelia. Cerebellar subtonsillar hernia and syringomyelia are independent indicators for evaluating CMI. Subcerebellar tonsillar hernia was associated with PCF crowdedness, MV, and the net flow of CSF at CVJ, while syringomyelia was associated with bony-PFV, MV, and the net flow of CSF at the CVJ. Thus, the bony-PFV, PCF crowdedness, and the degree of CSF patency should also be one of the indicators of CMI evaluation. Chiari malformation type I (CMI) is diagnosed when the cerebellar tonsil exceeds the foramen magnum (FM) by 5 mm on magnetic resonance imaging (MRI) , 2. ThisPhase-contrast magnetic resonance imaging (PC-MRI) has been rigorously developed, and the study of CSF dynamics is no longer limited to the anatomical perspective but to recognize and study the CMI disease dynamically, but the exploration of CSF dynamics is still unclear. We often observe patients with CMI with mild cerebellar tonsillar hernia , and somThere are few reports about the correlation between the morphological changes in CMI and CSF dynamics , 17, andApproval for this study was obtained from our institutional review board, and consent was obtained from all subjects. Seventy-three hospitalized and surgically treated adult patients were retrospectively evaluated from January 2019 to January 2022, and hospitalized adults diagnosed with unruptured intracranial aneurysms matched for sex and age served as the control group. All enrolled subjects underwent thin-layer CT and PC-MRI examinations of the neck. All data were measured preoperatively.The inclusion criteria were as follows:Primary diagnosis as CMI : the cerAge over 16 years.The exclusion criteria were as follows:Basilar invagination (BI) , atlantoAcquired CMI or spinal cord malformation, such as hydrocephalus, intracranial neoplasm, or tethered spinal cord.A history of skull or spinal trauma or surgery.Thin-slice CT imaging was performed on a 128-slice multidetector scanner  with a thickness of 0.5 mm. As described previously , the bonPhase-contrast magnetic resonance imaging was performed using a 1.5T scanner . The hydrodynamics of CSF measured during a cardiac cycle consisted of 36 phase and amplitude maps. The coding speed was 12 cm/s, the thickness was 4 mm, the reverse corner was 15°, and the direction of speed coding was cranial to caudal.(1) Tonsil descent: the distance between the lowermost margin of the cerebellar tonsils and McRae's line.(2) Syrinx length: the number of segments that syrinx span the spinal cord.(3) VI : Vaquero(4) HB area: hindbrain area, the area of the cerebellum and the brainstem on a midsagittal MRI image, excluding herniated tonsils.(5) PCF area: posterior cranial fossa area, the area bordered by the clivus, the tentorium, the occipital bone, and the FM on MRI in the midsagittal view.(6) PCF CI: PCF crowding index, calculated as HB/PCF × 100%.(7) Bony-PFV : definedmax: maximum positive velocity, the maximum cranial velocity of CSF at FM in a cardiac cycle.(8) PVmax: maximum negative velocity, the maximum caudal velocity of CSF at FM in a cardiac cycle.(9) NV(10) AbsMV: the absolute value of the mean velocity.(11) Net flow: the net CSF flow at FM during a cardiac cycle.Test–retest reliability was repeatedly measured within 2 weeks by two neurosurgery residents (S.X. and Y.B.R.), and the average value of the two groups was recorded and analyzed , 2.t-test was used to determine the significance of the measures between control groups and patients with CMI between CMI with and without SM. The chi-square test compared count data between the two groups. The Pearson correlation analysis was used to investigate the morphological and physiological indices. Statistical analyses were performed using IBM SPSS software version 25.0 . Significance was indicated by a P < 0.05. For the multiple corrections, the false discovery rate (FDR) was used based on the Benjamini–Hochberg procedure  or sex (P = 0.137). The CMI group presented with cough-related occipital headache (54.2%), limb numbness (50%), neuropathic pain (22.9%), sensory disturbances (20.8%), muscle weakness (25%), amyotrophy (2%), and choking or hoarseness on drinking water (2%).A total of 48 patients  in the CMI group and 46 control subjects  were included in this study. There was no difference in age , bony-PFV (P < 0.001), and net flow (P < 0.001) were significantly smaller in the CMI cohort. The PCF CI (P < 0.001), PVmax (P < 0.05), and NVmax (P < 0.05) in the CMI cohort were higher than those in the control group. There were no significant differences in the HB area (P = 0.066) or absMV (P = 0.254) between the two groups.In the CMI group, the cerebellar tonsillar hernia was (9.85 ± 0.74) mm, and the syrinx was across the level of the spinal cord (7.03 ± 0.46), VI was (64.79 ± 3.25). Compared with the control group, the PCF area (P < 0.05) was significantly higher in the SM group. Bony-PFV was smaller in the SM group (127.36 ± 4.87 ml) than in the non-SM group (134.77 ± 3.39 ml) though the difference was not statistically significant (P = 0.316).A total of 43 patients (89.6%) were complicated with SM in the enrolled CMI cohort . ComparePearson correlation coefficients and P-values are listed in R = −0.468, P < 0.01). The correlation that reached a moderate level was between bony-PFV and VI . Similarly, PCF CI was also weakly correlated with tonsil descent , PVmax , absMV , and net flow . However, neither tonsil descent  nor the degree of patency of CSF was significantly associated with bony-PFV.The indicators related to PCF are represented by PCF CI and bony-PFV. There was a significant correlation between bony-PFV and PCF CI  and net flow , while there was no correlation with syrinx expansion.In addition to PCF CI, tonsil descent was slightly associated with absMV  and absMV  and moderately correlated with CSF net flow . However, the degree of syrinx expansion was not correlated with the degree of tonsil descent.The degree of syringomyelia was measured by syrinx length and VI. The results showed that VI was slightly correlated with bony-PFV . Similarly, the absMV was correlated with tonsil descent , VI , and PCF CI . In addition, CSF net flow was correlated with tonsil descent , VI , and PCF CI .In this analysis, PVThe pathogenesis of CMI remains unclear, and a theory of bone dysplasia has been proposed since the malformation of PFV cannot match the normal development of the posterior fossa nerve tissue, resulting in cerebellar tonsillar hernia down into the spinal canal, and disordered circulation of CSF at CVJ. However, this theory cannot fully explain the pathology of CMI. The data from different studies are inconsistent; some studies have shown a smaller PCF in adults with CMI , 24–28, In previous studies, we described the underdeveloped clivus and occipital bone as well as a reduction of the volume of bony PCF in adults with CMI . We alsoP < 0.05 was considered significant. The FDR correction was for reference on account of the limited sample size.Pearson correlation analysis was performed for morphological and physiological measures, and a P < 0.001). In addition, MRI sagittal images were used to measure PCF crowdedness, which is well correlated with bony-PFV , and linear PCF measurement is a supplement to volumetric measurement (P < 0.001), which demonstrates that the PFV was disproportionate to its contents and suggests that a better feature of CMI is the bony volume and crowdedness of the PCF, which is consistent with previous reports , but there was no significant difference, and there was no difference in the bony-PFV, PCF CI, CSF peak velocity, or net flow at CVJ. The most notable finding is that the absMV in the CMI-SM group was higher than that in CMI without SM. This illustrates that the formation of syringomyelia has a close relationship with CSF circulation, and the examination of CSF dynamics is critically important. Changes in CSF circulation can be used to prospectively predict the direction of disease progression.Approximately 89.6% of patients with CMI had syringomyelia, which was similar to previous reports . When thPrevious studies have been limited to correlation analysis between PCF size and CSF flow . In our max of CSF. This confirmed that the congestion of the PCF may be one of the factors contributing to the downward herniation of the cerebellar tonsils into the spinal canal. The prolapse of the cerebellar tonsils exacerbates the stenosis of CVJ, and the CSF circulation is blocked.Among the parameters of PCF, the VI is the only parameter that is correlated with the bony-PFV, which suggests that patients with CMI whose bony-PFV are small are more prone to syringomyelia in the course of the disease. If abnormal narrowness of bony-PFV is found in the early stage of clinical diagnosis and treatment, close follow-up and vigilance should be increased, and intervention should be implemented in the early stage of syringomyelia progression. Interestingly, the severity of cerebellar tonsillar hernia was disproportionate to the bony-PFV. Therefore, we further measured the PCF CI and found that it was potentially correlated with cerebellar tonsillar hernia and PVAmong the relevant parameters of syringomyelia, the syrinx length seems to have no correlation with any of the parameters measured here. The VI was not only related to the bony-PFV but also related to the velocity of CSF, and even the net flow of CSF reached a moderate degree of correlation. This result suggests that the alteration of the high dynamic CSF flow of CMI may play an important role in the pathogenesis of syringomyelia.In the correlation analysis of cerebellar tonsillar hernia, PCF crowdedness, absMV, net flow of CSF, and tonsillar hernia all reached a relevant level. This result suggests that the cerebellar tonsillar hernia in patients with CMI may be the result of the combined effect of PCF crowding and CSF changes. This is, indeed, clinically true; however, some patients have a “spacious” PCF, but severe cerebellar tonsillar hernia can still be observed. This may be related to CSF circulation disorder, and the choice of future treatment strategy should take the PCF bony volume, crowdedness, and CSF circulation factors into consideration. In addition, we noted that cerebellar tonsillar hernia was negatively correlated with absMV. We hypothesized that the more severe the cerebellar tonsillar hernia, the more crowded the CVJ, and the decrease in net flow, and the CSF flow becomes more disrupted and the lateral fluid offsets some of the energy along the flow direction, thus showing a decrease in mean flow velocity.Among the hydrodynamic parameters of CSF at FM, as mentioned earlier, the absMV and net flow were weakly correlated with the degree of PCF CI, cerebellar tonsillar hernia, and VI. Lower herniated cerebellar tonsils and crowded PCF are often accompanied by faster CSF velocity and less CSF net flow, while high hydrodynamic velocity and high flow of CSF are closely related to syringomyelia formation.The bony-PFV in patients with CMI was smaller, and the MV was faster in CMI with syringomyelia. Cerebellar subtonsillar hernia and syringomyelia are independent indicators for evaluating CMI. Subcerebellar tonsillar hernia was associated with PCF crowdedness, MV, and the net flow of CSF at CVJ, while syringomyelia was associated with bony-PFV, MV, and the net flow of CSF at CVJ.The bony-PFV, PCF crowdedness, and the degree of CSF patency should be considered as combined indexes in the evaluation of patients with CMI.This study provides some clues for the clinical evaluation and treatment of patients with CMI by quantifying the changes in bony-PFV, PCF crowding, cerebellar tonsillar hernia, syringomyelia, and CSF circulation at CVJ.1) Cerebellar tonsillar hernia in patients with CMI may be the result of the combined action of PCF and CSF changes. If only the bony-PFV decreased or the PCF was crowded and the CSF PC-MRI examination did not detect an increase in CSF velocity or a decrease in net flow at CVJ, the diagnosis and treatment plan would be mainly to increase the PCF space with bone decompression.2) If the bony-PFV or PCF CI is within the normal range but the CSF cine indicates increased CSF velocity or decreased net flow at CVJ, subdural decompression or dilated duralplasty may be further performed to improve CSF circulation.3) If the patient not only has a narrow PCF but also has CSF circulation disorder, the diagnosis and treatment plan should also take into account the expansion of bony-PFV and the clearing of CSF circulation disorder. On the basis of subarachnoid decompression, a part of the cerebellar tonsils can be removed under the pia soft membrane for more complete decompression.There are several limitations of this study that need to be considered when analyzing the results. First, due to the limited number of samples, this study failed to analyze the possible influence of race, sex, and other factors on these parameters. Second, this study did not include asymptomatic patients or patients with cerebellar tonsillar hernias smaller than 5 mm, which should be investigated in future studies. Finally, this study provides a new direction for thinking about surgical strategies through correlation analysis of the parameters. The realization of this goal requires a large number of patients to receive surgical treatment and long-term follow-up during the study period.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 Ethics Committee of Beijing Sanbo Brain Hospital. The patients/participants provided their written informed consent to participate in this study.Conception and design: SW and TF. Acquisition of data: SW and KW. Drafting the article and approved the final version of the manuscript on behalf of all authors: SW. Statistical analysis: SW, DZ, and KW. Study supervision: TF. Analysis and interpretation of data, critically revising the article, and reviewed submitted version of manuscript: All authors. All authors contributed to the article and approved the submitted version.


Body composition assessment in cervical spinal cord injury (c-SCI) individuals is important to monitor the fat free-mass (FFM) loss, due to immobilization, or gain, due to exercise practice. Single frequency bioelectrical impedance analysis (SF-BIA) is low in cost, simple and easy.The aims of this study are: to evaluate the concordance between the FFM values obtained using dual X-ray absorptiometry (DXA) and the three SF-BIA previous predictive equations; and to test the applicability of the bioelectrical impedance vector analysis (BIVA).n = 13; at least 150 min/week) and non-active individuals (NPA) and were assessed by DXA and SF-BIA simultaneously.Twenty-three c-SCI males were divided into two groups: Physically active . However, Buchholz's et al. predictive equation showed FFM values similar to DXA, but presented poor concordance . BIVA showed consistency in ellipse distribution using FFM obtained using Buchholz et al. predictive equation.FFM values were similar between groups PA and NPA. Considering all participants, FFM values obtained by Kocina and Heyward (>11%) and Sun (<15.4%) predictive equations were different when compared to DXA (The use of non-specific BIA equations can lead to misinterpretation in FFM values in male c-SCI individuals. Predictive equations for this group need to be developed. Cervical spinal cord injury (c-SCI) implies serious complications, principally skeletal muscle atrophy, which are associated with adverse metabolic effects, including glucose intolerance, insulin resistance, type II diabetes and cardiovascular disease –3. RegarThe practice of physical exercises in c-SCI can have beneficial consequences on body composition and metabolic changes –6. ExercFFM can be assessed by high-accuracy methods, such as dual X-ray absorptiometry (DXA) , 13. HowBIA method estimate FFM from body electrical proprieties, the resistance (R) and reactance (Xc) vectors are used in predictive equations which consider sex, age, height and weight . Kocina The spinal cord contributes to venous return through muscle contractions. In high SCI, the lack of muscle contractions can cause edema, mainly in the lower limbs . This chBioelectrical impedance vector analysis (BIVA) is recommended for further nutritional assessment and monitoring, in particular when calculation of body composition is not feasible , 26, as Therefore, the aims of this study were: (a) to evaluate the concordance between the FFM values obtained using dual X-ray absorptiometry (DXA) as a reference method and the three SF-BIA previous predictive equations related to SCI, and one predictive equation related to elderly people; and (b) to test the applicability of BIVA in physically active and non-physically active chronic c-SCI individuals.n = 13; age = 25.0 years (IQR 23.0–33.0); had practiced physical exercise for at least 3 months, 3 times/week or more, totaling a minimum time of 150 min/week) ]. General information was obtained through a structured questionnaire; the participants answered questions about time of injury, and how long they practiced physical sports. None of the participants were taking nutritional supplements. All participants voluntarily agreed to participate in the research, and written informed consent was obtained.Twenty-three c-SCI individuals volunteers with a lesion between C5 and C7 participated in the present study. They were divided into two groups according to the frequency of physical exercise: Physically active which were wheelchair rugby players  ; and nonAlthough the sample is small, it is important to emphasize that all subjects are quadriplegic with lesions between c5 and c7, which makes the group homogeneous. Furthermore, the sample obtained here is consistent with the literature  showing ®). The stadiometer was extended on the stretcher of the DXA, where the individuals were placed in the supine position.Length was measured from the top of the head to the bottom of the heel using a stadiometer . The participants were placed in a dorsal position. Orthopedic surgical pins or other implants were identified as artifacts, and the software did not include them in the analysis. The exams were performed by a single trained and qualified professional, following the quality control procedures recommended by the manufacturer and the official recommendations of the International Society for Clinical Densitometry . MeasureR = 500 ohms); and the components inside the bioimpedance analyzer, such as the signal generator, the sensing apparatus, the scales of weight and height, and the electrical interference were tested as suggested by Kyle et al. The average of the two repeated measurements of R and Xc was used in the subsequent analyses. SF-BIA was performed for FFM prediction, two electrodes placed on the dorsal surface of the hands and two on the surface of the feet. The device was then connected, and the voltage was detected by proximal electrodes, and the values of R and reactance (Xc) were obtained.Body composition  was assessed using a single frequency (SF) bioimpedance analyzer , applying foot-to-hand technology. In order to avoid clinical disturbances in fluid distribution, participants were instructed to abstain from food and liquids for 4 h and to abstain from caffeine and physical activity for 24 h before SF-BIA. Bladder emptying was performed by catheter valve before arrival at the laboratory. Before each test, the analyzer was checked with the impedance calibration (resistance The predictive equations were selected based on the following criteria: (1) validated for SCI individuals or elderly, ideally using DXA; (2) BIA analyzer used to develop the equation at 50 kHz; (3) sex as a variable of the predictive equation. Three proposed predictive equations met the inclusion criteria: Kocina and Heyward , validatBIVA tolerance consists of plotting the experimental data in a bivariate graph considering the 95th, 75th, and 50th vector percentiles of the Z-score of the reference population. Considering the plotting position of the experimental data, it is possible to suggest an interpretation: abnormal situation, when experimental data are positioned outside of the 95th percentile ellipsis; high body cell mass, when experimental data are located above the long axis of the ellipsis; hypohydration, when experimental data are positioned to the right of the short axis of the ellipsis. Total body water is inversely related to the length of the impedance vector, and a combination of the vector length and its direction is defined as phase angle (PhA) . The refhttp://www.medcalc.org; 2014). Statistical tests were considered significant at the significance level of 5% (P ≤ 0.05).Statistical analyses were performed using SPSS software version 19  and MedCalc Statistical Software version 14.8.1 .Anthropometric measurements and body composition compartments were expressed as median and interquartile range. Mann-Whitney test was used to determine differences between groups, according to physical exercise . Wilcoxon test was used to determine the difference between the FFM values obtained by the three BIA predictive equations and values obtained using DXA. Lin's concordance correlation coefficient  was usedp = 0.029) and shorter time since injury (p = 0.023) than NPA. Since there was no significant difference between the groups in other variables, the statistical analysis considered all participants.General characteristics of the participants are shown in p ≤ 0.001) and Sun et al. (p = 0.012) predictive equations were significantly different from DXA. However, Buchholz et al. predictive equation showed no difference in FFM when compared to the value obtained using DXA  and CCC (0.65) than Kocina and Heyward, and Buchholz et al. predictive equations (Bland-Altman plots showed that Kocina and Heyward predictive equation presented higher bias (−5.9 kg) than Sun et al. (4.7 kg) and Buchholz et al. (0.1 kg) predictive equations. However, other concordance parameters showed that Sun et al. predictive equation presented higher SEE (5.21), RMSE (7.07) and MAPE (15.4%), and lower quations .When Z-score Xc and R values obtained by Sun et al. were used as reference population in the BIVA graph, the vectors were displaced below the high axis of the tolerance ellipses, showing little body cell mass. However, when plotted with Z-score Xc and R values obtained by Buchholz et al. predictive equation, most individuals were located within the tolerance ellipses .This pilot study showed that Buchholz et al. FFM-BIA predictive equation presented the highest concordance coefficient with FFM obtained using DXA; however, this is not sufficient to recommend it to c-SCI individuals. Therefore, BIVA could be used with caution, because according to the population reference used, different conclusions can be observed, such as demonstrated in this study. To our knowledge this is the first study to test BIVA in SCI individuals.Regular physical activity practice for at least 150 min/week may be responsible for the improvement of body composition, hormonal profile and bone health in SCI individuals –41. DespSun et al. predictive equation was developed with 734 able-bodied physically active males, including elderly individuals. c-SCI individuals have a body composition similar to that of the elderly population, presenting, for example, FFM loss and fat mass increase . In the Plotting the R and Xc z-score in BIVA tolerance graph, using Sun's predictive equation as reference, it was observed that all c-SCI individuals were located under the highest axis, which can be attributed to the lowest body cell mass (BCM). BCM is the metabolically active cell mass involved in energy production and energy expenditure and is an important component of FFM . Our resKocina and Heyward predictive equation was developed for SCI adults; however, the abstract does not present information about sample size, height and time of injury of the participants, resistance and reactance values. In the present study, FFM values obtained using the Kocina and Heyward predictive equation presented a high mean error percentage represented by MAPE (10.9%) and the lowest value of concordance coefficient, suggesting that despite having been developed with SCI individuals, it was not suitable for the group of the present study, possibly due to the wide range age group (18–73 years). The Kocina and Heyward predictive equation was not used in BIVA as a reference group, because there is no information on the bioelectrical data.Buchholz et al. FFM BIA predictive equation was developed for healthy elderly subjects and tested and validated for paraplegic individuals, using the TBW method as reference, which reflects the lean soft tissue as muscle mass, considering the hydration constant (0.732) . In the In the present study, BIVA tolerance ellipses of SCI individuals shifted to the right, when Buchholz et al. predictive equation was used as reference, indicating high cell mass and fluid content, which can be attributed to better cell functioning . This prIn conclusion, the present study was able to show that BIVA is sensitive to adaptations in body composition and to hydration status, responding consistently to the equations used as a reference, despite some limitations, such as: lack of hydration status control, and difference between age and time of physical exercise. In addition, future studies on new FFM predictive equations, specific for SCI individuals, should be developed according to spinal lesion characteristics and with a more representative sample size. The inaccuracies in assessing body composition and fluids at the c-SCI group may compromise an adequate assessment and monitoring of body fluids and may interfere with the clinical care of this specific and vulnerable group. Therefore, caution should be applied when interpreting data extracted from generalized equations.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 National Research Ethics System (COEP 052/2009). The patients/participants provided their written informed consent to participate in this study.FF performed data collection. AB, AC, FF, and JK analyzed the data and participated in the conceptualization of the work. AB wrote the original manuscript. AC and JK were involved in proofreading and editing. All authors read and agreed with the published version of the manuscript.This work was supported in part by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro . The Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) sponsored a part of this study - Finance Code 001, and the PROPESP/PAPQ UFPA.Author FF was employed by Brazilian Paralympic Committee. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Autophagy is a highly regulated and evolutionarily conserved process in eukaryotes which is responsible for protein and organelle degradation. Although this process was described over 60 years ago, the selective autophagy of mitochondria (mitophagy) was recently coined in 2005. Research on the topic of mitophagy has made rapid progress in the past decade, which proposed to play critical roles in human health and disease. This study aimed to visualize the scientific outputs and research trends of mitophagy.Methods: Articles and reviews related to the topic of mitophagy were retrieved from the Web of Science Core Collection on 30 November 2021. Two kinds of software (CiteSpace and VOSviewer) were used to perform a visualized analysis of countries/regions, institutions, authors, journals, references, and keywords.Results: From 2005 to 2021, total 5844 publications on mitophagy were identified for final analysis. The annual number of publications grew yearly over the past 17 years. United States (N = 2025) and Chinese Academy of Sciences is the leading country and institute (N = 112) ranked by the number of publications, respectively. The most productive author was Jun Ren (N = 38) and Derek P. Narendra obtained the most co-cited times (2693 times). The journals with the highest output and the highest co-citation frequency were Autophagy (N = 208) and Journal of Biological Chemistry (co-citation: 17226), respectively. Analyses of references and keywords suggested that “mechanism of mitochondrial quality control”, “molecule and signaling pathway in mitophagy”, and “mitophagy related diseases” were research hotspots, and parkin-mediated mitophagy and its roles in skeletal muscle and inflammation-related diseases may be the frontiers of future research.Conclusion: Although mitophagy research has flourished and attracted attention from all over the world, the regional imbalance in the development of mitophagy research was observed. Our results provided a comprehensive global research landscape of mitophagy from 2005– 2021 from a perspective of bibliometrics, which may serve as a reference for future mitophagy studies. As the powerhouse of the cell, mitochondria play essential roles in regulating cellular metabolism and physiology . Thus, tBibliometric analysis is a powerful approach that uses literature metrics or indicators to quantitatively measure the research performance in a certain field . It was In this study, a bibliometric-based analysis was performed to systematically evaluate the mitophagy studies from 2005 to 2021. By taking advantage of CiteSpace and VOSviewer, we comprehensively analyzed the publication output, disciplinary composition, countries/regions, institutions, publishers, funders, authors, journals, top-cited articles, references, and appeared keywords. Our results draw a visualization map of the global research landscape of mitophagy, helping researchers, especially for those who are new to this field, to deepen their understanding of the current status and future directions of mitophagy research.Publications were extracted from the database of the Web of Science Core Collection (WoSCC) in this study. WoSCC is the world’s oldest, most widely used, and authoritative database of research publications and citations, which contains records of articles from the highest impact journals worldwide . A literOf note, we have cleaned the data before analysis . These iCiteSpace software  is a freely available Java application, which was widely used for visualizing and analyzing trends and patterns in the scientific literature . It was VOSviewer software is a useful tool for constructing and visualizing bibliometric networks . It was www.webofscience.com) directly on 30 November 2021. Microsoft Office Excel 2016 was used to analyze the annual publications. WordArt (https://wordart.com/) was used to create the word cloud of the subject categories. GunnMap 2 (http://gunnmap.herokuapp.com/) was used to display the global publication distribution on a world map.Other information such as impact factor (IF) and Journal Citation Reports (JCR) division of journals were obtained from the Web of Science website . Among the top 10 prolific authors , Jun RenCo-citation is defined as the frequency with which two documents are cited together by another or more articles at the same time, providing a way to study the specialty structure of science . In thisAutophagy (N = 208) most productive one and had the highest IF 2020 (16.016). Eight (80%) of the journals had an IF 2020 over 5 and 6 (60%) were located in JCR (2020) Q1 region. A density map of the top 56 productive journals (with over 20 publications) was shown in Journal of Biological Chemistry (co-citation: 17226). Notably, Autophagy, Journal of Biological Chemistry, and PLoS One were the top 10 journals ranked both by a number of publications and co-cited frequency.A total of 1021 academic journals had published articles on mitophagy (data not shown). The top 10 journals published with the highest number of publications were shown in Journal of Biological Chemistry was the most frequently co-cited journal (co-citation: 17226) with the IF 2020 as 5.157 that far exceeded some high-impact journals, such as Nature , Cell , and Science . Also notably, Autophagy (IF 2020: 16.016), Journal of Biological Chemistry (IF 2020: 5.157), and PLoS One (IF 2020: 3.24) were the top 10 both productive and cited journals. These results provided some guidance to future authors deciding where to publish their work on mitophagy research.What are the publication patterns for mitophagy studies in general journals? In this study, we found that most articles on mitophagy were published in a cell or molecular biology journals . UnexpecAccording to the published time, we divided the 5844 papers into two groups. There were 644 papers that were published during 2005–2013; and 5200 papers that were published during 2014–2021. Then the publishers and funders of each group were analyzed separately to show the trends over time. The top 10 publishers and funders of each group were presented in During 2005–2013, over 40% of papers were funded by the National Institutes Of Health, NIH, United States (42.7%) or United States Department Of Health and Human Services (42.7%), all belong to the United States . Other tet al. obtained the largest number of citations . Of those, seven are articles (70%) and the rest are reviews (30%). As we can see from The top-cited publications and co-cited references were fundamental and the basis of a certain field. In this study, the 10 most cited publications on mitophagy are listed in Nature Cell Biology by Geisler S et al., in 2010.Next, we constructed a cluster analysis for all the co-cited references by CiteSpace software and presented the clusters in form of a timeline view in To investigate the research hotspots in the field of mitophagy, a total of 7506 keywords (author keywords) were extracted from the 5844 publications for co-occurrence analysis on VOSviewer and Citespace software. To further visualize the research frontiers in the field of mitophagy, the keyword co-occurrence analysis was performed on VOSviewer. In the overlay visualization map , differeNowadays, more and more research are being done around the world, and more and more scientific discoveries are being made. The biggest challenge is how to keep up with the remarkable explosion of knowledge in some active fields such as mitophagy. In this study, we took advantage of bibliometric analysis to visualize the global research landscape of mitophagy from 2005 to 2021. A total of 5844 articles were identified. Mitophagy research has flourished and attracted attention from all over the world, especially in United States, China, and the European Union. We found a list of outstanding institutions, researchers, journals, publishers, and funders which made a significant contributions to it. Research trends and hotspots were summarized and frontiers were predicted. Our findings provide a historical prospect and new insights into mitophagy.https://datacatalog.worldbank.org/search/dataset/0038130), our data showed that high-income countries were more productive than low-income countries. This was consistent with other bibliometric studies conducted on mitophagy . Third, although we have standardized some terms that have different expression types, bias may still exist if other synonyms were available.Autophagy (N = 208) and Journal of Biological Chemistry (co-citation: 17226). We summarized current research hotspots  and predicted future frontiers . This information will provide researchers with references for future mitophagy studies.In summary, by bibliometric analysis of 5844 publications over the previous 17 years, we found that mitophagy research has flourished and attracted attention from all over the world, especially in the United States  and China . A list of outstanding institutions and scholars made a significant contribution, such as Chinese Acad Sci , Univ Pittsburgh , Richard J. Youle (N = 38), and Derek P. Narendra (co-citation: 2693). Many journals played an important role in promoting the development of mitophagy research, such as


Thyroid nodule is a common health problem in endocrinology. Thyroid fine-needle aspiration biopsy (FNAB) cytology performed by palpation guided FNAB (PGFNAB) and ultrasound-guided FNAB (USGFNAB) are the preferred examinations for the diagnosis of thyroid cancer and part of the integration of the current thyroid nodule assessment. Although studies have shown USGFNAB to be more accurate than PGFNAB, inconsistencies from several studies and clinical guidelines still exist.The purpose of this study is to compare the diagnostic accuracy of Palpation versus Ultrasound-Guided Fine Needle Aspiration Biopsy in diagnosing malignancy of thyroid nodules.The systematic review and meta-analysis were prepared based on the PRISMA standards. Literature searches were carried out on three online databases  and grey literatures. Data extraction was carried out manually from various studies that met the eligibility, followed by analysis to obtain pooled data on sensitivity, specificity, Diagnostic Odds Ratio (DOR) and Area Under Curve (AUC), and the comparison of the two methods.p = 0.023), AUC difference test of 0.093 (p = 0.000023).Total of 2517 articles were obtained, with 11 studies were included in this systematic review. The total sample was 2382, including 1128 subjects using PGFNAB and 1254 subjects using USGFNAB. The risk of bias was assessed using QUADAS-2 with mild-moderate results. The results of sensitivity, specificity, AUC and DOR in diagnosing thyroid nodules using PGFNAB were 76% , 77% , 0.827 and 11.6  respectively. The results of sensitivity, specificity, AUC and DOR in diagnosing thyroid nodules using USGFNAB were 90% , 80% , 0.92 and 40 , respectively the results of the comparison test between PGFNAB and USGFNAB; Tsens USGFNAB of 0.99 (The diagnostic accuracy of USGFNAB is higher than PGFNAB in diagnosing malignancy of thyroid nodules. If it is accessible, the author recommends using USGFNAB as a diagnostic tool for thyroid nodules. Thyroid nodule, either it is solitary or multiple, is a common endocrinology problem in daily clinical practice . On physThe gold standard to diagnose thyroid nodules is the histopathological finding from surgical biopsy. However, the examination is invasive, expensive, and not easy to perform because it requires a long process from clinical evaluation to indicate surgery for the patient , 4. An aPrevious researchers have carried out systematic reviews and meta-analyzes of PGFNAB and USGFNAB. A study by Matz et al., which was carried out in 1108 patients with PGFNAB and 1197 patients with USGFNAB, indicated that USGFNAB had a higher diagnostic accuracy but with a lower inadequate sample rate than PGFNAB . On the Several organizations related to the thyroid nodule diagnosis approach have different recommendations for the use of USGFNAB and PGFNAB. The American Thyroid Association (ATA), US National Cancer Institute (NCI), the British Thyroid Association (BTA), the American Association of Clinical Endocrinologists (AACE), the Associazione Medici Endocrinology (AME), the European Thyroid Association (ETA) recommend that non-palpable, hard palpable, or partially cystic thyroid nodules should be evaluated by ultrasound. Meanwhile, for palpable thyroid nodules, AACE, AME, and ETA still suggest doing USGFNAB, while others may use PGFNAB or USGFNAB .Therefore, through this meta-analysis, a systematic review was conducted because of the inconsistence found in previous studies and existing guidelines Table . MoreoveThe literature search was performed on PubMed/ MEDLINE, Embase, and ProQuest. The search had been carried out with keywords based on MESH terms and their synonyms and with the use of Boolean operator assistance. Moreover, the author searched for other sources by searching the registry for observational studies or manuals for relevant studies or in the form of grey literature such as abstracts of symposiums/ conferences/ proceeding books/ theses/ dissertations or through the portal on the Garba Digital Referral (GARUDA) page – a local online database. Keywords used for the search and snowball search can be seen on Tables Two researchers (BSA and TJET) carried out the study selection independently, using guidelines based on predetermined eligibility criteria. The two researchers independently screened titles and abstracts from the search results for the study. Then, each study that was considered to meet the eligibility criteria was read in total. It was also reassessed to meet the eligibility criteria based on a form that had been prepared previously. The assessment of the two studies were hidden from each researcher. If any differences of opinion were to arise between the two researchers, it was resolved by consensus and consultation with a third independent researcher was conducted to determine the final assessment if needed. The level of agreement between researchers was assessed using Cohen’s Kappa statistics. The Covidence software was used to screen titles and abstracts and record all decisions made independently by researchers.All years publication studies included in this research met the inclusion criteria such as (a) diagnostic studies; (b) subjects of all ages; (c) quantitative data from the results to make the 2 × 2 table to obtain the true positive, true negative, false positive, and false negative; (d) the palpation-guided thyroid nodule compared with histopathology of surgery results; (e) ultrasound-guided thyroid nodule compared with the histopathology of surgery results; (f) the compared accuracy of thyroid-guided palpation versus ultrasound-guided. The exclusion criteria were publications in the form of reviews, correspondences, editorials, and commentaries.Data extraction was conducted independently by two researchers. Data from studies that met the inclusion and exclusion criteria included the basic study characteristics. It also included the name of the principal researcher, type of study, place/country, year of publication, basic demographic characteristics of study subjects, sample size, thyroid FNAB examination technique, operator characteristics, blinding, and comparison results. The output was in the form of a descriptive table. The output was written in a two-by-two table form and displayed in sensitivity, specificity, DOR, and AUC.Two independent reviewers assessed study quality and risk of bias. Any discrepancies were resolved through consensus with an independent third party. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 was used for the assessment of study quality, where each domain was assessed for risk of bias. QUADAS-2 consists of 4 main domains: patient selection, index testing, reference standards, flow, and time. Each domain has its risk of bias to assist in the suspicion of risk bias, including the cue questions.The statistical analysis in this study was performed using the RevMan software version 5.4  and Meta & Mada Package R version 4.0.3 , 21.2 test, and Cochran’s test. A random-effects model selected if there were significant heterogeneity, whereas a fixed effect model will be selected if it was not significant. The results of data analysis were presented in the form of a forest plot and The Summary Receiver Operating Characteristic (SROC) curve when meta-analysis could be performed. The expected results were in the form of accuracy, sensitivity, and specificity along with the confidence interval, DOR, and AUC. A comparative analysis of the accuracy of each index test was conducted using a likelihood-ratio test, diagnostic meta-regression and Characteristic Receiver Operating Comparison test (ROC) using R application [Heterogeneity was assessed using the snowballing method, Ilication , 22.In this study, we constructed funnel plots of the Diagnostic Odds Ratio (DOR) to appraise whether there was a publication risk bias or not. This study has also been pre-registered in PROSPERO with the registration number CRD42020207291.From the three databases and grey literature used, 2517 articles were screened of which only 50 articles were potentially relevant based on the title and abstract. After studies were screened, 14 studies were included. Of the 14 studies that fulfilled the screening process, two studies conducted by Choong 2018) et al. and Guo (2015) et al. [ et al. aThe total number of thyroid nodule patients in 14 studies was 6316 subjects. Among them, 3095 subjects used the PGFNAB method and 3221 subjects used USGFNAB. We evaluated 2382 subjects, of which 1128 subjects used PGFNAB and 1254 subjects used USGFNAB from those 11 articles , 19, 23.Cohen’s Kappa coefficient on the title and abstract filter was 0.254, indicating that the level of agreement was minimal. The coefficient of Cohen’s Kappa on the eligibility criteria assessment was 0.957, suggesting that the level of agreement was good . The difThe studies had similar study population characteristics, study design, study site location, gold standard, and expected outcome. The detailed characteristics of the studies can be seen in Table p < 0.05 in both the PGFNAB and USGFNAB methods.In general, the literature was relatively heterogeneous. There was heterogeneity in the results of each study; corresponding calculations of Cochran’s Q test were Moreover, there were varieties of the mean patient ages, gender, places, and countries . The pooled Diagnostic Odds Ratio (DOR) was 11.6  and the Area Under Curve (AUC) was 0,827.The sensitivity of USGFNAB in diagnosing thyroid cancer was in the range of 67 to 100%, with a pooled sensitivity calculation of 90% 95% CI, 49–89%). The specificity of PGFNAB in diagnosing thyroid cancer was in the range of 50 to 96%, with a pooled specificity of 80% . The pooled Diagnostic Odds Ratio (DOR) was 40  and the Area Under Curve (AUC) was 0.92. The forest plot of USGFNAB is shown in Fig. 9–89%. ThP = 0.0043. This suggests a significant differences between the two index tests. Subsequently, a diagnostic meta-regression was performed. This test assessed the sensitivity transformation and false positive rate transformation with the regression coefficient value of Tsens 0.99 (p = 0.023) and Tfpr − 0.120, (p = 0.760). The details of the comparison and SROC curve of PGFNAB vs USGFNAB can be seen in Table From the two index tests, a comparison test was conducted to determine diagnosis accuracy by performing the likelihood ratio test and getting a chi-square result of 6.28, p value < 0.0001.The rate of inadequacy varied between the two methods. For the PGFNAB method, the inadequacy rate ranged from 2 to 32%, with a mean value of 14.6%, while the inadequacy rate of USGFNAB ranged from 0 to 21.5% with a mean value of 9%. There was a significant difference with a A funnel plot of the diagnostic value of the ratio was made to assess a publication risk of bias in this systematic review. The results of the funnel plot of PGFNAB and USGFNAB can be seen in Fig. In this meta-analysis, we evaluated the diagnostic accuracy of PGFNAB and USGFNAB in diagnosing thyroid nodule malignancy. The results of the USGFNAB index test showed that the values for pooled sensitivity, pooled specificity, DOR, and AUC were 90, 80%, 40 and 0.92 respectively and had an estimated point on the SROC Curve in the upper left see Fig. . These rp value < 0.05 indicated that the result was statistically significant. The regression coefficient for Tfpr was negative, suggesting that the specificity of PGFNAB was better than USGFNAB, yet these results were not statistically significant. Relating to AUC value significance, a difference of 0.093 (p = 0.000023) was found. The comparison of the SROC curve image showed that the estimation points of the two curves were very distinct from the spheres or the CI values that were slightly intersected  approach. It included the risk of bias, imprecision, inconsistency, indirectness, and publication bias. Each section was assessed, one-point reduction for any significant findings and two-points reduction for very significant findings or no serious findings (not reduced). The results of the quality assessment were divided into high, moderate, low, and very low. The results of the assessment can be seen in Table The weaknesses of this study is that several studies did not display the results entirely, so that complete data cannot be obtained to make 2 by 2 contigency tables according to the research criteria. Therefore, no intersection point for measuring the output parameters was included in this meta-analysis. Also, heterogeneity is still present in this meta-analysis.The diagnostic accuracy (sensitivity and specificity) of USGFNAB is significantly higher than PGFNAB in diagnosing thyroid cancer with palpable or nonpalpable nodules. The quality of the studies reviewed in this study are good. As a result, the quality of output evidence based on GRADE is sufficient. If it is accessible, USGFNAB is more recommended as a diagnostic tool for thyroid nodules.


Acute aortic dissection (AAD), a serious and fatal cardiovascular disease, is characterized by inflammation that may further aggravate the condition. We evaluated the value of the neutrophil-to-platelet ratio (NPR) in the prognosis of AAD.  We collected records of patients with AAD and clinical data from 2010 to 2020 and followed up on the relevant information for 136 months. The Kaplan–Meier (K–M) survival along with the univariate and multivariate Cox analyses was used to examine the prognostic value of NPR in AAD. In addition, nomograms were constructed by combining NPR, age, Stanford typing, and treatment methods. The accuracy of nomograms was evaluated using calibration plots, and the prediction efficiency of nomograms was evaluated by receiver operating characteristic curve analysis and decision curve analysis (DCA).  The K–M analysis showed that AAD patients with higher NPR exhibited worse prognosis. In addition, different Stanford typing and treatment methods produced varied prognosis results. Univariate and multivariate Cox analyses showed that NPR value, age, classification, and treatment were independent prognostic factors for the overall survival time of patients with AAD. Nomograms constructed by combining NPR, age, Stanford typing, and treatment methods showed good predictive efficacy, and the AUC values for 1-, 3-, and 5-year predicting were 0.82, 0.79, and 0.74, respectively.  Our results suggest that pretreatment NPR can be used as a potential prognostic marker of overall survival time in patients with AAD. Acute aortic dissection (AAD) is a serious and fatal cardiovascular disease, characterized by intimal tear causing the blood from the cavity to enter the middle of the arterial wall . This fiThe specific pathogenesis of AAD has remained unclear. Studies have reported that AAD is associated with vascular inflammation and matrix degradation, including chronic infection and the activation of matrix metalloproteinases and the vascular endothelial growth factor . In addiIn the present study, we retrospectively collected the clinical data of patients with AAD in the recent 10 years and conducted a detailed follow-up to explore the effects of preoperative NPR on the overall survival of patients with AAD.This retrospective study collected the record of patients treated in Yue Bei People's Hospital from January 1, 2010, to December 31, 2020, and followed up on their relevant data until May 2021 to collect the relevant clinical information. The diagnosis of AAD is primarily based on the treatment and diagnosis guidelines for aortic diseases proposed by the European Society of Cardiology (ESC) 2014, whose classification standard is based on the Stanford standard as per the anatomical classification. The exclusion criteria were as follows: the time of onset was more than 14 days or was unknown, incomplete information, recurrent AAD, hematological diseases, cirrhosis, systemic lupus erythematosus (SLE), Marfan syndrome, traumatic AAD, malignant tumor, AIDS, and incomplete data. Finally, 309 patients were included in the study. The research scheme was approved by the Ethics Committee of Yue Bei People's Hospital (KY-2020-166). Because of the retrospective nature of the study, informed consent was not required.The first blood cell test results of patients with AAD were collected. Stanford typing was used to classify the patients, and the treatment methods received were recorded. NPR is defined as the absolute value of neutrophil count divided by the absolute value of platelet count. To facilitate scientific counting, NPR = number of neutrophils/number of platelets × 10.P value < 0.05 was considered significant. The “RMS” package was used to build nomograms, “survivalroc” was used for the receiver operating curve (ROC) analysis, and the “decisioncurve” package was used for decision curve analysis (DCA).All statistical analyses were performed using the R software (version 4.1.1). Kaplan–Meier survival analysis was performed using the “survival” and “surviviner” packages, and the “survival” package was used to perform univariate and multivariate Cox analyses. A A total of 309 patients with AAD were included in this study, of which 121 died during follow-up (39.2%). Statistics showed that 262 men accounted for 84.8% of the total patients. Among all cases, 204 cases were diagnosed as TBAD, accounting for 66% of the total. Among these patients, 123 cases were treated with thoracic endovascular aortic repair (TEAR), accounting for 39.8% of the patients. In addition, 47 patients used the traditional surgical treatment (ST), accounting for 15.2% of cases, and 139 patients were treated with conservative medication (CM), accounting for 45% of the total. The specific clinical information of the study population is summarized in P = 0.003; P < 0.001; The median value of NPR showed that the study population was divided into high- and low-risk groups, and the difference in the overall survival between the two groups was calculated using the K–M analysis. The results showed that patients with AAD in the high-NPR group had worse overall survival time than those in the low-NPR group  and serum amyloid A (SSA)—acute phase reactants in the serum—have been used in the early diagnosis and prognosis of several diseases . Wen et The levels of neutrophils and platelets are routine items in the clinic and can be easily obtained. To further facilitate the application of NPR in clinical evaluation, a nomogram was constructed by combining age, classification, and treatment methods, which are independently related to the overall survival time of AAD. ROC and DCA analyses confirmed the reliability of the nomogram as a prognostic index.This study still had certain limitations. First, this study was based on single-center clinical research. Further multicenter research is conducive to enhancing the credibility of the results. Second, this study was based on a retrospective study; a prospective cohort study in the recent 10 years will be more helpful to verify the prognostic value of NPR in AAD.NPR is a routine and easily accessible inflammatory biomarker in the clinical detection of AAD. This study showed that a high NPR value can serve as an independent adverse risk factor for the long-term prognosis of AAD. Nomogram constructed in combination with NPR, age, classification, and treatment is conducive to the hierarchical management of patients.


The aim of this study was to investigate the effectiveness of garlic (Allium sativum L.) tablets as a complimentary herbal medication in diabetic macular edema. μm), and intraocular pressure (IOP) were measured as the main outcomes.  A total of 91 diabetic participants (117 eyes) with central involved macular edema underwent a double-blind randomized trial. The patients used garlic tablets (500 mg) (2 tab/day) or placebo for 4 weeks and subsequently were examined by an expert ophthalmologist. Clinical manifestations including the best-corrected visual acuity , central macular thickness . CMT was decreased in both groups by a 102.99 μm decrease in the garlic group compared to 52.67 μm in the placebo group, albeit in a nonsignificant manner . IOP was decreased in the garlic group by 1.03 mmHg  and increased by 0.3 mmHg  in the placebo group.  BCVA was significantly improved by a 0.18 decrease in mean logMAR value in the garlic-treated patients in comparison with 0.06 in the control ones ( Our trial suggests that garlic supplements can improve visual acuity, decrease the CMT and lower the IOP, and can be considered as an adjuvant treatment in patients with diabetic macular edema. Garlic was satisfactorily tolerated in diabetic patients, and no significant adverse effect interrupting the safety profile was observed. Diabetic retinopathy (DR) is a common eye disease in adults that can lead to blindness, contributing to retinal neurodegeneration and microvascular abnormalities. DR is often associated with physical and psychological complications such as decreased quality of life and increased psychosocial problems , 2. FundThe results of several large clinical studies proposed that control of blood sugar and blood pressure plays an important role in preventing the progression of DR , 6. Despα), inducible nitric oxide synthase (iNOS), and metalloproteinase (MMP)-9 [Garlic (Allium sativum L.) is a traditional drug-containing diverse bioactive compound, including sulfur-containing compounds such as alline and allicin, saponins, and phenolic contents. Several biological effects have been reported for garlic including anti-inflammatory, antioxidant, antidiabetic, immunomodulatory, antiatherosclerotic, antihypertensive, and cardioprotective effects . Garlic  (MMP)-9 .To date, no report has been published on the efficacy of garlic supplementation to treat diabetic retinopathy. Since the effect of garlic as an antidiabetic and anti-VEGF agent has been confirmed in previous studies, for the first time, we used garlic as a complementary treatment for DR patients in this project and evaluated the effectiveness of this herbal treatment in the control of DR and diabetic macular edema (DME).This study was conducted in the Shiraz University ophthalmology center in Shiraz, Iran, between 2020 and 2021, and received the ethical approval of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.052). The trial also was registered in the Iranian Registry of Clinical Trials (IRCT20200415047083N1). The required total number of participants (case vs. control) was calculated with the help of statisticians and related studies. The trial was designed as a double-blind randomized trial.μm were included in the study. The follow-up was regularly done in this university eye center, and standard treatments were performed for them . The study was supervised by an expert vitreoretinal surgeon. It should be noted that the surgeon was not informed of the randomization pattern of participants.Spectral-domain optical coherence tomography (SD-OCT)  was done for diabetic participants, and patients with a central macular thickness (CMT) of more than 350 Patients with monocularity, glaucoma, previous retinal vascular occlusion, epiretinal membrane or vitreomacular traction on fundus examination or OCT, significant cataract, posterior capsular opacification, or vitreous hemorrhage that prevents posterior fundus view, previous history of vitrectomy surgery, previous history of cataract surgery during last three months, high myopia, getting a systemic or intravitreal injection of immunosuppressive and corticosteroid drugs, getting warfarin, clopidogrel or any blood thinner drugs, history of radiotherapy, cancers, gastrointestinal disease, and liver or kidney failure were excluded from the study. The study was performed on one or both eyes considering the aforementioned inclusion and exclusion criteria.In the first pilot study, fourteen cases were randomized by the random digits table in equal proportions to oral treatment with a garlic tablet or a placebo tablet. The standard dose of the oral garlic tablet was estimated based on its safety studies in hypertension and other cardiovascular risk factors treatment , 13. EacAt baseline, intraocular pressure (IOP) (air-puff tonometry by TOPCON KR 800), best-corrected visual acuity (BCVA) (Snellen chart), refraction (auto-refractometer by ZIESS Visuref 100), slit-lamp biomicroscopy, and fundoscopic examination were assessed by an unrelated ophthalmoscope, and CMT was evaluated by SD-OCT. After the fourth week, all these items were repeated after the initiation of the tablets. For BCVA measurement, the value of the logarithm of the minimum angle of resolution (logMAR) scale was used. Eye examination was performed randomly. The randomization of subjects was done by an assistant who had no role in treating the patients.According to the pilot study results, after confirming no significant general or ocular complications, the sample size was broadened to 91 cases. All the cases received their treatments of DME by intravitreal injection of bevacizumab  and laser photocoagulation and received oral garlic or placebo tablet as a complementary treatment. Due to randomization, we minimized the effect of previous treatments in creating any impact on the results.μm) were measured as a primary outcomes, and changing IOP and any general or ocular complication were secondary outcomes. Since garlic is a blood thinner, significant ocular complications such as new hyphema and vitreous or retinal hemorrhage were determined.Changing logMAR and the CMT  was used for data management and statistical analysis.In this study, the relative frequency was applied to report the qualitative variables, and for quantitative variables, mean and standard deviation (SD) was reported. Mann–Whitney test was accomplished for analyses of the treated patients vs. control. The statistical significance level of the test was considered as A total of 154 patients receiving treatment for CI-DME were studied. One hundred twenty-one of them were included due to inclusion criteria. Eight patients discontinued the study in the garlic group because of difficulty adhering to follow-up due to COVID-19 quarantine. Eight of them garlic were removed from this study due to not taking medicine according to the instructions. One patient in the garlic group manifested gastrointestinal upset on the first administration day and terminated the treatment. Seven patients left the study in the placebo group because of the farther distance, and six patients discontinued the study due to COVID-19 quarantine. P value: 0.319). A significant number of participants in this study were female in both the case and control groups , indicating a significant difference .Of the 91 cases of central involving macular edema in the sitting of diabetic retinopathy, 45 and 46 patients were randomly divided into two groups representing the cases and the controls, respectively. Participants had a mean age of 61.91 ± 6.35 years in the case group and 60.50 ± 7.04 years in the control group . HbA1c analysis also showed no significant change in the case/control treatments . Demographic and laboratory data are shown in P value: 0.437, Baseline laboratory evaluation revealed that the mean of fasting blood sugar (FBS) in the case vs. control group was 175.06 ± 73.88 vs. 177.5 ± 62.73 mg/dL, indicating no remarkable alteration  received pan-retinal photocoagulation (PRP) treatment.P value =0.027) ; however, this decrease was not statistically significant  (Baseline means BCVA LogMAR in the case group were 0.93 ± 0.36 (20/160 Snellen chart), and in the control group were 0.85 ± 0.33 (20.125 Snellen charts). After a four-week follow-up, the garlic receiving patients showed a more significant improvement in BCVA in comparison with control ones  . The bas: 0.094) .P value: 0.024) and increased by 0.3 mmHg  in the placebo group. Independent t-test showed that the IOP lowering effect of garlic compared to placebo was statistically significant in the four-week follow-up   .No significant ocular or systemic complications were seen in the cases except a mild gastrointestinal upset in one of the patients receiving garlic; notably, this side effect which was self-limited and predominantly resolved by the garlic tablets discontinuation. This patient was removed from the study.α and nitric oxide (NO) by macrophages dose-dependently [DR is one of the main causes of blind impairment and vision loss in the world . The mosendently . The antendently . It has endently . Moreoveendently –31. AccoIn the present study, diabetic retinopathy patients were supplemented with garlic, and the main clinical manifestations of patients in the pre- and post-garlic consumption period were examined. Our study implied that short-term garlic tablet consumption is effective in visual acuity improvement and reducing CMT when it is used as an adjuvant treatment with anti-VEGF agents in the management of DME. It was also demonstrated that garlic might be effective in lowering IOP. A dosage of two tablets daily  significantly increased BCVA compared to a placebo over four weeks; although it clinically decreased the CMT in our patients, this value was not statistically significant.α, and CRP were markedly decreased in subgroups of >8, >6, and ≥4 weeks of treatment periods, respectively, and hence, the effectiveness of garlic supplementation is directly related to the duration of consumption [DME, the leading cause of vision loss in diabetic retinopathy, is induced by the accumulation of extracellular fluid in the retina that disrupts the retinal cell structure . The ressumption . This daWe also showed that the patients who received garlic supplements manifest a significant improvement in visual acuity. This observation might be interpreted by the effect of garlic on the ocular perfusion flow. Garlic intake is demonstrated to have a remarkable role in increasing blood flow . RecentlOur data also showed that garlic intake could remarkably decrease the IOP. This study is in line with previous reports on the effect of garlic compounds on IOP . Garlic A review of the recent studies confirms that complementary therapies have recently found an important place in the treatment of diabetic retinopathy . Garlic In addition, Lafuente et al.'s study represented successful outcomes for adding a combined antioxidant treatment to anti-VEGF in the treatment of DME , 45. TheIt should be noted that garlic has anticoagulant and antihypertensive properties and may increase the tendency to bleed in susceptible patients. Therefore, it should be prescribed with caution in these patients. Although the present study confirmed that garlic consumption was safe and no adverse event was observed in patients who received garlic pills, no significant vitreous hemorrhage or other organ bleeding was observed in our study. We also checked the bleeding time and excluded the patients with a history of active gastrointestinal (GI) ulcers or cerebral vascular accidents (CVA).The main limitation of our study was its duration. Additionally, some circumstances, mainly the COVID-19 pandemic, caused poor follow-up of patients, and we could not follow patients for longer periods. The other restrictions and confounding factors were common dietary habits. In our country, garlic is used as a flavoring that may influence the results of the study. We tried to decrease the effect of these factors by randomization. For future research, the use of natural products such as garlic products to help treat diabetics, especially retinopathy, is recommended in studies with larger sample sizes and the control of confounding factors such as diet and other risk factors. The possible effects of long-term use of garlic products on reducing the incidence of vascular disease can also be examined. The use of higher doses of the drug and drug interactions with other drugs commonly used by diabetics are topics that may be the subject of future research.Overall, the presented data indicate that garlic supplementation can enhance visual acuity and decrease IOP in patients with diabetic retinopathy. However, we could not detect a significant change in macular thickness between garlic-treated patients in comparison to the control group. In addition to many experimental and preclinical studies reporting the anti-inflammatory, antiangiogenic, antioxidant, and neuroprotective effects of garlic, the present study, for the first time, provided valuable evidence on the improving effect of garlic consumption on diabetic retinopathy patients. Further clinical investigations are required to better evaluate this product. The ease of access, ease of use, and natural identity of garlic are its positive aspects. Garlic application as a complementary drug in patients with diabetic retinopathy might reduce the need for intravitreal injection or retinal surgery to improve visual acuity and control IOP in patients. This finding might extend novel platforms to the management of diabetic retinopathy.