The associations among the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR) and disease activity in rheumatoid arthritis remains unclear.To evaluate these indicators as potential markers of disease activity in patients with rheumatoid arthritis (RA).This cross-sectional study included 547 adult patients with RA. The patients were divided into two groups according to the disease activity score (DAS) system: remission and disease activity. Differences in the NLR, PLR and LMR of the two groups were assessed. Correlations were analyzed using Spearman analysis, and receiver operating characteristic (ROC) curves were used to identify the sensitivity, specificity, and optimal cutoff values to differentiate active RA patients from inactive RA patients.P = .034) and PLR  between the two groups, but not for the LMR . In addition, the DAS28 and traditional inflammatory markers, including ESR and CRP, were weakly positively correlated with the NLR and PLR. Based on the ROC curves, the NLR  and PLR  were less valuable than the ESR  and CRP  for differentiating inactive RA patients from active RA patients due to low sensitivity and specificity and combining NLR or PLR also cannot significantly improved the diagnostic value of ESR and CRP.There was a statistically significant difference in the NLR (4.2 ± 3.2 vs 3.4 ± 2.4, NLR, PLR and LMR may not be an useful independent diagnostic or complementary marker for disease activity in RA patients. Thus, accurate measurement of inflammatory activity is essential for customizing the treatment strategy. Although the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity score (DAS) are currently used to estimate RA, several studies have reported the limitations of these markers, such as flooring effects at lower disease activity.–6 Ultrasound and magnetic resonance imaging have been reported to show synovial inflammation, even when the ESR, CRP and DAS have reached the lowest or near normal levels.,8 However, these techniques are expensive and time consuming.Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease that affects synovial joints, leading to bone damage, disability and excess cardiovascular events and cardiovascular mortality. breast cancer, prostate cancer and non-small-cell lung cancer, cardiology, diabetes and infectious diseases). Recently, several studies have reported significant associations among the NLR, PLR, LMR and the presence of RA, as well as disease activity.–22The neutrophil-lymphocyte ratio (NLR), in addition to the platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), is a simple biomarker of systemic inflammation and has been reported to be a highly sensitive measure of inflammation in the field of oncology /European League Against Rheumatism (EULAR) in 2010. Individuals who had any conditions that may affect the NLR, PLR and LMR values were excluded, such as use of steroid at a dose of more than 7.5 mg/day of prednisone or equivalent, active infection, malignancy, or other autoimmune diseases. Age, sex, duration of illness, visual analog scale (VAS) score for pain, swollen joint count (SJC)-28, tender joint count (TJC)-28, and laboratory results for white blood cell count, neutrophil count, lymphocyte count, platelet count, monocyte count, CRP and ESR were recorded. The NLR and PLR for each participant were calculated manually by dividing the neutrophil count and platelet count, respectively, by the lymphocyte count after obtaining the laboratory results. The LMR was defined as the lymphocyte count divided by the monocyte count. The disease activities of patients with RA were determined by the Disease Activity Score of 28 joints (DAS28) system, which was measured by calculating the number of tender joints and swollen joints, the ESR or CRP, and the patient global health assessment using a visual analog scale. Accordingly, the disease can be categorized as the severe activity group (DAS28 ≥ 5.1), moderate activity group (3.2 ≤ DAS28 < 5.1), low activity group (2.6 ≤ DAS28 < 3.2) and remission (< 2.6). We divided the patients into two groups according to the DAS28 system. Group A included patients with a score lower than 2.6 by the DAS28 system (patients in remission), and Group B included patients with a score of 2.6 and higher (patients with active disease). The study protocol was approved by the Institutional Review Board of Chengdu Medical College in accordance with the Declaration of Helsinki, and patient approval or informed consent was required for our review of the patients’ medical records.2.2t test, chi-squared test, or Fisher's exact test. Spearman correlation was conducted to evaluate the linear relationship. The receiver operating characteristic (ROC) curve was used to assess the discriminative ability for RA disease activity. The area under the curve (AUC), optimal cutoff values, specificity and sensitivity were also determined. A two-sided P value of < .05 was regarded as statistically significant.Statistical analyses were conducted using SPSS version 22.0 , and all the graphics were plotted with GraphPad Prism 8.0 . The normality of distribution was assessed using the Shapiro-Wilk test. Continuous variables are expressed as the mean ± SD, while categorical variables are presented in absolute numbers and percentages (n [%]), and the differences were compared and analyzed using Student's sample 33.1P > .05). Age (P = .038) and hemoglobin (P < .001) were significantly higher in the remission group than in the disease activity group. However, the other indicators, such as doses of methotrexate, white blood cells, neutrophils, monocytes, platelets, rheumatoid factor, ESR and CRP, were significantly lower in the remission group than in the disease activity group .The detailed characteristics of RA patients are summarized in Table 3.2P = .034) and PLR  in the disease activity group were significantly higher than those in the remission group. No significant differences were identified in the LMR between the two groups . Next, we further divided the patients with active RA into three subgroups, including low disease activity (n = 56), moderate disease activity (n = 97) and high disease activity (n = 322)    and 167.5 for the PLR . However, the AUC for the ESR was 0.834 with a cutoff value of ≥34.5, sensitivity of 67.2%, and specificity of 91.7%. The AUC for CRP was 0.889 with a cutoff value of ≥7.5, sensitivity of 76.2%, and specificity of 91.7%. These parameters are shown in Fig. Furthermore, the NLR, PLR, CRP and ESR were valid fair tests to differentiate active RA from inactive RA by ROC analysis, where the AUCs for the NLR and PLR were 0.600 and 0.597, respectively, with 4 Although a deeper understanding of RA has been developed due to more in-depth studies in recent years, it remains a challenge to assess the severity of inflammatory activity in patients with RA. The current RA evaluation still has some limitations. For example, ESR, CRP, RF, DAS and the clinical disease activity index are often at cutoff thresholds and are overlooked in patients with low disease activity, but those patients are still at risk of synovial inflammation and progressive joint damage. In a previous study, the data also demonstrated that bone and joint damage can continue to progress in certain patients due to persistent synovial inflammation, even in clinical remission. Thus, it is critical to accurately evaluate the severity of inflammation.The inflammatory response can promote the formation of pannus in the joint, which is the major cause of joint damage.,26–28 The NLR represents two compartments of the immune system. Neutrophils representing the innate system are at the front line of the defense system and are responsible for the production of lytic enzymes, oxygen free radicals, and cytokines. Lymphocytes represent the adaptive system. The persistent accumulation of lymphocytes at the sites of inflammatory joints might result in a decreased lymphocyte count in peripheral blood in patients with RA so that peripheral lymphopenia and the gradual increase in neutrophil count have often been noted with the progression of RA. Monocytes and platelets also have regulatory effects on the immune system, have an active role in inflammation and are involved in the production of cytokines. Thus, the changes caused by inflammation in neutrophils, lymphocytes, monocytes and platelets have turned the NLR, PLR, and LMR into inflammatory markers.In recent years, the NLR, PLR and LMR have served as novel nonspecific inflammatory markers that are attractive to investigators in different fields, including inflammatory diseases .–20 Du's study suggested that the LMR is an important inflammatory marker that could be used to identify disease activity in patients with RA, but no significant differences were identified in the LMR between patients in remission and patients with active disease in our present study.Our present study assessed the relationships among the NLR, PLR, and LMR and disease activity in patients with RA. According to the DAS28, the NLR and PLR were lower in patients in remission, with a score of less than 2.6, than in patients with active disease, which is consistent with previous studies.A weak positive correlation was observed between the CRP, ESR and DAS28 score used to assess disease activity and the NLR and PLR. Receiver operating characteristic analysis showed that CRP was the best laboratory diagnostic indicator for disease activity in RA, with an AUC of 0.889, a diagnostic sensitivity of 76.2% and a specificity of 91.7%. For the NLR  and PLR , the diagnostic values were all lower than the corresponding values for CRP and ESR. These data indicated that the NLR and PLR were less valuable than CRP and ESR for differentiating inactive RA patients from active patients and combining NLR or PLR also cannot significantly improved the diagnostic value of ESR and CRP, which means that they may not be useful indicators in detecting disease activity due to low sensitivity and specificity.Inevitably, our study still has some potential limitations. First, our present study was a retrospective and single-center study. There is a huge difference between those with high disease activity and the others that may cause selection bias. Therefore, a multicenter prospective study is required in the future. Second, due to the relatively small number of patients included in the study, a larger number of patients could enable better statistical evaluation. Third, we did not explore the relationship of hematological markers with indices other than DAS28, such as the CDAI or SDAI.Taken together, although the patients with disease activity presented higher NLR and PLR compared to patients in remission, both the NLR and PLR showed lower discrimination power than CRP and ESR in detecting disease activity and combining NLR or PLR cannot significantly improved the diagnostic value of ESR and CRP. Thus, NLR, PLR and LMR may not be useful independent diagnostic or complementary markers for disease activity in patients with RA.Conceptualization: Wang Lijuan, Liang Chaoyang, Yang Ju.Formal analysis: Wang Lijuan, Zhou Yuting.Investigation: Wang Lijuan.Methodology: Wang Lijuan, Zhou Yuting, Liang Chaoyang, Yang Ju.Validation: Liang Chaoyang, Yang Ju.Writing – original draft: Wang Lijuan, Zhou Yuting.


Hypothermia has been used in postoperative management of traumatic brain injury (TBI); however, the rhythmic variation and prognostic value of brain temperature after TBI have never been studied. This study describes diurnal brain temperature patterns in comatose patients with TBI. Mesors of brain temperature, amplitude, and acrophase were estimated from recorded temperature measurements using cosinor analysis. The association of these patterns with clinical parameters, mortality, and functional outcomes in a 12-month follow-up was examined. According to the cosinor analysis, 59.3% of patients presented with circadian rhythms of brain temperature in the first 72 h postoperatively. The rhythm-adjusted mesor of brain temperature was 37.39 ± 1.21 °C, with a diminished mean amplitude of 0.28 (±0.25) °C; a shift of temperature acrophase was also observed. Multivariate logistic regression analysis revealed that initial Glasgow coma scale score, age, elevated blood glucose level, and circadian rhythm of brain temperature seemed to be predictive and prognostic factors of patients’ functional outcomes. For the prediction of survival status, younger patients or those patients with mesor within the middle 50% of brain temperature were more likely to survive. The analysis of brain temperature rhythms in patients with moderate and severe TBI provided additional predictive information related to mortality and functional outcomes. Improvements in diagnosis, surgical intervention, and intensive care have allowed many patients to survive traumatic brain injury (TBI); however, the long-lasting disability has led to significant functional, emotional, and economic sequelae ,2. Long-Circadian rhythms are a biological adaptation to the light-dark cycle. They regulate sleep-wake cycles, melatonin levels, body temperature, and other body functions. As a part of the circadian rhythm, brain temperature mostly reflects body temperature under physiological conditions. From human and animal data, brain temperature is generally higher than body temperature by approximately 0.3 °C, and correlates well with body temperature ,8,9. HowIn this prospective, observational study, we collected the clinical characteristics, brain temperature, and postoperative outcomes of patients with TBI. All patients were followed-up after surgery until they regained a Glasgow Outcome Scale (GOS) score of 5 for 12 months. The primary endpoints were mortality and functional outcome following TBI surgery. The study was conducted at the National Taiwan University Hospital according to the applicable local regulations and the Declaration of Helsinki. This study was approved by the institutional review board of the National Taiwan University Hospital (IRB number: 201211025RIB). Written informed consent was obtained from the caregivers of patients, as patients were in the comatose state.Upon admission to the hospital, a physician immediately evaluated the GCS score and conducted brain computed tomography (CT). Prehospital management was completed according to the standards of the Taiwan Society of Emergency Medicine, which is compatible with the Brain Trauma Foundation Guidelines for Prehospital Management of Traumatic Brain Injury. At the emergency room (ER), patients were examined and treated following the Advanced Trauma Life Support guidelines and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Guidelines for the Management of Head Injury.Surgical approach selection  for an acute subdural hematoma, epidural hematoma, or other intracranial hemorrhages was based on GCS score, pupillary examinations, comorbidities, CT findings, age, and occurrence of neurological deterioration .2 concentration, and postoperative blood sugar levels. Tympanic body temperature was measured every 3 h, while neurological assessments  were performed hourly. Mean arterial blood pressure (MAP) and ICP were continuously monitored to maintain a minimum cerebral perfusion pressure (CPP) of 70 mmHg. Blood pressure support  was provided as necessary.All patients were admitted to the intensive care unit (ICU) after surgery. Brain temperature was continuously recorded using an intracranial pressure (ICP) monitoring device screwed into the skull, with hourly data collected for circadian rhythm analysis. Conduction cooling, including ice packs, ice pillow, or circulating cold water blankets, was used for patients with febrile episodes (>38.5 °C). Standard monitoring procedure included invasive measurement of arterial blood pressure , pulse oximeter oxygen saturation, end-tidal COPostoperative management included ventilation, oxygenation, head elevation (30°), fluid resuscitation, and the use of sedatives . Hypothermia treatment was not applied, while antibiotic prophylaxis was administered to each patient for at least 3 days after surgery. Enteral feeding was initiated on postoperative day 2 using nasogastric or orogastric tubes for patients without upper gastrointestinal hemorrhage. An ICP of >25 mmHg for 4 h during the first 3 days was considered the threshold to initiate head CT scan and treatment; otherwise, the head CT scan was performed on postoperative day 3.After being transferred to the ward, patients participated in outpatient rehabilitation programs and were followed-up for at least 12 months. Postoperative follow-up included GOS assessment and survival status. The GOS is a 5-point scale: 1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; and 5, good recovery. A favorable outcome was defined as a GOS of >3 at 12 months, and an unfavorable outcome was defined as a GOS of 1–3 at 12 months.All patients were admitted to the National Taiwan University Hospital–Yunlin branch from May 2011 to December 2017. Patients who met the following criteria were included: moderate to severe TBI (GCS score 3–12 at admission), >18 years of age, underwent TBI surgery with ICP monitoring, and brain temperature recorded for at least 72 h after surgery. TBI was defined when a patient had at least one of the following diagnoses: subdural hematoma, epidural hematoma, cerebral contusion, subarachnoid hemorrhage, or diffuse axonal injury. Patients with pre-existing brain diseases , substance abuse, combined traumatic injuries , brainstem injury, diffuse axonal injury, infection within 72 h after admission, or survival time less than 3 days after TBI surgery were excluded. Patients who signed a do-not-resuscitate order were also excluded.Temperature measurements over 72 h were divided into 24-h segments, beginning 2 h postoperatively, to ensure sufficient temperature records for unbiased estimation of cosinor parameters and to minimize potential confounders from postoperative hypothermia.The following brain temperature characteristics were collected: waveform of temperature oscillations; mean level (referred to as the mesor) of temperature oscillations; amplitude of the temperature rhythm, defined as half the difference between the lowest and highest temperature; and the acrophase, the time when the temperature rhythm reached its maximum value for the day. The mesor is the circadian rhythm-adjusted mean based on the parameters of a cosine function. The mesor of the body temperature varies depending on where the body temperature is measured.The circadian rhythm of brain temperature was analyzed using the cosinor method, which is the most used statistical method for modelling diurnal temperature patterns. Cosinor analysis involves fitting the data to a 24-h cosine curve, with estimates of the rhythm parameters, including mesor, amplitude, and acrophase .The ICU had natural light through translucent frosted glass windows and fluorescent lighting turned on from 06:00 to 22:00. To evaluate the effect of light intensity in the ICU, illumination was recorded using the Actiwatch-L monitor . The monitor was placed <100 cm from the head of the patient; light intensity was measured for 7 days with an acquisition interval of 30 s. Light intensity was also analyzed using the cosinor analysis to acquire the 24-h pattern. According to the Actiwatch-L monitor, the light pattern in the ICU showed diurnal changes and was generally brighter during the daytime .p-value of <0.05. Data were analyzed using SPSS 14.0 for Windows .A chi-squared test (or Fisher’s exact test) and t-test were used to compare outcomes between patient subgroups for categorical data and continuous data, respectively. Significant variables found in the univariate analysis were added into multivariate logistic regression models, which were performed with stepwise selection to identify independent predictors of mortality and functional outcomes. Missing data were not included in the analysis. Statistical significance was set at a The demographics and clinical characteristics of patients are presented in After surgery , the mea2 ≥ 0.10. Regarding the acrophase of brain temperature in 63 patients with intact circadian rhythm, the acrophase of 24 patients (38.1%) fell between 12:00 and 18:00, and the acrophase of 25 patients (39.7%) peaked between 18:00 and 24:00 , which is situated in the anterior part of the hypothalamus. The cosinor analysis in our study identified changes in brain temperature rhythm after TBI. The brain temperature rhythm was abnormal in 41.7% of patients with TBI. In 58.3% of patients with preserved brain temperature rhythm, amplitudes of brain temperature were blunted in 82.4% of patients, and acrophases shifted in 61.9% of patients.Impaired rhythm of brain temperature after TBI may be explained by several factors, such as direct or indirect injury to the hypothalamus, medical care, nursing activities, and ICU settings. Previous studies have revealed TBI may cause microscopic hemorrhage of the retinohypothalamic tract—the neuronal pathway extending from the SCN to the pineal gland that synthesizes melatonin, which may lead to the disruption of circadian rhythms ,33. IncrConsidering multiple factors may contribute to the disturbance of brain temperature rhythm and the shift of acrophase, further study is needed to determine other potential factors. Our results could potentially be applied to other neurocritical patients, such as patients with SAH and intracerebral hemorrhage . In addiOur study had several limitations. First, the heterogeneity of patients’ characteristics, including age, comorbidity, and the type of hematoma  may affect the postoperative outcome. The mean age of our patients (57 years) was greater than that of the populations of most TBI studies because the data were collected in Yunlin County, Taiwan, where 13% of the population is over 65 years of age. The effects of age on the pattern of circadian rhythms, such as decreased magnitude, lower mean values, and greater intra- and inter-individual differences, should be considered. Notably, a relatively stable rhythm of body temperature was observed in old age until the end of life ,43. SecoIn summary, this study investigated the circadian rhythm of brain temperature in the acute stage of TBI and its correlation with mortality and functional outcome. Our findings suggest that circadian brain temperature rhythm in the first 72 h after surgery may be a predictor of mortality and long-term functional outcome.


Epilepsy is a brain disorder disease that affects people’s quality of life. Electroencephalography (EEG) signals are used to diagnose epileptic seizures. This paper provides a computer-aided diagnosis system (CADS) for the automatic diagnosis of epileptic seizures in EEG signals. The proposed method consists of three steps, including preprocessing, feature extraction, and classification. In order to perform the simulations, the Bonn and Freiburg datasets are used. Firstly, we used a band-pass filter with 0.5–40 Hz cut-off frequency for removal artifacts of the EEG datasets. Tunable-Q Wavelet Transform (TQWT) is used for EEG signal decomposition. In the second step, various linear and nonlinear features are extracted from TQWT sub-bands. In this step, various statistical, frequency, and nonlinear features are extracted from the sub-bands. The nonlinear features used are based on fractal dimensions (FDs) and entropy theories. In the classification step, different approaches based on conventional machine learning (ML) and deep learning (DL) are discussed. In this step, a CNN–RNN-based DL method with the number of layers proposed is applied. The extracted features have been fed to the input of the proposed CNN–RNN model, and satisfactory results have been reported. In the classification step, the K-fold cross-validation with k = 10 is employed to demonstrate the effectiveness of the proposed CNN–RNN classification procedure. The results revealed that the proposed CNN–RNN method for Bonn and Freiburg datasets achieved an accuracy of 99.71% and 99.13%, respectively. Epilepsy is a noncontagious disease and one of the most prominent brain disorders. About 1% of the world’s population has been diagnosed with epilepsy ,3. AboutIn 2017, the International League Against Epilepsy (ILAE) presented a new classification of the epileptic seizure types: focal epilepsy, generalized epilepsy, and epilepsy with unknown symptoms  is the normalized PSD, and IMWF is the mean frequency of the input signal epoch. Whenever the PSD changes sharply, it results in a lower IWBW . PE can be calculated as follows [log is a natural logarithm, and ln Hm=−fined by .(34)HnmHere is a new definition of PE based on Rényi’s theory as follows :(35)HRm=(7)Graph Entropyith node and the jth node, and m is the number of nodes connected to the ith node [A new entropy method based on graph theory was proposed by Reference . The relith node .(8)Fuzzy Entropym is the length of the sequences.For a time series en below :(38)Xim=and  Xjm .(39)DijIn Equations (40) and (41), ion (41) :(41)Φmn,Finally, the ion (42) :(42)FuEn(9)Refined Composite Multiscale Fuzzy Entropy (RCMFE)The RCMFE follows :(43)RCMFr), Fuzzy entropy power (n), and the embedding dimension (m) [RCMFEsion (m) .(10)Inherent Fuzzy EntropyThis section expresses inherent fuzzy entropy (IFuEn). The steps of IFuEn are as follows :x(t) signal and reconstructing the 1.Calculating the extremes to cover nd emaxt .2.Calculating the average :(44)mt=e3.Candidates of inherent functions are derived intrinsic mode functions (IMFs) :(45)dt=x4.r(t) as follows [Calculating the value of  follows :(46)rt=x5.t = t + 1, consider d(t + 1) as the input EEG data; while iterating on the residual m(t), which continues until the final residue r that becomes a monotonic function from which no more IMF can be extracted [Given xtracted .6.The total accumulated residual IMFs are used to reconstruct the t signal :(47)x^t=Step 1. Multiple IMFs are made by breaking down the original  follows :1.CalculFuEn to evaluate the complexity, which is similar to Equation (42) [Step 2: ion (42) .Step 3: Multi-scale version  follows :(48)yjτ=τ is the scale factor. Also, the length of each coarse-grained time series is N/τ [In this regard, s is N/τ .(11)Averaged Fuzzy EntropyAverage fuzzy entropy (AFuEn) is an improved model of FuEn. In AFuEn method, an improved m_ pattern  follows : (49)D kn samples, A translation of n, A reflection at the position n, An inversion at the position n samples, A glide reflection of In the following, four different types of  follows :A translIn this case,  follows :(50)FuEnFinally, the ion (51) : (51)AFu(12)Fractional Fuzzy EntropyIn Reference , researcα is the fractional-order derivation. Moreover, In Equation (52), FuEn is introduced. Placing Equation (53) in Equation (42), fractional fuzzy entropy (FFuEn) may be stated asIn Equation (42), (13)Spectral EntropyThis method is normalized Shannon entropy, which quantitatively defines the spectral complexity of the EEG signals as follows :(55)Sent(14)Sample EntropyA refers to the total number of vector pairs of length m + 1, and B comprises the total number of vector pairs of length m [In the equation below, the sample entropy formula is shown :(56)Samplength m .(15)Permutation Entropyn defines the sequence length, and nth occurrence [Permutation entropy estimates the complexity of biomedical signals, such as EEG signals, by measuring the couplings between two classes. The equation of permutation entropy is presented as follows :(57)PE=−currence .While these methods have been around for longer than many other machine learning algorithms, in recent decades, despite many advances in machine learning and the introduction of a wide variety of novel algorithms, support vector machines  have notOne of the simplest and, at the same time, most practical machine learning methods is the KNN algorithm , which iIn this section, the proposed DL architecture for the detection of epileptic seizures based on EEG signals is discussed. The network used in this paper has a CNN–RNN structure with the use of extracted features. Nowadays, combined deep learning models such as CNN–RNN have achieved successful results in diagnosing and predicting diseases from medical data.Convolutional layers are usually used in the primary layers to combine CNN models with RNN, which are responsible for extracting the features. The output of the convolutional layers is then applied to the RNN layers to use their superiority to identify the global pattern ,109. TheIn this paper, a deep CNN–RNN network with the proposed number of layers, along with handcrafted features, is used to diagnose epileptic seizures. The proposed CNN–RNN model is applied to the Bonn and Freiburg datasets, along with the handcrafted features. The CNN–RNN model has the same structure for both datasets. In the proposed deep learning method, there are three convolutional layers in the convolutional section to extract features and one max-pooling layer with a feature reduction purpose. After that, there is a flatten layer to transform the extracted features into feature vectors. Then, an LSTM block with 64 neurons was used to extract the RNN features. Afterwards, a combination block was used to combine the CNN–RNN and handcrafted features. Finally, three fully connected layers were implemented to classify the data. In the proposed CNN–RNN model, each layer’s selection and its parameters were made by trial and error.Spec), sensitivity (Sens), accuracy (Acc), and F1-score (F1-S), and precision (Prec). The true positive (TP), true negative (TN), false negative (FN), and false positive (FP) parameters are extracted from the confusion matrix [In this paper, the classification results are evaluated using the 10-fold cross-validation techniques. In K-fold cross-validation, the total number of observations are split into K-folds, where the data samples are limited. Finally, the performance of the algorithm was estimated using statistical metrics include specificity (n matrix .(58)AccQ = 1, r = 3, and J = 8 for both datasets.The experiments are performed on a Ryzen 1700 machine with 8-GB RAM using MATLAB for feature extraction and TensorFlow 2 and scikit-learn for the classification algorithms. In this part of the paper, we present the results of the proposed method. The proposed method includes the preprocessing, feature extraction, and classification steps. The preprocessing step includes windowing, noise removal, and decomposition of the EEG signals into various sub-bands by the TQWT. In the first step of preprocessing, the signals from the Bonn and Freiburg datasets are decomposed into different time windows. For the Bonn dataset, each EEG signal is segmented into time windows of 5 s, and for the Freiburg dataset, each EEG signal is segmented into time windows of 4 s. In the following, a Butterworth band-pass filter is used to preprocess the signals of the datasets. In the third preprocessing step, TQWT is used for EEG signal decomposition. As mentioned earlier, the important TQWT parameters are selected as In the following, various statistical, frequency, and nonlinear features are extracted from the TQWT sub-bands. The combination of these features has been done for the first time in this paper and is considered an important novelty.In the final part of CADS, the epileptic seizure detection based on EEG signals, ML classifier algorithms, and deep learning was examined and tested. The ML classifier techniques include SVM and KNN methods. On the other hand, the DL method is a CNN–RNN model. This method of classification is another novelty of this paper. Here, the proposed CNN–RNN method has two separate inputs. In the first input, Bonn or Freiburg dataset signals are applied to one of the proposed CNN–RNN network inputs. After passing the raw signals of the datasets through the one-dimensional (1D) convolutional layers, they finally reach the flatten layer. On the other hand, handcrafted feature extraction methods are applied to the second input of the proposed CNN–RNN architecture . Then, tIn the proposed CNN–RNN implementation on the Bonn dataset, each data is broken into 5 s windows, and after preprocessing, some features are extracted from it. At the same time, each 5 s window, which contains 868 frames of data, is broken by 25 overlaps into 33 windows, each containing 50 frames, which are used for CNN–RNN input as the raw data. In the proposed method, each 100-epoch network is trained using the categorical cross-entropy error function and Adam optimizer.It is also important to note that the implementation and configuration of the proposed CNN–RNN model for the Freiburg dataset are similar to the Bonn dataset. As can be seen in The classifications were chosen similar to the research papers about epileptic seizure diagnosis based on EEG signals using the Bonn dataset ,60,61,62Additionally, the results of the Fribourg dataset are shown in In this section, the limitations of the study are discussed. As mentioned before, epileptic seizures have various types, and their on-time diagnosis has great importance. There has been no dataset on the types of epileptic seizures so far. Therefore, researchers cannot do serious research in this field. In addition, the available EEG datasets for epileptic seizure diagnosis have limited use, and achieving actual and accurate epileptic seizure detection based on AI techniques is not possible due to this limitation. Another limitation of epileptic seizure diagnosis from EEG signals is that there are no dataset of EEG signals with preictal, ictal, and interictal times being highlighted in them. In the case of addressing these limitations, it is possible to use advanced and novel DL models to diagnose various types of epileptic seizures.Epileptic seizures are defined as a group of neurological disorders, and their early diagnosis is of particular importance for specialist physicians and neurologists ,111. In So far, various AI methods have been proposed to epileptic seizures detection, aiming to aid specialist physicians in the rapid diagnosis of epileptic seizures based on EEG signals. Researchers in the past have mostly exploited ML methods to diagnose epileptic seizures. Inefficiency in large amounts of input data, the complexity of the methods, the need for great knowledge to use ML methods in diagnosing epileptic seizures, etc. are the most important deficiencies of these methods. To address this issue, in recent years, DL approaches have been proposed that possess appropriate efficiency and performance for diagnosing various diseases, including epileptic seizures, by using a large amount of input data.The proposed method consisted of three parts: preprocessing, feature extraction, and classification. Two datasets, Bonn and Freiburg, were exploited for the experiments. Bonn dataset signals were selected for 5 s time windows and Freiburg dataset signals for 4 s time windows. In the preprocessing step, first, a Butterworth band-pass filter was utilized for the initial preprocessing of the two dataset signals. Following the preprocessing step, the TQWT technique was adopted to decompose the EEG signal datasets into different su-bands. The TQWT parameters were selected to be applied to the two datasets similar to Reference .In the following, a variety of statistical, frequency, and nonlinear features were extracted from TQWT sub-bands. Statistical features contain statistical moments. Nonlinear features also involve two categories of FDs and entropies. FD-based nonlinear features include Higuchi, Katz, Petrosian, and DFA. Entropy-based feature extraction techniques also include Shannon, Log-Energy, spectral, Sample, permutation, Fuzzy, refined composite multiscale fuzzy, graph, Permutation Rényi, average Shannon wavelet, average Rényi wavelet, average Tsallis wavelet, inherent, fractional fuzzy, and average fuzzy. In the feature extraction section, for the first time, a combination of these features has been used to epileptic seizures detection based on EEG signals and is considered the first novelty of this article.Finally, ML methods and a CNN–RNN based on a DL model were exploited in the classification step. Among the classification methods, the CNN–RNN was applied for the first time in this study and was carried to account for another novelty. Here, the proposed CNN–RNN approach entailed two separate inputs. In the first input, the EEG signals of the Bonn or Freiburg datasets were fed to one of the proposed CNN–RNN network inputs. After the raw signals of the datasets passing through the 1D convolutional layers, they eventually attained the flatten layer. On the other hand, handcrafted feature extraction methods were applied to the second input of the proposed CNN–RNN architecture . Then, tThen, in According to As shown in In future works, graph theory methods will be utilized, coupled with novel handcrafted features ,113. Add


Background: Virtual reality-based therapy (VRBT) is a novel therapeutic approach to be used in women with fibromyalgia syndrome (FMS). The aim of our study is to assess the effect of VRBT to reduce the impact of FMS in outcomes such as pain, dynamic balance, aerobic capacity, fatigue, quality of life (QoL), anxiety and depression. Methods: Systematic review with meta-analysis was conducted from a bibliographic search in PubMed, Scopus, PEDro, Web of Science and CINAHL until April 2021 in accordance with PRISMA guidelines. We included randomized controlled trials (RCTs) that compare VRBT versus others to assess the mentioned outcomes in women with FMS. Effect size was calculated with standardized mean difference (SMD) and its 95% confidence interval (95% CI). Results: Eleven RCTs involving 535 women with FMS were included. Using the PEDro scale, the mean methodological quality of the included studies was moderate (6.63 ± 0.51). Our findings showed an effect of VRBT on the impact of FMS ; pain ; dynamic balance ; aerobic capacity ; fatigue ; QoL ; anxiety  and depression . Conclusions: VRBT is an effective therapy that reduces the impact of FMS, pain, fatigue, anxiety and depression and increases dynamic balance, aerobic capacity and quality of life in women with FMS. In addition, VRBT in combination with CTBTE showed a large effect in reducing the impact of FMS and fatigue and increasing QoL in these women. Fibromyalgia syndrome (FMS) is a chronic disease of unknown etiology that courses with generalized and diffuse non-inflammatory pain and hyperalgesia in different human body points . Other FAlthough the pathogenesis of FMS is unknown, the mechanisms responsible for dysfunctional pain in FMS, without having identifiable tissue lesions, are mainly related to disorders of the central nervous system (CNS) that may explain diffuse musculoskeletal pain . SeveralIn recent years, numerous therapeutic proposals have been implemented in an attempt to reduce the symptoms and the impact of FMS . In addiThe usability and feasibility of VRBT in CT protocols with promising results in the management of pain, anxiety or mood states have been shown . For exaThis systematic review is reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement  and it wTwo authors (I.C.-P. and M.C.O.-P.), independently, performed a bibliographical search in PubMed Medline, Web of Science (WOS), Scopus, CINAHL Complete and PEDro (Physiotherapy Evidence Database) to select articles published up to April 2021. The authors reviewed the reference lists from retrieved full-text studies and previously published grey literature, expert documents and congress abstracts. Based on Medical Subjects Headings (MeSH) the keywords used in the search strategy were “fibromyalgia”, “virtual reality” and “virtual reality exposure therapy” with its synonyms. Based on the particular database, the Boolean operators “AND”/“OR” were used to combine the keywords and entry terms, according to PICOS tool of Cochrane Collaboration , for theTwo blinded reviewers (N.Z.-A. and F.A.N.-E.), independently, screened the titles and abstracts of all references retrieved in each database. When one of these authors selected an article during the inclusion phase based on the title and abstract, it was examined in detail. All disagreements were resolved by a third author (M.C.O.-P.). A study was included in the present SR when it met all the following inclusion criteria: (1) RCTS or RCT pilot study; (2) comprised by women with FMS; (3) with at least two groups; (4) of which one group received VRBT; (5) compared with controls; (6) and reported quantitative data of different outcomes related with FMS impact see . The excTwo authors (I.C.-P. and E.O.-G.) independently collected data from the included studies in a standardized Microsoft Excel data-collection form. To resolve disagreements, a third author was consulted (M.C.O.-P.). We extracted the following data: (1) overall characteristics of the study ; (2) characteristics of the intervention and control groups ; (3) data related to the post-intervention outcomes ; and (4) evaluation time sequence (right at the end of the therapy or follow-period). When a study did not provide statistics appropriate for performing the meta-analysis, we extracted the median, standard error, range or interquartile range to be transformed into a SD . The main outcome assessed in this SR was the impact of FMS, which was assessed in patients with FMS after receiving VRBT in comparison to other interventions  or stretching [ST]) or no intervention (NI). The Fibromyalgia Impact Questionnaire (FIQ) was selected to assess the impact of FMS in the selected studies. In addition, other variables assessed in this SR were pain, dynamic balance, aerobic capacity, fatigue, QoL, anxiety and depression. Different assessments examining the same outcome were grouped together for analysis .The PEDro Scale was used to assess the risk of bias of the included studies . The PEDThe Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment  was usedTwo authors (N.Z.-A. and M.d.R.I.-L.) independently assessed the risk of bias, and quality evidence and doubts related to this assessment were resolved in consultation with a third researcher (M.C.O.-P.). The quality evidence of each meta-analysis was downgraded from high quality by one level for each factor that was found. In the case of the presence of several limitations, the overall quality level was downgraded by two levels. Finally, the level of evidence in each meta-analysis was categorized as (1) high: the findings are robust; (2) moderate: it is possible that new research may change our results; (3) low; the level of confidence in our pooled effect is very slight; or (4) very low: any estimate of effect is very uncertain.p-value < 0.1, there exists a risk of publication bias) ,,2 and a ive VRBT ,64,66,69ive VRBT ,68,70,71ive VRBT ,68,70,71ive VRBT ,68,70,71The risk of bias scores for 7 RCTs ,68,70,712 and a mean duration of symptoms of 10.49 years) were included in the quantitative synthesis. Ten RCTs ,69,70,71p < 0.001) (p = 0.9) or heterogeneity (I2 5.18%) were found. Sensitivity analysis did not reported variation.Six RCTs ,66,69,71< 0.001)  showing Subgroup analysis showed a reduction in FIQ scores favors VRBT  compared to NI and in the combined use of VRBT + CTBTE  in comparison to CTBTE, with low- and very low-quality evidence, respectively.p < 0.001) compared to controls (p = 0.2 and trim-and-fill variation of 28%) without heterogeneity (I2 0%). Sensitivity analysis showed a variation of 17% when Collado-Mateo [Six RCTs ,66,69,70controls . The risdo-Mateo  was remoSubgroup analysis showed low-quality evidence of a medium effect of VRBT in comparison with NI , favored VRBT.p < 0.001) on dynamic balance in comparison with NI was found (p = 0.52) and low heterogeneity were present (I2 4.35%). There was an estimated variation of 20% with respect to the original SMD when Villafaina was excluded [Three RCTs ,68,71 reas found . No risk2). Low-quality evidence of a small effect of VRBT  on aerobic capacity was shown compared to other therapies or NI (2 0%). The risk of publication bias was low (Egger p = 0.31 and trim-and-fill variation of 12%). Sensitivity analysis showed a variation of 41% with respect to the original pooled effect when excluding Polat [Five RCTs ,67,69,71es or NI  without p = 0.31). Subgroup analysis was performed for the comparison VRBT vs. NI, without find statistical significant between therapies  on fatigue compared with other interventions or NI (2 5.4%). Risk of publication bias was present (Egger p = 0.09 and variation of 20% with the trim-and-fill method). Sensitivity analysis showed a variation of 31% when excluding Polat [Four RCTs ,62,66,69ns or NI  with lowSubgroup analysis showed low-quality evidence of a reduction in fatigue (MD −2.21 95% CI −4.33 to −0.1) when VRBT was used in combination with CTBTE compared to CTBTE alone, favored VRBT intervention.p < 0.001) on QoL was shown in comparison to CTBTE or NI (2 0%). Sensitivity analysis did not show variation.Five RCTs ,66,69,70TE or NI . No riskSubgroup analysis showed a medium effect  of VRBT and VRBT + CTBTE  compared to NI and CTBTE, respectively, with low-quality evidence.p = 0.037) in comparison to other interventions or NI (2 0%) and with a possible risk of publication bias (trim-and-fill variation of 22%). Sensitivity analysis showed a variation of 36% when excluding Polat [Anxiety was assessed in 3 RCTs ,62,69 thns or NI  without p = 0.003) was shown compared to other interventions or NI (p = 0.14) and low heterogeneity (I2 4.59%). Sensitivity analysis displayed a variation of 19% with respect to the original pooled effect when Silva-Carvalho was excluded [p = 0.008). Four RCTs ,62,65,69ns or NI . A possiexcluded . A subgrp < 0.05) between PVO2 and the left and right regions of the hippocampus and the left and right regions of the amygdala were found with VRBT compared to NI. Villafaina, S. et al., 2019a [p < 0.05) in the VRBT group. VRBT was more effective in the group with a shorter duration of symptoms, showing between-group differences in some frontal and temporal areas.Two RCTs ,67 asses., 2019a  evaluateFMS is a chronic disease characterized by widespread muscle pain that reduces functional capability and QoL. In addition to other therapies, such as pharmacotherapy , balneotOne of the most important impairments of FMS is its impact on ADLs, which is mainly assessed with the FIQ . Our resSome studies have suggested that VRBT is a novel approach in the field of orthopedic rehabilitation , in the Balance disorders appear in women with FMS, increasing the risk of falls . A recenWomen with FMS reported a decreased aerobic capacity, which could have a negative impact on functional capacity and consequently on QoL. Our findings showed an improvement in aerobic capacity in women who were exposed to VRBT. VRBT could provide the training of representative tasks included in ADLs that require less muscle strength and allow individuals to perform the activity for longer periods of time, which increases the cardiorespiratory fitness of these patients .Generalized fatigue induces a sedentary lifestyle in women with FMS, which reduces aerobic capacity . For thiIn our study, we report that QoL improves after to use of VRBT. Restoring and balancing physical activity is a challenge in patients with FMS and chronic pain. Low mood, pain, and fatigue decrease the willingness to perform ADLs, causing low motivation and a poor sense of self-efficacy and QoL. Recent studies have shown that VRBT improves mood states, positive emotions, motivation, and self-efficacy in FMS patients , which sOur results showed that the levels of anxiety and depression improved after the use of VRBT in women with FMS, although a major effect was found on depression outcomes. Physical exercise in FMS patients has previously been shown to improve anxiety  and depr2 and the left and right regions of the hippocampus and the left and right regions of the amygdala after training with VRBT [One study included in our review found significant relationships between pVOith VRBT . These fith VRBT . The autith VRBT ,97. Findith VRBT  indicateith VRBT ,99, as with VRBT . Thus, Vith VRBT . These rOur results may be considered to have some limitations. First, the low number of studies included may make generalization of our findings difficult. Related with the generalization of our findings a limitation is that our findings are applied to women with an age that varied between 38 and 55 years old (mean of 51.4 years old) and BMI between 25 to 28 (mean of 27.7). It would be important to perform new studies in all groups of age. Second, the impossibility of blinding the therapy to participants increased the risk of selection bias. Third, it is important to consider the possible risk of publication bias that may have reduced the reported effects of therapy. Another limitation was the low number of participants per study, which reduced the precision level of our findings. Besides, it is important to highlight that the large variations in sensitivity analysis may have affected the quality of our findings. Finally, it is important to remark that all studies were performed in Spain, Turkey or Brazil and it can affect to the generalization of our findings. It would be necessary to perform studies in more countries to increase the application of our findings.This is the first SR with meta-analysis that demonstrates the effect of VRBT in women with FMS in reducing the health impact of symptoms of FMS, in short-term follow up. Our results showed an effect of VRBT in comparison to other interventions or NI and favored VRBT intervention based on the impact of FMS, pain, dynamic balance, aerobic capacity, fatigue, QoL, anxiety and depression. In addition, when VRBT was combined with CTBTE and compared to CTBTE alone, our findings showed a large effect of VRBT + CTBTE intervention on the measures of the impact of FMS fatigue and QoL. However, it is necessary to conduct further research on this topic, while increasing the sample size and extending the assessments to the long term.


Reclaimed asphalt pavements (RAP) provide economic and environmental benefits. In recent decades, their use has increased, but rheological properties are affected by RAP aging, increasing stiffness, cracking, and susceptibility to water. To counteract these effects, rejuvenating agents are used, but they must be properly dosed to design quality mixtures. Therefore, different binders were analyzed, including virgin binder (VBB), binder modified by SBS polymer (MB), AC-RAP, binder softened using a rejuvenating agent, and binders softened with doses  of AC-RAP. The rheological properties were evaluated by dynamic shear rheometry (DSR) and beam-bending rheometry (BBR) tests, while the linear amplitude sweep (LAS) test was used to measure fatigue cracking and the multiple stress creep recovery (MSCR) test was used to measure rutting. A mixing chart was constructed based on a high temperature AC-RAP to satisfy the performance grade (PG 76-22). The results showed that softened binders become flexible, but when AC-RAP is added, they turn stiff and behave better than MB. Moreover, combining a rejuvenating agent and AC-RAP reduces the aging stiffness of RAP, improving its rheological properties without compromising the rutting or cracking resistance. The pavement industry is a vital sector that can actively serve a country’s economy by contributing to the GDP , althougIn accordance with Milad, Taib, Ahmeda, Solla and Yusoff , The Dep2 emissions were reduced by 2%.Consequently, if 100% of the RAP is used, the need for virgin materials would be reduced, thereby inducing sustainability in pavements ; hence, However, the maximum quantity of RAP that can be used to produce HMA is limited ,11, sincThese properties have been of interest, since they directly affect the behavior and performance of asphalt mixtures ,30,31,32To counteract the negative effects of the use of RAP, there are methods that help reduce stiffness and increase rutting resistance, such as the use of WMA technologies, the use of a softer binder, increasing the binder dosage, or the application of rejuvenating agents ,33,37,38Currently, the absolute viscosity and PG methods are used to estimate the proportion of RAP . Superpa®” , and softened binders blended with different percentages  of AC-RAP , which were designed based on a high-temperature mixing chart constructed by linear characterization of the performance grade (PG). The rheological performances were measured using a dynamic shear rheometer (DSR) and a beam-bending rheometer (BBR), while through the linear amplitude sweep (LAS) and multiple stress creep recovery (MSCR) test the fatigue cracking behavior was measured. The frequency sweep accelerated the rate of damage accumulation using the continuous viscoelastic damage theory (VECD).Consequently, the objective of this article is to evaluate the rheological performances of different asphalt binders, including virgin binder (VBB), RAP asphalt cement (AC-RAP), a modified binder (MB) with styrene-butadiene-styrene polymer (SBS), softened binders using the rejuvenating agent “Maro-1000The asphalt binder used in this experimental research was classified by its PG grade, 64-22, through the standardized procedure described in AASHTO M323 . The VBB was modified using an SBS-GP100 polymer at a proportion of 2.25% with respect to the weight of the asphalt binder. SBS-GP100 is a powder polymer designed to modify binders, which has a radial block structure and contains 30% styrene and 70% butadiene by weight.In addition, sulfur was added at 2.5% with respect to the weight of the SBS polymer. This is composed of 48% cumulative percentage of diluents, dispersants, and conditioners, as well as elemental sulfur (52% by weight) containing particles smaller than 2 μm.Thus, the product obtained after SBS and sulfur addition corresponded to a modified binder (MB) with a PG 76-22 grade.® was used to improve the rheological properties of the new binder while reducing the stiffness caused by oxidation or aging of the AC-RAP. This rejuvenating agent is a viscous yellow-greenish liquid at 25 °C temperature. Its moisture content is 0.314%, its specific density is 0.9546 g/cm3, and its Saybolt-Furol viscosity is 292. It has a high inflation point, which does not affect its behavior.As the modified binder was to be combined with different dosages of AC-RAP , the rejuvenating agent Maro-1000The RAP used in this research’s development was derived by crushing the asphalt binder on the MEX80D “Zapotlanejo-Lagos de Moreno” highway, Jalisco, Mexico. The recovered material was mixed, dried, and homogenized by successive quartering, obtaining representative samples to characterize it.The experimental design of this article is shown schematically in the flow diagram presented in Likewise, AC-RAP, VBB, MB, and asphalt binder were obtained for the low RAP rate (L), medium rate (M), and high rate (H), as well as the combination of the three percentages of AC-RAP by mass ratio with their respective softened binder, which resulted in 9 asphalt binders, as described in Finally, the rheological properties of the binders were analyzed by rheology tests on a DSR and BBR, while the nonlinear viscoelastic responses of the nine binder products were evaluated using the MSCR and LAS tests.In order to simulate the aging of the binder contained in the RAP (AC-RAP) during the manufacturing process of the HMA mixture (short-term) and to eliminate any trace of the solvent that could affect the results of the rheological tests, the short-term aging process for the AC-RAP was performed. The binder specimens were maintained for 85 min at a temperature of 163 °C in the rotary thin-film oven  according to ASTM D2872 . In addiTo perform the RAP rheology tests (DSR and BBR), it was necessary to determine the amount of AC-RAP contained in the RAP, as well as to obtain the solvent–binder solution necessary for the recovery of the AC-RAP. Therefore, the procedure used to quantify the asphalt binder content was carried out in accordance with ASTM D2172  “StandarFinally, after performing the above procedure repeatedly, a sufficient amount of the solvent–binder solution was obtained. Subsequently, the AC-RAP was recovered through distillation by the Abson method, which follows the standardized procedure described in ASTM D1856  “StandarThe PG classification of VBB, MB, and AC-RAP binders was performed by rheology tests on a DSR and BBR. Critical failures at high and low temperatures were characterized using the procedures described in AASHTO T315  “StandarA dynamic shear rheometer  was used to evaluate the rheological properties of bitumen in the domain of linear viscoelastic behavior under different conditions . The binder samples were tested between parallel plates with a spacing of 1 mm and a plate diameter of 25 mm. The complex shear modulus (G*), phase angle (δ), and rutting factor (G*/sinδ) of the control (unaged) and aged bitumen samples were investigated according to the standard AASHTO T315 .The bending beam rheometer  was used to determine the minimum temperature at which the asphalt binder can withstand thermal cracking. The test consists of fabricating a beam of asphalt binder after long-term aging (PAV). The asphalt binder beam was subjected to a load of 0.98 N for 60 s; the temperatures used ranged from 0 to −18 °C. The low failure temperature was determined when the stiffness (St) was 300 MPa and the slope  of deformation with respect to time was 0.3.RAP = the failure temperature of the aged binder from the RAP  after RTFO.The selection of the binder was based on the HPG grade, calculated using mixing charts governed by Equation (1) .(1)Tv=T®, were added. For the homogenization of the MB with different doses of rejuvenating agent, a helix agitator equipped with a digital indicator  was used, applying speed rates of 500 and 600 rpm. To guarantee correct homogenization, a vessel containing the binder was preheated in an oven at temperatures in the range of 150–160 °C  was obtained and divided into smaller samples, to which different percentages (dosages ranging from 0% to 35%) of the rejuvenating agent, Maro10000 °C see .Similarly, the high-temperature PG for each of the samples dosed with rejuvenating agent was obtained. As shown in Analogous to the characterization of the VBB and MB binders, the softened modified binders with rejuvenating agent (at doses established for each RAP rate) were subjected to DSR and BBR rheological analyses to determine the PG at high and low temperatures.Thus, softened modified binders with the rejuvenating agent  and softened modified binders combined with their respective percentages of AC-RAP  were tested with a DSR before and after RTFO at 163 °C for 85 min. Subsequently, long-term aging was performed with a pressure aging vessel (PAV) test for a re-analysis using the DSR and BBR. The tests were used to determine the permanent deformation parameter (G*/sinδ) and to characterize the PG binders.As the main part of the study, the nonlinear viscoelastic responses of the nine resulting binder products  were evaluated. To determine the effects of the combination of binder, SBS polymer, rejuvenating agent, and AC-RAP, MSCR and LAS tests were performed. The test parameters considered load stresses, corresponding to high levels of stress and accumulated damage, to reference the mechanical behaviors of the binders within the HMA.The MSCR test evaluates the mechanical properties of a binder at high temperatures, specifically the performance pertaining to permanent deformation, which correlates to the resistance to deformation accumulated in an asphalt binder . The tesAs a result of the test, the nonrecoverable creep compliance (Jnr) and the elastic response (%RE) values were obtained, and both parameters were correlated with the rutting performance. This analysis aimed to determine whether the rejuvenating agent dosage was counterproductive to binder performance.The nonrecoverable creep compliance is a measure of permanent strain and is defined as the percentage of residual unit strain (%ε) of a specimen after being subjected to a loading and recovery cycle divided by the applied stress. The mathematical expression of Jnr is given by Equation (2) :(2)Jnr=NOn the other hand, the %RE represents the recovery of the asphalt binder in the recovery time. The calculation is given by Equation (3):The results reported in this investigation concerning the MSCR test correspond to the Jnr and %RE values calculated in each of the ten cycles for each applied stress level (0.1 kPa and 3.2 kPa).In this paper, an LAS test was performed based on the standardized test in AASHTO TP101  “StandarFor the purpose of obtaining comparable results, the temperature selection criterion was taken into account according to the work of van Rooijen, Planque, Wegmann, Di Benedetto, Mangiafico, Sauzeat, Olard and Pouget . FatigueThe test consists of two phases for the same sample. First, a frequency sweep is performed at a constant strain level of 0.1%. The application of load by oscillatory shear stress is performed at frequencies of 0.2, 0.4, 0.6, 0.8, 1, 2, 4, 6, 8, 10, 20, and 30 Hz. The dynamic shear modulus (G*) and phase angle (δ) are recorded at each frequency.During the second stage, a linear amplitude sweep is performed. Subsequently, the sweep is conducted under the temperature criteria shown in max = the maximum strain due to expected tension in the binder under vehicular load; A and B = the coefficients of the VECD model depending on the characteristics of the material. Details of the formulations of coefficients A and B can be found in [The asphalt binder performance can be calculated using the simplified viscoelastic continuous damage theory (S-VECD). Equation (4) shows the potential model , based ofound in .The coefficient A represents the ability of the asphalt to maintain its integrity during stress cycles and when under accumulated damage. Meanwhile, coefficient B describes the sensitivity of the asphalt to changes in the level of applied strain. High values of coefficient B indicate that the fatigue life decreases at a faster rate as the amplitude of the strain level increases. Usually, higher A values and lower absolute B values are associated with binders with higher fatigue resistance . The A vmax ≈ 500 μs (εt)) and weak pavement structures with asphalt layers less than 4 inches thick (5.0% γmax ≈ 1000 μs (εt)) [To compare the fatigue resistance between the different binders used and their influence on the mechanical performance of the mixtures that were part of it, it was necessary to calculate by means of the fatigue laws the number of cycles necessary for failure when maximum strains of 2.5% and 5.0% occurred in the binders. The above criteria correspond to the level of deformation that could be expected in binders that are part of strong pavement structures with asphalt layer thicknesses greater than 4 inches (2.5% γμs (εt)) .The binders analyzed in this research were based on a virgin base binder (VBB) and aged asphalt (AC-RAP). First, through the addition of SBS-PG100 polymer at a ratio of 2.25% by weight of VBB plus 2.5% sulfur by weight of SBS-PG100 polymer, the VBB binders were modified (MB). Therefore, the rheological properties of VBB, MB, and AC-RAP aged at short term (RTFO) and long term (PAV) were assessed through BBR and DSR rheometry to find the viscoelastic responses of asphalt binders in their initial conditions.From The results in On the other hand, the value of G*sinδ is the parameter used to evaluate the behavior at medium temperature at which fatigue cracking occurs. It can be observed that the minimum temperature reached by the binder recovered from the RAP (AC-RAP) after long-term aging using the PAV equipment is 37.3 °C, which is a high temperature compared to the temperatures of the new asphalts without polymer and with polymer . This means that any temperature below 37.3 °C at which the AC-RAP test is performed will not satisfy the maximum permissible G*sinδ value of 5000 kPa. This shows how stiff and brittle the AC-RAP binder is due to aging during its service life.The St value of AC-RAP (temp = 0 °C) increases by 197.24% compared to that of VBB (temp = −12 °C), meaning that the AC-RAP binder is hardened, becoming more rigid and brittle. This was because the binder was exposed to atmospheric conditions , which lead to aging, resulting in the loss of its rheological properties and converting it into a considerably more viscous (stiff) material.An additional criterion of the BBR test is the m value, which represents the tangent of the creep curve at 60 s time vs. load and indicates the capacity of the binder to dissipate stresses or relax. According to the minimum failure temperatures for the VBB binder of −12 °C and AC-RAP of 0 °C, the m-value of MB is slightly higher than that for VBB, showing a slightly steeper time vs. load curve, indicating that it can resist cracking for longer.After characterizing the MB binder, it can be seen in RAP) of AC-RAP was 117.2 °C, whereas the minimum temperature was considered to be the most unfavorable (0 °C).On the other hand, the binder coming from the RAP was extracted, and a sufficient portion of AC-RAP was obtained. Thus, upon verifying that there were no more residues of the solvent used for its separation from the binder with the mineral aggregate, a sample of the AC-RAP binder was analyzed using DSR after undergoing short-term aging in RTFO. The results showed that the critical failure temperature  for the binders SMBL, SMBM, and SMBH , Equation (1) was employed. In From the information shown in The percentages of rejuvenating agent calculated based on the mixing chart and The softened binders SMBL, SMBM, and SMBH presented significant reductions in the St values of 25.77%, 59.36%, and 89.31%, respectively, when compared to that shown by the MB binder. This provides evidence that the rejuvenating agent improved the rheology and viscosity of the binders, i.e., they were less viscous, which caused a softening of the binders, indicating that they were significantly more flexible than MB.Similarly, the m-values increased by 10.23%, 151.49%, and 200.33% in comparison with the MB binder. Therefore, these values are considered acceptable, and it is expected that they will continue to comply with required the specifications of AASHTO M320 . This isTo validate compliance with the mixing charts, the softened binders were combined with the percentage of AC-RAP corresponding to each RAP rate, resulting in the combination of 85% SMBL containing 15% AC-RAP (SMBL15), 70% SMBM containing 30% AC-RAP (SMBM30), and 55% SMBH containing 45% AC-RAP (SMBH45). Additionally, to achieve a part of the objective of this research, the rutting resistance was evaluated through the MSCR test, while the LAS test was used to evaluate fatigue resistance. In this way, high stress levels were applied to assess the accumulated damage using the S-VECD method.−1 and Jnr 0.1 kPa−1, and the percent elastic response (%RE) were measured in the MSCR test. Both parameters were determined by tests performed at HPG temperature. The Jnr results are summarized in The nonlinear response of the binders shown through the values Jnr 3.2 kPa3.2 = 1.364 kPa−1. If this value is compared with those obtained in softened binders containing the rejuvenating agent , reductions of 3.59%, 39.44%, and 71.19%, respectively, can be observed. Similarly, when analyzing the values of softened binders combined with AC-RAP , a variation in the Jnr3.2 value can also be observed, but at a lower magnitude, i.e., the SMBL15 binder shows an increase of 0.73%, while the SMBM30 and SMBH45 binders present reductions of 19.94% and 27.64%, respectively. This means that the softened binders are softer (more flexible) than MB, being more prone to rutting, even though they adequately comply with the specifications shown in 0.1 value, their behavior is very similar to that of the Jnr3.2 value.In contrast, the softened binders blended with AC-RAP  due to AC-RAP aging were hardened (stiffened), but the addition of the rejuvenating agent softened them, renewing the rheological properties of the binder and counteracting the aging of AC-RAP. The above made it possible to establish a balance by improving the crack resistance without compromising the rutting.−1, while at 3.2 kPa−1 the increases are 29.02%, 77.72%, and 212.44%, respectively. This indicates that the rejuvenator has softened and mitigated the stiffness of the binders, causing them to be significantly softer and prone to permanent strain, yet benefiting cracking behavior.The above is evident when the %RE values are analyzed, i.e., the %RE values of the softened binders with the rejuvenator  show increases with respect to MB of 14.13%, 32.17%, and 68.04% at 0.1 kPa−1, respectively. Likewise, at 3.2 kPa−1, the %RE values of these same binders are 15.54%, 36.27%, and 89.64%, respectively. This shows that softened binders blended with AC-RAP are hardened and stiffened by the aging of the AC-RAP, but when the rejuvenating agent is added the rheological properties are restored, thereby softening the binder. This shows that SMBL15, SMBM30, and SMBH45 binders exhibit a more balanced behavior, improving the rutting and fatigue resistance. This coincides with Devulapalli, Kothandaraman and Sarang [Analogously, observing the %RE of the binders softened with the rejuvenator blended with AC-RAP , it can be observed that these also undergo increases of a lesser magnitude, being 9.13%, 16.52%, and 28.485 under 0.1 kPad Sarang . How muc−1), while at low stresses (0.1 kPa−1) the mechanism of the polymer indicates that at the end of ten loading cycles, the SMBL has a recovery of double its original form, as compared to the VBB having unaltered properties, as obtained from the refinery.In addition, the results in Additionally, it is important to note that the softened binders blended with AC-RAP do not show behavior similar to MB, which is due to the amount of AC-RAP, i.e., the higher the AC-RAP content in the mixture, the more difficult it is to soften it with a rejuvenating agent, as Wang, Zeng, Qin, Huang and Xu  explaine−1 present a standard deviation of 0.204 kPa−1 and a standard error of 0.068 kPa−1, while for Jnr 3.2 kPa−1 the standard deviation and standard error are 0.387 and 0.129 kPa−1, respectively.It is important to mention that the Jnr measurement was performed using a standardized method and under controlled conditions, as shown in Observing −1 and 3.2 kPa−1, respectively, it can be observed that the AC-RAP binder shows the highest levels of accumulated strain in each of the loading cycles. This result is consistent with Therefore, analyzing the total accumulated strain shown in The VBB and the binders softened with SBS polymer (SMBM and SMBH) show the best rutting performance , but since the test temperature is the lowest of all the tests , they are stiffer and prone to fatigue cracking.Analogously, in When analyzing the softened binders blended with AC-RAP (SMBM30 and SMBH45), it can be observed that they perform better against rutting compared to MB, SMBL, and SMBL15 binders. In contrast, SMBM30 and SMBH45 binders show better fatigue cracking performance compared to SMBM and SMBH. Thus, in this analysis, it can be observed that binders with a low percentage of AC-RAP (15%) do not present significant variation with respect to virgin binders, while the addition of AC-RAP in higher proportions (30% and 45%) results in binders with balanced rutting and fracture cracking resistance.However, due to differences in test temperatures, the binders exhibit inconsistent behavior. Therefore, future work will seek to evaluate the rheological properties and mechanical behavior of softened binders with different polymers, blended with AC-RAP (using different proportions), and using similar test temperatures, in order to characterize the binders using SEM and XRD techniques.The fatigue phenomenon was calculated using the simplified viscoelastic continuum damage (S-VECD) theory; this model’s input variables depend on the results obtained in the LAS test. However, the current test protocol does not specify a test temperature for binders that have characteristics similar to those analyzed in this paper. Temperature is a relevant factor in evaluating the viscoelastic behavior and mechanical performance of an asphalt binder . TherefoThe previous criterion was based on the performance of the binder, avoiding temperatures that could underestimate or overestimate the performance of the analyzed binders.The LAS test relates the behavior of asphalts to fatigue cracking. From Equation (4) and The parameter B (slope) is related to the binder’s susceptibility to cracking due to changes in applied shear stress. Thus, AC-RAP is the binder with the highest value of B, while the softened binders SMBL, SMBM, and SMBH have the lowest values.Additionally, by analyzing the load cycles to failure (Nf/ESALs) of the binders under an applied shear strain range of 2.5 to 5.0%, which represents the interval that relates the fatigue cracking behavior of an asphalt layer with thicknesses greater than 4 inches and less than 4 inches, respectively, SMBL and SMBL15 binders show the best behavior under both applied shear strains, while AC-RAP shows the lowest values under both strains, being susceptible to fatigue cracking due to age hardening.In summary, according to the results shown in The objective of this work was to analyze the behavior of different binders, including virgin binder (VBB), binder modified by SBS polymer (MB), AC-RAP, binder softened using a rejuvenating agent, and binders softened containing doses  of AC-RAP. The rheological properties were evaluated by dynamic shear rheometry (DSR) and beam-bending rheometry (BBR) tests. To verify the integration and rejuvenation of the binder, as well as the proportion of rejuvenating agent needed to soften each AC-RAP content was obtained from the mixing chart. Thus, the linear amplitude sweep (LAS) test was used to measure fatigue cracking and the multiple stress creep recovery (MSCR) test to measure rutting. The frequency sweep accelerated the damage accumulation rate using the continuous viscoelastic damage theory (VECD).SMBL = 74.92 MPa, StSMBL = 41.02 MPa, and StSMBL = 10.79 MPa) showed decreased stiffness  compared to the MB binder (StMB = 100.93 MPa). This shows that the rejuvenating agent improved the rheology and viscosity of the binders, making them less viscous, softer, and significantly more flexible than MB. Therefore, an optimum dose of rejuvenator is required to produce a stable mixture (with adequate flexibility and stiffness).From the rheological tests, it was observed that the VBB, MB, AC-RAP, SMBL, SMBM, and SMBH binders correctly satisfied the specifications. It was also observed that adding a rejuvenating agent to the VBB resulted in a 16.19% more flexible MB binder due to the addition of the SBS polymer and sulfur, which promoted adhesion within the binder structure, reducing its viscosity and stiffness. AC-RAP increased in stiffness by 197.24% compared to VBB, which meant that it was hardened and brittle, because the AC-RAP was exposed to aging by temperature, ultraviolet light, rain, and oxygen, turning it into a viscous (stiff) material. Additionally, the softened binders (StRAP) of AC-RAP was 117.2 °C and the minimum temperature was the most unfavorable (0 °C). Therefore, it can be confirmed that the aging of AC-RAP reflected in TCRAP is an indicator of brittleness and stiffness compared to that exhibited by the VBB or MB.After characterizing the MB binder, the test temperature was 76 °C, thereby determining that the PG of the project binder was PG 76-22, while the theoretical classification of AC-RAP corresponded to PG 112-10 because the critical failure temperature , reductions of 3.59%, 39.44%, and 71.19%, respectively, can be observed. Analogously, comparing the Jnr3.2 values of softened binders blended whit AC-RAP , the SMBL15 binder shows an increase of 0.73%, while the SMBM30 and SMBH45 binders present reductions of 19.94% and 27.64%, respectively. The MCSR tests show that the softened binders are softer (more flexible) than MB, being more prone to rutting, while softened binders blended with AC-RAP are hardened by RAP aging, although the addition of the rejuvenating agent softens them, renewing the rheological properties of the binder and counteracting the aging of AC-RAP. Thus, the softened binders blended with AC-RAP show a balanced behavior by improving the crack resistance without compromising rutting.The MB binder (reference binder) presented a value of JnrFrom the LAS test, it can be observed that the binders softened with the polymer  show the best cracking behavior, but when blended with a percentage of AC-RAP (SMBM30 and SMBH45) higher than 15%, they are more prone to cracking due to RAP aging. The SMBL and SMBL15 binders again show similar behaviors to MB, indicating that by adding a low percentage (15%) of AC-RAP, the fracture behavior is not significantly affected. As demonstrated in this analysis, the AC-RAP should be added with a rejuvenating agent to recover its flexibility and rheological resistance, since it will improve the cohesion, adhesion, and resistance to fatigue cracking in the asphalt mixture.Due to differences in test temperatures, the binders showed inconsistent behavior throughout the MCSR test. Therefore, future work will attempt to evaluate the rheological properties and mechanical behavior of binders softened with different polymers, blended with AC-RAP (using different ratios), and with similar test temperatures in order to characterize the binders through SEM and XRD techniques.