Retinal imaging is a non-invasive technique used to scan the back of the eye, enabling the extraction of potential biomarkers like the artery and vein ratio (AVR). This ratio is known for its association with various diseases, such as hypertensive retinopathy (HR) or diabetic retinopathy, and is crucial in assessing retinal health. HR refers to the morphological changes in retinal vessels caused by persistent high blood pressure. Timely identification of these alterations is crucial for preventing blindness and reducing the risk of stroke-related fatalities. The main objective of this paper is to propose a new method for assessing one of the morphological changes in the fundus through morphometric analysis of retinal images. The proposed method in this paper introduces a novel approach called the arteriovenous length ratio (AVLR), which has not been utilized in previous studies. Unlike commonly used measures such as the arteriovenous width ratio or tortuosity, AVLR focuses on assessing the relative length of arteries and veins in the retinal vasculature. The initial step involves segmenting the retinal blood vessels and distinguishing between arteries and veins; AVLR is calculated based on artery and vein caliber measurements for both eyes. Nine equations are used, and the length of both arteries and veins is measured in the region of interest (ROI) covering the optic disc for each eye. Using the AV-Classification dataset, the efficiency of the iterative AVLR assessment is evalutaed. The results show that the proposed approach performs better than the existing methods. By introducing AVLR as a diagnostic feature, this paper contributes to advancing retinal imaging analysis. It provides a valuable tool for the timely diagnosis of HR and other eye-related conditions and represents a novel diagnostic-feature-based method that can be integrated to serve as a clinical decision support system. Various morphological abnormalities in the retinal vasculature, such as increased artery tortuosity, altered arteriovenous width and ratio (AVR), arteriovenous (AV) nicking, and the onset of macular edema in severe cases, characterize hypertensive retinopathy (HR)  and diabCurrent ophthalmology practices involve using fundus cameras and computerized images to analyze morphometric changes in retinal blood vessels for identifying and grading HR. However, early HR symptoms can be subtle and challenging to detect, leading to delays in diagnosis and complicating treatment ,3,4. TheThis paper introduces a novel approach called the arteriovenous length ratio (AVLR), which has not been utilized in previous studies, to address the morphological abnormalities caused by hypertensive retinopathy (HR) in the retinal vasculature or which could also be used to observe the morphological changes caused by diabetic retinopathy. Unlike commonly used measures such as the arteriovenous width ratio or tortuosity, AVLR focuses on assessing the relative length of arteries and veins. By harnessing deep learning techniques, this innovative method accurately quantifies the proposed AVLR, providing a unique perspective on the morphological changes associated with HR. Additionally, the proposed approach incorporates the analysis of vascular tortuosity and utilizes a combination of nine length feature measurements. The algorithm is trained on the AV-Classification dataset , consistWe propose a unique automated method that combines vascular tortuosity assessment with AVLR analysis, which could be used to detect and grade HR. Since this is a novel approach and is not present in existing medical literature, our study represents a substantial development in the area.We provide a novel iterative approach to compute the AVLR inside the ROI (region of interest) around the optic disc using vessel caliber data. This technique improves the AVLR assessment’s precision and dependability.In the assessment of vessel AVLR, we employ a unique combination of nine features, which helps with accurately quantifying the severity of AVLR and effectively minimizing the subjectivity and variability associated with manual assessments conducted by ophthalmologists.The AV-Classification dataset has been expanded with new labels for AVLR metrics, creating the AV-Classification dataset extension. This extension includes vessel segments and image-level AVLR metrics, quantified using the proposed methodology.The main contributions of this research work are listed below:The rest of this paper is organized as follows: The evaluation of retinal vascular morphology has been studied as a means to quantify biomarkers for ocular diseases. Two key quantitative measures that have been investigated are the arteriovenous width ratio (AVR) and the arteriovenous tortuosity index. Accurately measuring these metrics requires robust vessel segmentation and classification .For AVR analysis, several semi-automated approaches relying on manual input have been explored. Akbar et al. calculated AVR from manually labeled vessels , demonstTo enable high-throughput screening, fully automated vessel segmentation and classification techniques are needed. Narasimhan et al. proposed a method using median filtering, top hat transform, and ROI detection to calculate AVR. However, performance was only demonstrated in a small dataset of 75 images without disease grading, thereby limiting clinical validation. The authors of  developeMore recently, advances in machine learning have enabled more reliable automated vessel analysis. Badawi et al. optimized vessel segmentation and artery/vein classification by developing B-COSFIRE filters and training convolutional neural networks (CNNs). This enabled accurate pixel-wise vessel labeling to derive vascular morphology metrics. Similarly, their proposed automated pipeline using unsupervised learning for vessel classification and wavelet transforms for diameter measurement to quantify AVR demonstrated accurate AVR measurements compared to manual grading. Further research on interpretable and robust machine learning techniques is critical in order to employ automated retinal vascular analysis for clinical use.Additionally, Badawi et al. developed a method to automatically grade the tortuosity severity of retinal images into four levels: normal, mild, moderate, and severe. They calculated 14 tortuosity metrics for each vessel segment and used these metrics to train machine learning models to classify images. The best model, distributed random forest (DRF), achieved 99.4% accuracy on the AV-Classification dataset. This demonstrates the feasibility of automatic tortuosity severity grading.Beyond AVR, quantifying vessel tortuosity could provide complementary information about vascular health. However, fewer studies have investigated automated measurement of the arteriovenous tortuosity index. The authors of  segmenteA major limitation of the existing techniques is that most of them focus exclusively on either AVR or tortuosity, whereas simultaneously quantifying both could improve disease detection. Towards this goal, the authors of  presenteIncorporating domain knowledge to derive interpretable biomarkers is an active area of research. Poplin et al. developed a deep learning system to predict cardiovascular risk factors by extracting interpretable vascular features, mimicking how clinicians qualitatively assess retinal images. However, the model was trained on only two datasets, requiring broad validation. Developing and rigorously evaluating hybrid machine learning systems that integrate vascular domain knowledge could advance clinical translation and adoption .Emerging imaging modalities also provide new opportunities for vascular analysis. OCT angiography enables depth-resolved visualization of the retinal capillary network. However, few automated algorithms have been developed to quantify morphological changes in these volumetric scans. A key challenge is accurately segmenting the capillaries, which have low contrast and discontinuity compared to major vessels in enface projections .In summary, the robust quantification of retinal vascular morphology shows strong promise as a non-invasive biomarker for systemic and ocular diseases. While progress has been made, especially in AVR measurement, substantial opportunities exist to improve interpretability, incorporate multimodal data, and move these technologies toward clinical integration. Key priorities for further research include: (1) developing unified algorithms that simultaneously quantify multiple morphology measures; (2) advancing machine learning techniques that integrate anatomical domain knowledge to derive explanatory biomarkers; (3) expanding rigorous validation across diverse patient populations and eye diseases; and (4) innovating volumetric analysis methods for emerging modalities like OCT angiography. Advances in these areas could enable more accurate disease risk stratification and unlock the full potential of retinal vascular imaging as a precision medicine tool.The evaluation of AVLR has undergone rigorous examination using the AV-Classification dataset  See Fig. This coThe methodology for calculating the AVLR involves the application of nine metrics. Optic Desk Localization: The fundus image undergoes a process to detect the location of the optic disk.ROI Segmentation: The fundus images are subjected to ROI segmentation to detect and extract the ROI-2-3 ROD and 2-5 ROD from the rest of the image.Vessel segmentation: The retinal images are subjected to a vessel segmentation process to separate the blood vessels from the background.Artery–vein classification: The segmented vessels are analyzed to differentiate between arteries and veins in the vascular structure of the ROI.Vessel skeletonization: The segmented vessels are further processed using skeletonization techniques to obtain a thin representation of the vascular structure.Identification of the bifurcation/intersection points: Key points along the skeletonized vessels are identified to extract the vessel segments between them.Generate the optimized vessel segments: Optimized vessel segments are generated based on the verified points, focusing on specific regions of interest.Calculate each of the nine metrics long feature vectors: The nine length/tortuosity metrics are calculated for each optimized vessel segment, providing quantitative measurements for AVLR assessment.Finalize the new AVLR feature set: The calculated AVLR values from each vessel segment are compiled to form a new feature set specifically for AVLR analysis.Firstly, branch points were detected using a morphological operation to identify the locations where the vessel tree branches . This stA deep learning strategy is employed using the author’s method in  to categThe encoder part of the FCN is responsible for acquiring high-level distinctive features from the input retinal images. It comprises several convolutional layers, each followed by a ReLU (Rectified Linear Activation) function to introduce nonlinearity. Additionally, max-pooling layers are inserted to gradually reduce spatial dimensions and encode the most salient features.The decoder component of the FCN operates on the encoded feature representation and generates dense pixel-wise predictions to produce a segmentation mask output. It incorporates upsampling layers to restore the original input dimensions, ensuring the output segmentation masks match the input image size. Convolutional layers and ReLU activations are also employed in the decoder.Unlike typical convolutional neural networks, this FCN includes only convolutional layers in both the encoder and decoder, omitting any fully connected layers. This design allows it to accept input images of varying dimensions and produce corresponding output segmentation masks.The network is trained end-to-end, utilizing the raw retinal images as input without any preprocessing steps like vessel segmentation. A multi-loss function is developed to optimize the learning of arterial and venous labels at the pixel level. This function incorporates both pixel-wise and segment-wise loss components.The pixel-wise loss assesses predictions and ground truth labels individually for each pixel. On the other hand, the segment-wise loss introduces contextual information by considering the predominant label within each vessel segment. It adapts pixel-level predictions based on segment-wise vascular labeling. This combined approach enhances performance compared to relying solely on pixel-wise loss.By directly learning highly distinctive features from the retinal images, the FCN can accurately classify individual pixels as artery, vein, or background, eliminating the need for hand-crafted features or pre-segmented vessel maps. The inclusion of a multi-loss function with both pixel and segment-level components further elevates the performance of artery/vein classification.The segmentation of blood vessels in retinal images is a complex task due to various challenges, such as poor contrast, uneven lighting, and background artifacts. Despite these difficulties, several supervised and unsupervised methods have been developed for retinal vessel segmentation. In this study, we optimize the parameters of a filter to effectively segment retinal vessels based on the work in . Our prop-value threshold of less than 0.05 to determine the significance of the parameters influencing the performance. This analysis allowed us to identify the most influential parameters in the process.To generate the optimized retinal image, we utilized a blood vessel segmentation method that builds on the trainable B-COSFIRE filter. To find additional optimum parameters, the selection of the thresholding parameter was thoroughly analyzed, and background artifact removal methods were used, according to the process description in . The finThe process begins by traversing the extracted skeleton segments of each image. The feature extraction procedure begins by calculating the straight-line and geodesic distances inside each vascular segment. Subsequently, all nine measures of AVLR that are given in Equations –9) are  are 9) aArteriovenous Chord Length Ratio: A ratio of the average Euclidean length of all veins to all arteries in the retinal picture is represented by this measure. It measures the proportional variations in length between veins and arteries.Arteriovenous Arc Length Ratio: The ratio of all the arteries’ mean geodesic distance to all the veins’ mean geodesic distance in the retinal picture is represented by this measure. It sheds light on the differences and curving routes of veins and arteries.Arteriovenous Distance Metric Ratio: The ratio of the average tortuosity length metric of all veins to all arteries in the retinal picture is represented by this measure. The overall tortuosity and variations in vein and artery curvature are quantified.Arteriovenous Inflection Count Metric Ratio: This measure shows the proportion of the average tortuosity. The total inflections measurement of each artery to the average tortuosity total inflections measurement of every vein in the retinal picture. The quantity of inflection points is counted, which represents the degree of vascular tortuosity.Arteriovenous Inflection Count Metric Binomial Ratio: The mean tortuosity inflection count measure binomial of all arteries divided by the average tortuosity inflection_Count_Metric_Binomial of all veins in the retinal picture is represented by this measure. It evaluates the veins’ and arteries’ binomial distribution of inflection sites.Arteriovenous Sum of Angles Metric Ratio: This metric is the average tortuosity inflection count divided by its ratio. Comparing the average inflection count metric of all arteries to the binomial of all veins in the retinal image; it assesses the binomial distribution of artery and vein inflection points.Arteriovenous Norm of Curvature Ratio: This measure represents the proportion of the average curvature of all vein segments to all artery segments in the retinal picture. It gauges the vessel segments’ curvature.Arteriovenous of Average Curvature Ratio Standard Deviation: This statistic calculates the difference between the average curvature of all arteries’ mean standard deviation and the average curvature of all veins’ mean standard deviation. the retinal picture. Quantification is used to the curvature variation along vessel segments.Arteriovenous of Centerline Length Ratio: This metric represents The mean centerline length of all the arteries divided by the mean centerline length of all the veins in the retinal image. It determines the distances between the arteries’ and veins’ centerlines.The AVLR calculation for the entire AV-Classification dataset 504 images) is performed using the proposed method. The initial step described in 04 imagesThe comparison of AVLR values between the left and right eyes is the final step in our analysis, providing a comprehensive assessment of any asymmetry or significant differences. This comparison allows for a detailed evaluation of the retinal characteristics of each eye and serves as a valuable tool in identifying potential abnormalities or discrepancies.To conduct this comparison, AVLR values are obtained separately for the left and right eyes. We apply the AVLR calculation methodology outlined in the previous steps to the retinal images of each eye, recording and compiling the AVLR values for further analysis.Once we have obtained the AVLR values for both eyes, we conduct a thorough comparison using statistical methods and techniques to assess the level of asymmetry or significant differences between the AVLR values of the left and right eyes.The results of this comparison provide valuable insights into retinal health and potential variations between the eyes. Clinicians and researchers carefully examine any notable discrepancies or asymmetry in AVLR values and interpret these findings. These results contribute to a deeper understanding of retinal conditions and may have implications for diagnosis, treatment, and overall eye health management.Incorporating this step into the methodology enables a comprehensive evaluation of retinal health and asymmetry between the left and right eyes, enhancing the diagnostic process and assisting in developing personalized treatment plans tailored to the specific needs of each individual.In the second stage, we create ring-cut images by segmenting the regions of interest (ROIs) with radii ranging from 2ROD to 3ROD and an extended range up to 5ROD See . Each seThe third step utilizes the previous work of  to optimIn the fourth step, deep learning is applied using the method in In the next step, the segmented vasculature is skeletonized and optimized using the method from , prepariEach extracted vessel segment is passed to calculate its length to be ready as input for tortuosity metrics calculations using the method in  see Fig.The intricate analysis of fundus images, along with their corresponding metric values, not only provide valuable insights into the complex domain of retinal morphology but also unveil important characteristics of arteriovenous length and the AVLR. In this section, we delve into a detailed discussion of selected fundus images, highlighting our observations and findings.Upon a meticulous analysis of the selected fundus image metrics results, we discerned a noteworthy pattern: the reported length in the arteries was generally consistent with that of the veins, thereby reinforcing the hypothesis that the lengths of arteries and veins in the retina exhibit a considerable degree of similarity in the normal situation . Figure We made an interesting observation while curating the AV-Classification dataset, which inspired further research. We noticed that the fundus images showed clear patterns of tortuosity in the arteries and veins, which could be classified into one of three categories.Atypically Elongated Arteries and Normal Veins: In a subset of retinal images within the AV-Classification dataset, we encountered instances where the arteries displayed significant elongation while the veins retained a relatively normal appearance. This divergence in vascular morphology raises intriguing questions about the potential factors driving this asymmetry and may help physicians to efficiently diagnose retinal abnormalities. Atypically Elongated Veins and Normal Arteries: On the other hand, a contrasting pattern was evident in certain other fundus images. The veins showcased noticeable elongation, while the arteries preserved a normal appearance. This polarized pattern adds another layer of complexity to our understanding of retinal vascular abnormalities; such cases may be signs of specific further diagnoses.Mixed Elongation: A subset of images revealed that both the arteries and veins exhibited varying degrees of elongation or, conversely, both appeared to be normal. This variability within individual retinas underscores the intricate nature of vascular architecture and emphasizes the need for a more holistic investigation; Furthermore, our analysis led us to a specific pair of fundus images  that shoThe myriad variations in vascular AVLR elucidate the complexities of retinal vasculature and its potential implications for ocular health. The underlying reasons for these asymmetries remain enigmatic and necessitate further exploration. Potential contributing factors could range from genetic predispositions and systemic diseases to localized pathologies impacting specific regions of the retina.The findings put forth in this study provide pivotal insights into the diversity of retinal vascular morphologies, indicating that a generic, one-size-fits-all approach to retinal analysis may not be adequate. A comprehensive understanding of these variations could be instrumental in the early detection of ocular diseases and the development of personalized treatment strategies.Our observations underscore the critical role of the in-depth analysis of fundus images and corresponding metric values in augmenting our understanding of ophthalmology and propelling advancements in ocular health diagnosis and care. To unravel the mysterious mechanisms governing these observed patterns and their clinical implications, further research and interdisciplinary collaboration are indispensable.Box plots of the generated AVLR metrics—specifically the ratio of the mean artery to a mean vein—for each image across the AV-Classification dataset are given in The above observation reaffirms our statistical findings. To delve deeper into this relationship, we compute the image-based ratios across the 504 images in the AV-Classification dataset. We calculate them for each image as given in the equations. Additionally, we compute the ratio of the average tortuosity metric of retinal arteries over the average tortuosity metric of the retinal veins for each of the following length metrics: SOAM, ICM, ICMb, DM, and LC. The box plots shown in The ratios for veins and arteries often show a comparable length pattern, indicating that the morphological lengthiness of veins and arteries is almost the same, with a ratio approaching 1.The center value of the box plots, or the median, slightly surpasses 1, indicating that the mean length of a vein is shorter than the average length of the artery.The ratio moves toward the top of the box plot when the artery-length mean is higher than that of the veins. As a consequence, when the length difference grows, the retinal image point rises in the box plot to approximately 50% of the normal distribution data.On the other hand, the ratio veers toward the bottom of the box plot when the average length of both arteries is smaller than the average length of both veins. The retinal image point in the box plot moves below the median as the length difference decreases. This tendency is seen in around 50% of the data from the normal distribution plot.In order to evaluate the difference between the lengths of the arteries and veins, the arc and chord lengths may be substituted because of the normal distribution of both ratios. In the meanwhile, for certain pictures in the AV-Classification dataset, the box plot in The arteriovenous SOAM ratio illustrates how the curvature angle influences the calculation and limits the findings within the constrained range of the y-axis (0 to 360) by displaying a regular distribution with a mean and median of 1. However, any possible distinctions between veins and arteries may not be readily apparent because of this narrow range.The lengths of the arteries and veins lengthen and the ratio becomes closer to one when they have the same degree of AVLR. While the mean and median of the other AVLR ratios range from 0.99 to 1.4, the AV SOAM ratio has both a mean and a median of 1. The variations in the artery and vein diameters and their visibility on the retinal surface in each picture may be ascribed to this deviation.The ratio moves to the top part of the box plot if the average length of veins is shorter than the average length of arteries. This implies that the tortuosity of arteries is much greater than that of veins in the retinal image.Conversely, in the event that the average length of the arteries is lower than the mean lengths of the veins, the ratio will shift towards the lower end of the box plot. Vein tortuosity does not deviate substantially from the median in the box plots shown in Based on the examination of the aforementioned arteriovenous length, it can be inferred that the observed results align with the statistically calculated outcomes, indicating that the measured lengths in the arteries are equivalent to those in the veins. However, the motivation for this study originates from a finding made during the creation of the AV-Classification dataset.The retinal images in the AV-Classification dataset display inconsistencies in the length and tortuosity of arteries and veins.Specifically, some images show tortuous arteries with normal veins, while others have tortuous veins but normal arteries.Additionally, there are images where both artery and vein lengths are either tortuous or normal.Although numerous studies have focused on evaluating the tortuosity of retinal vessels, there is currently no formula available to specifically identify abnormalities in either veins, arteries or both. Such phenomena present a novel avenue for future research in ophthalmology, as it marks the first exploration of this aspect within the field. Furthermore, it is worth noting that existing tortuosity calculation methods found in the literature primarily assess overall tortuosity, whereas this study delves into the distinction in arteriovenous length behavior. The calculations for the arteriovenous length ratio (AVLR) were conducted for all segments of arteries and veins in each of the 504 retinal images from the AV-Classification dataset. Subsequently, formulae were developed to describe these phenomena, and statistical analysis demonstrated that, From a geometric standpoint, there are parallels in the tortuousness of veins and arteries. The quantification discussed by the authors is regarded as a distinctive and encouraging avenue for further exploration within the domain of retinal image pathology diagnosis.The retinal vessel morphometry (RVM) research in  has beenArteriovenous chord length ratio;Arteriovenous arc length ratio;Arteriovenous distance metric ratio;Arteriovenous inflection count metric ratio;Arteriovenous inflection count metric binomial ratio;Arteriovenous sum of angles metric ratio;Arteriovenous norm of curvature ratio;Arteriovenous standard deviation of average curvature ratio;Arteriovenous centerline length ratio.Specifically, as illustrated in Additionally, image-level statistics are calculated by aggregating the segment-wise metrics for each image. The image-level statistics consist of summary values like count, mean, standard deviation, minimum, maximum, and median for all the above AVLR metrics.In total, the enhanced AV-Classification dataset contains over 17,000 newly labeled AVLR values spanning across vessel segments and images. This expanded dataset with the additional AVLR annotations serves as a valuable resource for research and analysis of retinal vasculature morphology. The inclusion of the new AVLR metrics significantly augments the RVM dataset, providing a more comprehensive set of labels to quantify arteriovenous asymmetries and vascular abnormalities associated with various diseases.The AV-Classification dataset will be made publicly available to the research community upon request, enabling further advancements in this domain. The dataset can facilitate the development of machine-learning models for automated AVLR computation from retinal images. In addition, the detailed AVLR labels can help identify morphological patterns and aid in screening vascular conditions like hypertensive retinopathy. Overall, the extended dataset allows a more in-depth analysis of retinal vessel morphology and its relationship to systemic diseases.In conclusion, this paper proposes a novel method for evaluating retinal vasculature morphology and its diagnostic potential in hypertensive retinopathy (HR) and other eye-related diseases. The method introduces a new approach called the AVLR, which focuses on assessing the relative length of arteries and veins in the retinal vasculature. The methodology involves segmenting the retinal blood vessels, distinguishing between arteries and veins, and measuring the length of both within the area of interest encompassing the optic disc using an iterative approach. The effectiveness of the AVLR measurement was evaluated using the RVM dataset, demonstrating superior performance compared to existing techniques.The major contributions of this research include the development of an automated system that integrates AVLR analysis and vessel tortuosity evaluation for the detection and grading of HR. This system provides a unique perspective on the morphological changes associated with HR and offers a valuable tool for the timely diagnosis of HR and other eye-related conditions. The methodology incorporates nine metrics that can accurately quantify the severity of AVLR, minimizing subjectivity and variability with manual assessments. Additionally, the comparative analysis of AVLR between the eyes enables a comprehensive evaluation of retinal vasculature in relation to HR and other conditions.Finally, we enhanced prior retinal vessel morphometry research by adding new labels for metrics in an extended dataset called AV-Classification. This incorporates vessel segment-wise and image-wise AVLR metrics quantified using the proposed methodology.The proposed method holds great promise for improving the efficiency and accuracy of HR diagnosis, facilitating timely treatment, and improving patient outcomes. Further research and validation on larger datasets and in clinical settings are warranted to fully establish the diagnostic potential of the AVLR and its integration into clinical decision support systems for ophthalmology.


Background: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. PPH-preventing interventions need to be prioritized and can be integrated with conventional methods of PPH prevention. The introduction of negative intrauterine pressure using a suction cannula can be one of the cheapest modalities to decrease PPH secondary to uterine atonicity. This method has brought a renaissance to practical obstetrics in low-middle income countries (LMIC), where the cost and availability of uterotonics are major health issues.Methods: It was a prospective quality improvement (QI) study conducted in the labor and delivery wards of a tertiary care medical institute and teaching center over the duration of one year. We aimed to assess the decrease in the incidence of atonic PPH with a negative intrauterine pressure suction device (NIPSD) integrated with active management of the third stage of labor (AMTSL) in the prevention of atonic PPH following normal vaginal delivery in low-risk antenatal women. In the initial six months, routine AMTSL was instituted for all consenting women (group 1). In the next six months, NIPSD was integrated with AMTSL (group 2). Data pertaining to the amount of blood loss, the incidence of primary PPH, uterine tone, fall in hemoglobin and hematocrit levels post-delivery, need for blood transfusion, and doctor and patient satisfaction were tabulated for all patients.Results: A total of 1324 consenting women were eligible for enrollment during the study time frame. In the initial six months , 715 participants were subjected to routine AMTSL in the third stage of labor. During the intervention phase (group 2), 609 parturient women were recruited. There was no significant difference in baseline parameters between the two groups. With the introduction of NIPSD to routine AMTSL, there was a significant decrease in the average volume of blood loss during vaginal delivery . The incidence of atonic PPH was reduced by more than 75%  after the introduction of NIPSD complementing routine AMTSL. The introduction of NIPSD has also been instrumental in reducing the cost burden on patient and hospital expenditures. The net benefit of its introduction resulted in a reduction of the overall cost burden of blood transfusions by around 70%.Conclusion: PPH is a public health problem, and measures to reduce PPH must be implemented to decrease this health burden. In countries with low resources, complementing routine AMTSL with NIPSD can be instrumental in decreasing the incidence of PPH. Considering its cost-effectiveness and reusability, LMIC can adopt NIPSD as a routine measure in all vaginal deliveries. Postpartum hemorrhage (PPH) is the most dreadful obstetric emergency and is a leading cause of maternal death in low-income countries, with an incidence as high as one in 45 among low-resource settings . Every yThe maternal mortality rate (MMR) in Indian women stands at a figure of 97 per one lakh live births ,2. HowevPostpartum hemorrhage is defined as blood loss from the genital tract exceeding 500 ml within 24 hours of vaginal delivery and 1000 ml or more during a cesarean section. The American College of Obstetrics and Gynecology (ACOG) defines PPH as the amount of blood loss that decreases the hematocrit by 10% or any amount of blood loss that necessitates a blood transfusion. For clinical purposes, any amount of blood loss that has the potential to produce hemodynamic instability should be considered PPH [It was a prospective quality improvement (QI) study conducted in the labor and delivery wards of ESIC Medical College and Hospital for a duration of one year. Written informed consent was obtained from all participants. All procedures in the study involving human patients were performed in accordance with the ethical standards of the Institutional Ethics Committee of ESIC Medical College and Hospital  and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consecutive consenting women undergoing normal vaginal delivery in this tertiary care teaching hospital during the study time frame were recruited into the trial. We aimed to assess the decrease in the incidence of atonic PPH with a negative intrauterine pressure suction device (NIPSD) integrated with active management of the third stage of labor (AMTSL) in the prevention of atonic PPH following normal vaginal delivery in low-risk antenatal women. The objectives were to measure the blood loss after using NIPSD along with AMTSL as compared to the use of AMTSL alone and to assess the tone of the uterus before and after the application of NIPSD. All antenatally consenting women (nulliparous and multiparous) with both spontaneous and induced labor were recruited during active labor. Exclusion criteria consisted of women undergoing cesarean delivery, women with a previously scarred uterus who were at risk of scar dehiscence during the trial of labor, participants sustaining genital tract trauma  during delivery, women with diagnosed uterine anomalies or known cases of inherited and acquired coagulopathies, and patients with evidence of clinical or biochemical chorioamnionitis.After a thorough history, general physical examination, and obstetrical examination, all antenatal mothers admitted to the labor room for normal vaginal delivery were recruited during the active stage of labor . For the initial six months (baseline phase), women undergoing vaginal delivery and consenting to participate in the QI project were subjected to routine AMTSL  in the third stage of labor as per the hospital protocol (group 1). The incidence of primary PPH and uterine atonicity was assessed in all recruited women. For the next six months , NIPSD along with AMTSL was provided to all participants . No separate inclusion criteria were used for assigning groups to the participants. The incidence of atonic PPH was also noted. Blood for hemoglobin and hematocrit was sent at the onset of active labor and again 24 hours after delivery for post-delivery assessment. Data pertaining to the amount of blood loss, the incidence of primary PPH, uterine tone, fall in hemoglobin and hematocrit levels post-delivery, need for blood transfusion, and doctor and patient satisfaction were tabulated for all patients. Patient and doctor satisfaction were rated according to the five-point semi-quantitative Likert scale . A comparison was made in the above parameters between the two groups of participants , and bivariate analysis was done to calculate the p-value for each parameter.All the collected data were tabulated in a Microsoft Excel worksheet , and statistical analysis was performed by SPSS software 23.0 . Rates and proportions were calculated for categorical variables. A bivariate analysis using an independent Student t-test and Fisher’s exact was used to compare the demographic features between women with AMTSL alone and NIPSD with AMTSL. Continuous variables were presented as mean + SD. A p-value of <0.05 was considered statistically significant.A total of 1324 consenting women were eligible for enrollment during the study time frame. In the initial six months , 715 participants were subjected to routine AMTSL in the third stage of labor. During the intervention phase (group 2), 609 parturient women were recruited. The demographic features of the study population are tabulated in Table Table The introduction of NIPSD has also been instrumental in reducing the cost burden on patients and hospital expenditures in our study. No previous study has been conducted to identify and assess the available evidence related to the cost-effectiveness of uterine NIPSD. Considering the clinical scenario in which the study has been conducted, procurement of one unit of packed red cell concentrate costs Rs. 1500 to Rs. 2500, while each unit of random donor platelets and fresh frozen plasma costs Rs. 500 to Rs. 800, respectively. The additional burden of expenditure due to blood grouping and cross-matching cannot be forgotten. Calculating the cost burden incurred upon the hospital system due to blood and blood product transfusion during the study time frame, it was estimated that the net expenditure reduced to less than one-fourth after the introduction of NIPSD . The metallic NIP suction cannula is reusable and is readily available in the market at an affordable cost (around 1500 rupees). Considering the moderate delivery load of around 95 to 118 vaginal deliveries per month, two reusable metallic NIP suction cannulae were sufficient for this setup. If the cost of purchasing a suction cannula were added (2 × 1500 = 3000 rupees), even then the net benefit of its introduction would result in a reduction of the overall cost burden by around 70%.Although the introduction of NIPSD to routine AMTSL did not bring about a change in patient satisfaction according to the Likert scale, obstetricians reported that they found it better to use the suction cannula. A reduction in the incidence of atonic PPH resulted in lesser anxiety among the treating obstetricians Table .According to the Millennium Development Goal, maternal mortality reduction can be achieved if only PPH management is prioritized . WHO hasTondge and Burande retrospectively studied 168 patients suffering from PPH by record analysis with respect to maternal age, parity, socio-demographic and etiological profile, and maternal consequences. They showed that uterine atonicity was the most common cause of PPH (69%) leading to 20% of maternal deaths due to hemorrhage. The study concluded that proper anticipation and skilled management, along with timely referral of PPH cases, lead to a significant reduction in maternal morbidity and mortality . ShanthiThangaraju et al. conducted an RCT for the comparison of high-dose and low-dose continuous infusions of oxytocin in the prevention and management of PPH. Outcomes were measured by the additional need for uterotonic medications to control hemorrhage and the assessment of vital volumes. This study concluded that lower doses are preferred over higher doses; the incidence of uterine atony in the low-dose group was 0.7% and in the high-dose group was 5.1%. It indicates that higher doses cause uterine atony because of receptor desensitization, resulting in ineffective action on the uterine myometrium, and concludes that there is no difference in the regular dose (10 U) and high-dose groups as low doses are better tolerated and have similar efficacy . WHO recThe World Health Organization (March 2022) published recommendations on intrapartum care for a positive childbirth experience, which recommended oxytocin  as the preferred uterotonic drug for the prevention of postpartum hemorrhage. Other injectable uterotonics (ergometrine/methyl ergometrine) and oral misoprostol 600 µg) can be used when oxytocin is not available. Delayed cord clamping (not earlier than one minute after birth) and controlled cord traction by skilled birth attendants must be done. However, sustained uterine massage is not recommended as an intervention to prevent PPH in women who have received prophylactic oxytocin 00 µg can.Panicker et al. conducted a prospective interventional study on 40 women who had NVD and 15 who had LSCS and concluded that negative suction resulted in the aspiration of all the blood collected in the uterine cavity. The quantity of blood sucked varied from 50 to 300 ml. When the collected blood was completely sucked out, the bleeding ceased. The suction was maintained for 30 minutes, which resulted in the contraction of the uterus. In all cases, the bleeding stopped after negative intra-uterine suction pressure, except in five patients who had fresh bleeding even after connecting suction; these were found to have vaginal tears and were sutured. In two patients, the cannula got blocked by blood clots, and replacing the cannula immediately controlled the bleeding . Damor eMeena et al. conducted a prospective observational study on 20 NVD women and 5 LSCS women who developed atonic PPH. In 40% of cases, the bleeding stopped within 3 to 3.9 minutes of application of a suction retraction (SR) cannula for 10 minutes every hour for three hours with a negative pressure of 650 mmHg, and in 24% of cases, the bleeding stopped within 2.1 to 2.9 minutes, and in another 24% of cases, the bleeding stopped within two minutes after application of the cannula. The majority of cases, 23 (92%), survived following the use of the SR cannula . SowjanyThe current study has also shown the benefit of introducing NIPSD to routine AMTSL in reducing the incidence of primary atonic PPH and the need for blood transfusions in parturient women. The major advantage is the minimal expenditure associated with a suction cannula. No other previous study has assessed the reduction of expenses due to the introduction of NIPSD in a hospital setting (with the decrease in expenses due to uterotonics). NIP cannulas come in different shapes and sizes and are readily available in the market. The metallic reusable ones can be used any number of times after thorough washing and autoclaving. Considering the true scenario in LMIC, where purchasing uterotonics and the cost burden of storage and refrigeration are major practical concerns, this NIPSD can be a great savior in the lives of many.This study had a few limitations as well. It was a single-center, non-randomized study. The study was approved for a period of one year. Only vaginal deliveries were included in this trial. PPH during cesarean deliveries was not addressed in the index study. The use of other uterotonics in difficult situations (like severe PPH) would have been a confounding factor in the study. However, risking a life for the sake of a study would not have obtained ethical approval. Large multicentric data and systematic reviews need to be conducted before formulating any guidelines.PPH is a public health problem, and measures to reduce PPH must be implemented to decrease this health burden. In countries with low resources, complementing routine AMTSL with NIPSD can be instrumental in decreasing the incidence of PPH. This quality improvement initiative has demonstrated that NIPSD is an effective method of preventing atonic PPH. However, stress must be given on training the ground staff for better awareness and acceptance of this method. LMIC can adopt NIPSD as a routine prophylactic measure for all vaginal deliveries. However, large, long-term, multicentric randomized controlled trials with a huge sample size and diverse ethnic groups are needed before drawing a solid conclusion.


Heart failure is the leading cause of death in the US and worldwide. Despite modern therapy, challenges remain to rescue the damaged organ that contains cells with a very low proliferation rate after birth. Developments in tissue engineering and regeneration offer new tools to investigate the pathology of cardiac diseases and develop therapeutic strategies for heart failure patients. Tissue -engineered cardiac scaffolds should be designed to provide structural, biochemical, mechanical, and/or electrical properties similar to native myocardium tissues. This review primarily focuses on the mechanical behaviors of cardiac scaffolds and their significance in cardiac research. Specifically, we summarize the recent development of synthetic (including hydrogel) scaffolds that have achieved various types of mechanical behavior—nonlinear elasticity, anisotropy, and viscoelasticity—all of which are characteristic of the myocardium and heart valves. For each type of mechanical behavior, we review the current fabrication methods to enable the biomimetic mechanical behavior, the advantages and limitations of the existing scaffolds, and how the mechanical environment affects biological responses and/or treatment outcomes for cardiac diseases. Lastly, we discuss the remaining challenges in this field and suggestions for future directions to improve our understanding of mechanical control over cardiac function and inspire better regenerative therapies for myocardial restoration. Heart failure (HF) is the leading cause of morbidity and mortality worldwide and in the US despite many breakthroughs in medicine and biotechnology ,2,3,4. Acell-based therapy with tissue-engineered bioscaffolds  to promote the renewal of myocardial tissues. However, traditional cell or gene therapy requires a single injection of billions of cells or therapeutic molecules, and most of the delivered particles (~90%) are lost in the bloodstream. Even among the homing cells, approximately 90% of the injected cell population dies quickly  even when delivered via intramyocardial injections ,5712,57]Mechanical anisotropy in a scaffold can be imparted by fiber alignment and organization. To date, the methods to generate aligned, anisotropic scaffolds can be classified into the following categories: electrospinning with a rotating collector, gap electrospinning, and 3D bioprinting. Brief descriptions of the main strategies and examples of each category are provided below.Electrospinning utilizing a rotating collector permits the modulation of fiber alignment through alterations in the geometry and/or rotational speed of the collector. A rotating cylinder mandrel is the most commonly used method A, althouAchieving fiber alignment requires the careful selection of the processing conditions when using a cylinder rotating mandrel to achieve fiber alignment. First, the induction of fiber alignment occurs within a narrow range of the rotational speed  . When thTo further enhance the fiber alignment, some researchers have utilized a rotating disc B. In thiAdditional modifications to the collector enable the replication of the 3D geometry of the tissue. For example, a 3D tube construct can be formed for vascular graft applications using a small-diameter rotating rod (<5 mm) C 72,73],7372,73]Gap electrospinning induces aligned nanofibers by an applied electrical field. By applying a positive voltage to the polymer solution and a negative voltage to two neighboring plates separated by a gap, the fibers are deposited and stretched from one plate to the other due to the residual electrostatic repulsion between the plates A. NumeroGap electrospinning offers significant benefits in producing controllable, aligned electrospun fibers. It is cost-effective since, in most configurations, no extra equipment is required beyond a typical electrospinning device. In addition, the fiber orientation and gradient of alignment can also be adjusted. However, there are a few drawbacks to the approach. The technology is restricted by the mesh thickness, as the residual charge increases with the mesh thickness. The rise in residual charge causes electrical repulsion and, consequently, a loss of fiber alignment . FinallyThree-Dimensional printing can also be used to induce fiber alignment in anisotropic scaffolds. There are two strategies to deposit aligned fibers: (i) direct depositing into a customized pattern to achieve the complex alignment of micro/nanofibers A 80,81],8180,81]The advantages of this method include the simultaneous control over the micro-geometry and macro-architecture , the feasibility of achieving a high resolution (~5–50 μm) in the fiber organization, and the proper cell density within the scaffolds . It is iThe incorporation of anisotropy in tissue-engineered scaffolds not only replicates the structural features of native cardiac tissues but also allows for mechanistic studies that can improve our understanding of heart diseases. One important consideration in replicating tissue anisotropy is the fiber angle distribution. As described above, the ventricular wall exhibits a normal distribution of myofiber angles in the tissue sections, and this feature can be achieved by electrospinning with a cylindrical rotating mandrel . In contA successful biomimetic scaffold should exhibit not only a similar elasticity but also a similar degree of anisotropy to the native tissue. We summarize the reported anisotropy of native cardiac tissues and biomimetic scaffolds in The benefit of using or implanting an anisotropic scaffold for the whole organ function has been reported previously. Mathematical modeling and in vivo studies have shown that anisotropic scaffolds, compared to isotropic ones, enhanced the functionality of a diseased heart by improving depressed LV pump function and increasing systolic function without compromising the filling (diastolic function) ,104. ThrAnisotropic structures of native tissues, resulting from the aligned arrangement of ECM components or cells, play an essential role in carrying out and maximizing their direction-dependent physiological functions. Studies probing the cellular responses to anisotropic mechanical environment have been conducted by comparing the outcomes obtained from isotropic and anisotropic scaffolds. The first response of cells to aligned substrates is to change their shape and orientation. Cardiomyocytes cultured on (isotropic) plastic are oriented randomly. As a result, their contractile force is distributed in all directions. However, when cultured in anisotropic scaffolds, the CMs will adopt the fiber alignment and be properly positioned on the scaffold . The eloOther groups have examined the effect of matrix anisotropy on stem or progenitor cell function to elucidate cell mechanobiology and its regenerative potential for the heart. For instance, the role of matrix anisotropy in mesenchymal stromal cell (MSC) behavior and paracrine functions has been investigated. Matrix anisotropy has been shown to play a role in MSC morphology, differentiation fate, and other paracrine functions ,115,116.Like many biological tissues, cardiovascular tissues exhibit J-shaped stress–strain behavior. This feature is known as nonlinear elastic behavior. For instance, the right ventricle passive stiffness increases nonlinearly with an increased strain/load because of the recruitment of collagen fibers . DiseaseInspired by biological tissues, the fabrication of crimped, extendable fibers is the main strategy to impart nonlinear elasticity on a biomaterial. One way to induce crimped fibers is by permanently lengthening the sheet along the main-fiber direction first and then returning the sheet back to the pre-stretched length. Meng et al. applied this method to electrospun scaffolds made with polylactocaprone (PCL), poly(lactic acid) (PLA), and poly(l-lactide-co-caprolactone) (PLCL), and they found that the mixture of the three was effective in the formation of crimped structures . In the Another way to produce crimped fibers is by controlled heating and/or chemical treatment, as briefly reviewed by Szczesny et al.  and ZhanFinally, certain materials may exhibit nonlinear behavior and can be used to fabricate scaffolds. For example, poly(glycerol dodecanedioate) (PGD) is a shape-memory, biodegradable elastomer that is linearly elastic at room temperature but has nonlinear elasticity at body temperature. Ramaraju et al. showed that the incorporation of the small intestinal submucosa (SIS) into the PGD sheets induced nonlinearity in the scaffolds. The mechanical properties of PGD can be tuned with native SIS by altering the thermal curing conditions used. The reason for the nonlinear elastic behavior is thought to be the void spaces formed during the incorporation of SIS sheets into PGD, but increasing the void spaces also decreases the stiffness of the scaffolds .The nonlinear elasticity of matrices changes cell–matrix interactions by regulating cell adhesion, spreading, and signal transduction. Prior studies have shown that cells grown on fibrous ECM with mechanical nonlinearity perceive the mechanical signal distance to be far greater than those grown on synthetic linear elastic polymeric material ,124,125.Crimped fibrous scaffolds promote cell spreading and adhesion, but the effect on cell proliferation remains unclear. However, the mechanisms for altered cell responses are mostly attributed to the matrix topography (rough surface or porous structure) or surface chemistry (hydrophilicity) of the crimped fibrous scaffolds. Whether the mechanical behavior (nonlinear elasticity) is just a side product of the crimped fibers or directly affects the mechanical transduction of the cells is unknown. The exact role of the nonlinear elastic behavior of the substrate in the mechanical signaling pathway of cells should be investigated in future work.Above, we summarized the current methods for nonlinear elastic scaffold fabrication and some known cellular responses to crimped fibrous scaffolds. While it is encouraging to see the advancement in this biomimetic mechanical property in tissue-engineered scaffolds, it should be noted that the previously mentioned studies focused on applications in soft tissues such as tendons , ligamenAnother less investigated mechanical behavior of scaffolds is viscoelasticity. A viscoelastic material has elastic behavior that is time-dependent and strain-history-dependent. Viscoelasticity is universally present in biological tissues. Heart valves are viscoelastic , and morUnlike the increased awareness of the importance of viscoelasticity in cancer research , the visHydrogels are the most commonly used biomaterials for constructing viscoelastic substrates. Hydrogels can be classified based on the source of the polymers—natural ECM biopolymers ; synthetic hydrogels  or polyacrylamide (PAM) hydrogels); and naturally derived macromolecular hydrogels . Currently, the main approaches used to modulate the viscoelasticity of hydrogels include: (1) crosslinking polymers; (2) altering the polymer architecture, such as length and branching; (3) tuning the composition; and (4) altering the concentration of the polymer or polymer mixture .3 s) to months . Pauly et al. prepared agarose hydrogels containing proteoglycan mimetic graft copolymers with various polysaccharide side chains  [Crosslinks in polymeric hydrogels can be physical  and can be static or dynamic. Vining et al. generated various alginate–collagen hydrogels via combined ionic and covalent crosslinking at different densities to tune the matrix viscoelasticity. Across a narrow range of moduli , the equilibrium stress relaxation of the scaffolds was similar to that of the native ECM ,134. Thiluronan) . AgaroseWhile hydrogels are the main type of biomaterials used for viscoelastic studies in the literature, there are a limited number of studies investigating the viscoelastic property of synthetic scaffolds. For instance, the viscoelasticity of PCL scaffolds can be tuned by blending natural or synthetic components at different ratios. Kim et al. attempted to tune the viscoelasticity of PCL scaffolds by adding different concentrations of alginate. They showed that the fluidic viscosity of the scaffold increased by increasing the alginate weight fraction in the composites. The storage modulus (G′) of the blended scaffolds was higher than that of pure PCL scaffolds, and it was increased with an increasing alginate concentration  . MoreoveRecent pioneering work has revealed some new findings on the impact of substrate dynamic mechanical behavior (viscoelasticity) on various cellular behaviors, including cell morphology and spreading, migration, proliferation, differentiation, and ECM deposition.Cell spreading is closely related to cell–matrix interactions, which affect the distribution of cell traction forces and mechanotransduction pathways and maintain the mechanical homeostasis of the cell. To examine how cell spreading is influenced by matrix viscoelasticity, Cameron et al. modulated the viscosity (the loss modulus) of polyacrylamide (PAM) hydrogels while maintaining the same elasticity (storage modulus) to study the spreading effect of hMSCs on these hydrogels . IncreasBoth regulatory effects may be explained by focal adhesion (FA) formation and ligand clustering . FA formViscoelastic matrices promote cell proliferation. Chaudhuri et al. showed that MSC proliferation was elevated in a PAM-alginate hydrogel with a faster relaxation rate . Ryan etThe effect of substrate viscoelasticity on cell differentiation has been mostly studied in MSCs and the application of orthopedic tissue regeneration. For example, hydrogels with rapid stress relaxation induced the greater osteogenic differentiation of MSCs ,148,149.ECM deposition is a key outcome in the regeneration of connective tissues including bone and cartilage. Chondrocytes encapsulated in scaffolds with similar viscoelasticity to native cartilage tissue displayed the greater deposition of a cartilage-like matrix composed of type 2 collagen and aggrecan and the lower expression of type 1 collagen . MSCs enAs an emerging area in tissue engineering and mechanobiology, the research into substrate viscoelasticity in cardiac applications is in its infancy stage. We summarized the reported viscoelastic properties of tissue-engineered scaffolds and native biological tissues in Furthermore, while the elastic property of cardiac bioscaffolds is often reported, it remains unknown whether they are viscoelastic. We recently reported different MSC responses to varied matrix stiffness and anisotropy degrees using PEUU scaffolds mimicking healthy and diseased right ventricles. The biaxial elastic behavior was measured in the main fiber and cross-fiber directions, and anisotropic elastic behavior was confirmed . A re-exIn summary, future work should focus on addressing the limitations of current scaffold fabrication techniques, such as the degree of anisotropy and the thickness limitation of hydrogel-based scaffolds. Additionally, efforts should be made to improve the repeatability and reproducibility of scaffold fabrication methods to ensure consistency across different studies or research groups and to allow for the easier comparison of results. Furthermore, there is a need for the appropriate characterization of scaffold mechanical properties and comparisons with the measurements obtained from myocardium tissues to ensure that engineered scaffolds exhibit the most important mechanical behaviors of native tissues. As biodegradation is expected in many tissue-engineered scaffolds, it is equally critical to investigate the mechanical changes in scaffolds during this process, data that are lacking in the current literature. Overall, continued efforts to improve scaffold design and fabrication techniques will enable the better investigation of the pathology of cardiac diseases and the development of patient-specific treatments for different types of HF, translating the research from bench to bedside.Heart failure remains a major cause of morbidity and mortality worldwide, and tissue engineering offers promising therapeutic strategies for cardiac regeneration. The inclusion of biomimetic mechanical properties in cardiac scaffolds, such as anisotropy, nonlinear elasticity, and viscoelasticity, is crucial for promoting cell functions and myocardium tissue regeneration. This review summarized recent advances in cardiac scaffolds that achieved these mechanical properties, as well as the advantages and limitations of each method. The biological responses to tissue-specific mechanical environments were also discussed. In summary, this review highlighted the importance of considering mechanical properties in myocardium tissue engineering and regeneration. By developing biomimetic scaffolds, researchers and clinicians can create new opportunities to promote cardiac tissue regeneration and improve patient outcomes. These findings offer hope for the development of new therapeutic strategies to treat heart failure, the leading cause of death in the US and worldwide.


The achievable compressive strength of a few MPa makes these materials applicable also in terms of ground strengthening in case it is required in light of the expected land development options to be employed. All principal materials used in the injection mixtures developed  are industrial waste, and the carbonation method employed is simple and performed under ambient conditions, which reduces the required energy and cost input of filling mixture production, avoids the surface waste storage requirements, and contributes to the development of low energy-intensive carbon dioxide utilization and solid waste valorization methods.The utilization of carbon dioxide and combustion products in cost- and energy-efficient technologies is an important element of creating sustainable energy systems, particularly in the transition period towards carbon neutrality and in light of the latest political developments, when solid fuels are still competing for a dominant role in securing energy supplies. Within the study presented, bituminous coal-derived fluidized bed fly ash samples of high calcium content, treated using a dry carbonation method under ambient conditions, were tested in terms of their specific properties to determine their usability in the preparation of injection mixtures for the filling of voids after shallow mining activities and other selected geo-engineering techniques. The study goes beyond the existing literature in terms of the carbonation method used, alkaline earth metal source, scale of the experiment, process conditions employed and product application studied. The results showed that the bituminous coal-derived fluidized bed fly ash, carbonated using the direct method adopted, may be successfully employed as the main solid component (over 82%  Th. Th51]. 226Ra + 228Ra and/or 224Ra below 104 Bq/kg , with no detriment to the mechanical properties of the product, in particular the compression strength. Most of the injection mixtures tested also complied with the recommended value of the overlying water below 7% , and most of the injection mixtures tested were also used for the preparation of plugs and packwalls (0.5 MPa) . One injw/w of solid components, 2.5% w/w cement) of injection mixtures for filling old goafs after shallow mining activities, with good rheological and mechanical properties . Depending on the location of the injection site and the expected land development option in this area, and in a case when it is desirable to increase the compressive strength of the injection mixtures for filling old goafs after shallow mining activities to a few MPa, this may be achieved with the addition of cement in relatively small amounts of 5–7.5% w/w. The properties of the injection mixtures tested and prepared with the use of the carbonated fluidized bed fly ash as the main solid component were proven as well, making them applicable in both gravity and pressurized filling methods.On the basis of the experimental results of the study performed, it may be concluded that the bituminous coal-derived carbonated fluidized bed fly ash can be successfully applied as the dominant component  are industrial waste and the carbonation method employed is simple and performed under ambient conditions, which reduces the required energy and cost input of filling mixture production, avoids the surface waste storage requirements, and contributes to the development of less energy-intensive carbon dioxide utilization and solid waste valorization methods.The carbonation method adopted enables the valorization of bituminous coal-derived fluidized bed fly ash with an increased calcium oxide content.Additional research into the various applications of carbonated fluidized bed fly ash as a cementitious material are needed to further investigate the impact of carbonation conditions and cement substitution on the properties of the selected final materials and/or by-products.The results of the experimental study performed indicate the following:


The Negev Highlands arid region (southern Levant) shows evidence of sharp settlement fluctuations, with several periods of strong human activity separated by centuries with no evidence of sedentary life. In this study, we used the palynological method in order to shed light on the region’s demographic history in the Bronze and Iron Ages. Fifty-four samples of pollen were collected and analyzed from secure archaeological contexts in four Negev Highlands sites: Nahal Boqer 66, dated to the Early Bronze Age and Early Intermediate Bronze Age (ca. 3200–2200 BCE); Ein Ziq, dated to the Early Intermediate Bronze Age (ca. 2500–2200 BCE); Mashabe Sade, dated to the Intermediate Bronze Age (ca. 2500–2000 BCE); and Haroa, dated to the Iron Age IIA (ca. late 10th through 9th centuries BCE). Our study revealed no evidence of cereal cultivation, with some hints that the inhabitants’ diets may have included plants gathered from the wild. Only one of the sites, Nahal Boqer 66, showed micro-indicators of animal dung remains, suggesting that the inhabitants herded animals. The palynological evidence did, however, emphasize that the livestock there were not fed or supplemented with agricultural by-products but rather grazed freely on wild vegetation. The pollen data also suggest that all four sites were occupied only during late winter and spring. The activity in the Negev Highlands during the third millennium BCE was probably related to the copper industry in the Arabah and to copper transportation to settled neighboring lands, especially Egypt. A relatively humid climate supported the trade through the Negev Highlands. Deterioration in both climate conditions and settlement activity was documented in the second half of the Intermediate Bronze Age. Herding was deduced from stone structures interpreted as animal pens, and agriculture from the occurrence of grinding stones and sickle blades, as well as by stone walls along ephemeral streams .Several factors have been suggested as the cause of the settlement fluctuations in the Negev Highlands. Because this area is part of the southern Levant desert environment .Seasonality: Were the Negev Highlands sites inhabited year-round or just seasonally?Vegetation and climate: What was the role of the environment in the demographic trends of the region?As will be demonstrated in this study, our analysis of fossil pollen from several Negev Highlands sites allowed us to address these questions.The Negev Highlands area receives an average annual precipitation in the range of 100–200 mm . SummersThe Negev Highlands is situated in a geographical transition zone between the Mediterranean climate to the north and the harsh arid conditions characterizing the rest of the area further to the south . Today tThe shift of this semi-arid steppe zone is reflected in the regional pollen diagrams  by changes in the arboreal Mediterranean pollen values: decreasing percentages indicate the shrinkage of the natural Mediterranean maquis/forest and the shifting of the semi-arid boundaries to the north and west due to less available moisture; increasing values of the natural Mediterranean tree pollen marks the opposite.18O) and carbon (δ13C) values within the Soreq Cave speleothems during the Bronze and Iron Ages revealed almost similar trends to those observed by the palynological studies [Since there is no high-resolution paleoclimatological record that originated from the Negev area itself, we are using the pollen records from Lake Kinneret and the Dead Sea to describe the climate conditions during periods of occupation in the Negev Highlands –38. Thes studies . This wa studies , 43. SliPistacia atlantica). A regular companion of the Pistacia, but much less abundant, is the Two-seeded Buckthorn (Rhamnus disperma) and a less common companion is the Ramon almond . The open areas between the sparsely spaced trees are covered by largely diffuse shrub vegetation, primarily steppe-Irano-Turanian in character. The leading taxon in the shrub layer is white wormwood (Artemisia sieberi). At favorable habitats even more mesic shrubby species may be countered, such as leafless ephedra  are often characterized by tree and shrub cover, commonly found in areas with considerably higher precipitation, thus giving the vegetal landscape of this district a steppe-forest-like appearance , 44. At foemina; ). Most aRetama raetam), chenopods, twisted acacia (Acacia raddiana), and several tamarisk species . Large bushy bean caper (Zygophyllum dumosum) shrubs grow between the trees in the wadi beds and are also sporadically spread over the flanking slopes.At lower elevations, the vegetation becomes increasingly sparse and much more xeric. The flora displays a mosaic of Saharo-Arabian desert vegetation with tropical (Sudanian) elements. The wide wadi beds are dominated by white broom (Juniperus phoenicea) were also common in the Negev Highlands . Archaenia BCE; , 46. Thenia BCE; , and in nia BCE; .14C and/or OSL dating [Until recently, all periods represented in the Negev Highlands settlements were studied using traditional macroarchaeological methods. The scarcity of faunal and botanical remains resulted in an interpretational lacuna regarding subsistence economies during settlement peaks, as well as their exact duration . Hence all sites and features representing a given settlement peak have been considered as belonging to a single wave of activity. In other words, both the period-by-period interpretation and the overall, long-term, socio-economic reconstruction of human activity in the Negev Highlands have been based on partial data. In order to overcome this problem, we collected materials for our palynological investigation only from sites that were recently dated at a higher resolution by L dating , 48, 49.L dating .14C determinations from the site provided evidence for activity from the Early Bronze Age IB through the first half of the Intermediate Bronze Age (ca. 3200–2200 BCE), most probably in the form of discontinuous, short-term presence [Nahal Boqer 66 , is a small site (0.2 hectares), ca. 4 km north of modern Sede Boqer  is the largest Intermediate Bronze Age site in the Negev Highlands, spreading over 2 ha of a pair of alluvial terraces above the dry wadi bed of Nahal Ziq  covers an area of 1.2 ha, with over 200 rounded, stone-made structures visible on the surface Figs , making Haroa . A total of 54 samples were analyzed. All necessary permits from the Israel Antiquity Authority were obtained for the collection of the pollen samples analyzed in this study, which complied with all relevant regulations.Nine samples were retrieved from Nahal Boqer 66 during the 2016 excavation . Three sTen samples were taken from Ein Ziq during the 2014–2015 excavations . Two samAt the Intermediate Bronze Age site of Mashabe Sade pollen was extracted from eleven sediment samples (P21-P31) during the two short winter excavations in 2013 . The samAt Haroa site one sample was analyzed from the central open courtyard (P32) and two samples were taken from surface activities . According to Boaretto et al.  and ShahLycopodium spore tablet was added to each sample in order to calculate pollen concentrations [2 solution (with a specific gravity of 1.95) in order to float the organic material, together with three minutes of sonication. After sieving (150 μm mesh screen) and short acetolysis, the unstained residues were homogenized and mounted onto microscopic slides using glycerin. Pollen grains were identified under a light microscope, with magnifications of 200X, 400X and 1,000X (oil immersion), to the most detailed systematic level. For each sample, the entire extracted residue was counted. For pollen identification, a comparative reference collection of the Israeli pollen flora of Tel Aviv University  was used, in addition to pollen atlases [Pollen extraction followed a physical-chemical preparation procedure common to Levantine desert sediments : One Lyctrations . Samples atlases –62.Only 31 out of the 54 analyzed samples contained well-preserved pollen and were in satisfactory concentration to allow identification and interpretation of the pollen spectra. The results of these samples are summarized in Tables The three samples that were retrieved from the light pale brown sediments suggested as belonging to surface activity were pollen barren (P1-P3). All the samples collected from the grey sediments contained well-preserved pollen grains , Crocus (croci), Limonium (Sea Lavender), Gundelia (tumble thistle), Erodium (stork’s bill) and Bunium type (which includes species such as dill). There is also the possibility that this exceptional pollen assemblage actually represents plants that were brought to the site deliberately in order to enrich the diet. The appearance of both desert sunrose pollen type (Helianthemum sancti-antonii type) and desert truffle spore type (kmehat hanegev) at some of the Mashabe Sade pollen assemblages also provides evidence for the gathering opportunities which were prevalent near the site. These two species grow in a symbiotic relationship  in the arid zones of the Mediterranean Basin. The gathering season of the truffle is late winter to early spring.All eleven analyzed samples from the central Intermediate Bronze site of Mashabe Sade yielded pollen. Most archaeological samples (P21-P27) are dominated by wind-pollinated taxa of chenopods. The presence (though in very low ratios) of Mediterranean air-borne trees such as Aleppo pine, olive and cypress/juniper also points to pollen accumulated over a long distance. The high frequencies of chenopods in all of the samples extracted from structures together with their appearance in clumps  may alsoPinus and Olea. This probably stems from the fact that it is an open rock shelter that is probably composed of both degraded livestock dung deposits, aeolian loess sediments and airborne pollen, as was shown for another rock shelter in the region [The palynological spectrum of the sample taken from the central courtyard was composed of typical desert elements, and most probably represents the ancient pollen rain (P32). The components of this sample show a clear resemblance to those identified in the recent surface sediment sample (P35). This observation suggests that similar flora existed near the site during the Iron Age II and in modern times. In sample P33 proposed as degraded mudbricks and in sample P34 suggested as dung pollen was not preserved. Within the section composed of fifteen samples collected from the rock shelter, only the six uppermost samples  included well-preserved pollen grains . These se region . The preAll of the pollen taxa identified in this study from various archaeological contexts  are still characteristics of the Negev Highlands today. The same observation emerged from wood charcoal analyses conducted at Ein Ziq and Intermediate Bronze Be’er Resisim , 67. ThiArtemisia) and acacia pollen, which bloom during autumn and early winter. The only sample with autumn bloomer taxa did not originate from activity surfaces but from the nearby rock shelter of Umm Urgan  pollen type and Chenopodiaceae (goosefoot). It is therefore suggested that the animals were free grazing  rather than fed or supplemented with agricultural by-products . Indeed, all Nahal Boqer 66 palynological assemblages, from all periods of occupation, point to a total absence of cereal pollen type. The lack of dendritic phytoliths at the site  , corrobomm Urgan . Based oThe nearly total absence of cereal pollen from the four Negev Highlands sites studied here, together with the relatively good state of pollen preservation, indicates that the inhabitants of the region did not engage in agricultural activities [supporting The three earlier sites studied here  are representative of the long period of human activity in the southern Levant arid land—throughout the Early Bronze and the first half of the Intermediate Bronze Age . While Though the Negev Highland settlement pattern is mostly related to the copper industry, climate changes should also be taken into consideration. Specifically, dryness is synchronized with the decline of the Negev settlement system during the second half of the Intermediate Bronze Age. The Negev Highlands area receives most of its rain from the Mediterranean climate system , 30. A dTriticum pollen type). Some other components within Timna’s pollen samples seem to originate from the Mediterranean zone and penetrated into the assemblages probably from the nearby vegetation which surrounded the fields where the wheat was cultivated . The study shows that the gatehouse area at Timna was used for storing donkeys (or mules), which were the common draught animal at the time, together with other livestock  and phytolith  from they goats; ). The any goats; .th-mid-8th centuries CE, spring-time herding at Shivta was based on free-grazing of wild vegetation, supplemented by chaff and/or hay from domestic cereals. For the late 8th-mid-10th century CE samples, phytolith and pollen reconstruction indicate autumn-winter free-grazing with no evidence of foddering [A study conducted at Early Islamic Shivta (located in the western Negev), on dung pellets of domestic sheep and goats, clearly demonstrates the ability of archaeobotanical proxies to infer herding practices from dung material. The study is based on a combined archaeobotanical reconstruction , suggesting that during the mid-7oddering . When coThis study presents the results of palynological investigations conducted at Bronze and Iron Age sites in the Negev Highlands. The interpretation of the palynological spectra sheds light on the subsistence economy mode and the nature of occupation at these sites. The study also enables us to evaluate the role played by environmental and climatological changes in shaping trends in the Negev Highlands settlement oscillations. The following conclusions can be drawn:While our pollen evidence indicates that the Negev Highlands vegetation during peaks of occupation was similar to that which presently prevails, it is assumed that the wet climate conditions reconstructed in the Mediterranean zone during the Early Bronze and first half of the Intermediate Bronze Age supported the activity in the Negev Highlands (since the area receives most of its rain from Mediterranean climate systems). The lack of settlement activity in the region during the second half of the Intermediate Bronze Age coincides with ca. 300 years of dry climate in the entire Near East, beginning at ca. 2200 BCE.The palynological spectra retrieved from dung deposits indicate that livestock herds during the Intermediate Bronze Age were free grazed on wild vegetation only, and were not supplemented with agricultural by-products. It can therefore be concluded that Negev Highlands inhabitants of that period who herded animals were engaged in a purely pastoral herding strategy and were not involved in an agro-pastoral economic strategy.It also seems that the Negev Highlands sites where herding activities took place, were occupied only seasonally, during late winter and spring, rather than year-round.The lack of cereal pollen type indicates that the occupation in the Negev Highlands sites during the third millennium BCE, as well as during the Iron Age IIA was probably related to the copper industry in the Arabah and to copper transportation to the neighboring settled lands.Our results also hint at the potential for plant gathering in the Negev Highlands based on the presence of edible plant remains.S1 FigA 10-fold exaggeration is used to show changes in low taxa percentages.(PDF)Click here for additional data file.


The prediction of drug metabolism is attracting great interest for the possibility of discarding molecules with unfavorable ADME/Tox profile at the early stage of the drug discovery process. In this context, artificial intelligence methods can generate highly performing predictive models if they are trained by accurate metabolic data. MetaQSAR-based datasets were collected to predict the sites of metabolism for most metabolic reactions. The models were based on a set of structural, physicochemical, and stereo-electronic descriptors and were generated by the random forest algorithm. For each considered biotransformation, two types of models were developed: the first type involved all non-reactive atoms and included atom types among the descriptors, while the second type involved only non-reactive centers having the same atom type(s) of the reactive atoms. All the models of the first type revealed very high performances; the models of the second type show on average worst performances while being almost always able to recognize the reactive centers; only conjugations with glucuronic acid are unsatisfactorily predicted by the models of the second type. Feature evaluation confirms the major role of lipophilicity, self-polarizability, and H-bonding for almost all considered reactions. The obtained results emphasize the possibility of recognizing the sites of metabolism by classification models trained on MetaQSAR database. The two types of models can be synergistically combined since the first models identify which atoms can undergo a given metabolic reactions, while the second models detect the truly reactive centers. The generated models are available as scripts for the VEGA program. The in silico evaluation of the ADME/Tox  profile for new chemical entities has attracted great interest in the last decades since this represents a rapid and cost-effective strategy to discard molecules with unfavorable drug-like properties at the early stages of the drug discovery process ,2. TheseThe prediction of drug metabolism has played a crucial role as the involved metabolic reactions and the formed metabolites influence the overall pharmacokinetic profile of any xenobiotic compound determining, above all, its efficacy and safety . In the The situation evolved in the last years due to the general increase of the available scientific data which also concerned the field of drug metabolism. The recent progress in artificial intelligence methods also played a crucial role offering convenient approaches for the metabolism prediction . Among tNotably, the development of reliable predictive models requires highly accurate metabolic data because even some inaccurate data can undermine the overall predictive power of the resulting models. Unfortunately, several available metabolic resources do not possess a suitable accuracy since they are collected by automatic interrogation of other databases  and ofteMetaQSAR proved successful in developing predictive models for two conjugation reactions (glucuronidation and reaction with glutathione), which play crucial roles in determining the safety of chemicals ,20. DataThe here-reported study can be seen as a step further since it is based on the same MetaQSAR-based datasets, and its aim involves the development of RF-based models to recognize the specific sites of metabolism (SOM) for all the reaction classes and subclasses already considered by the MetaClass approach. Similarly to what was already done for MetaClass, the here-developed predictive models are released into a suite of freely available scripts, called MetaSpot, to predict which atoms undergo specific metabolic reactions for a given input substrate.The study was based on the same first-generation metabolic reactions utilized by the previous study . SpecifiFor each class and subclass, the performed predictive analyses can be subdivided into two steps. In the first step, the utilized datasets comprised all collected NR and R atoms. Each dataset was balanced by randomly undersampling the majority NR class and this task was repeated 100 times to minimize the randomness. The second step was based on specifically collected datasets comprising only atoms of the same atom type(s)  of the Overall, the models appear to be quite stable as confirmed by the accuracy ranges see , which aS) and atomic charge are the most frequently included descriptors. The role of atomic self-polarizability agrees with previous studies which exploited such a descriptor to predict the sites of metabolism [Among the stereo-electronic parameters, atomic self-polarizability  of the reactive sites.Taken together, the results of this second round of predictions suggest that the reactive atoms of redox reactions largely depend on stereo-electronic factors, which are conveniently captured by the considered descriptors. In contrast, reactive atoms involved in hydrolyses and conjugations seem to be influenced by different factors not completely encoded by the considered descriptors. Future studies involving additional descriptors and/or docking simulations could enhance the predictive models for these classes.S) in describing the chemical reactivity. In addition, the HOMO/LUMO energies appear 13 times, thus underlining the relevant role played by nucleophilicity and electrophilicity in drug metabolism. The frequencies of the physicochemical descriptors agree with what was observed in the previous models and emphasize the marked role of H-bonds and molecular size (the related descriptors appear 10 times in both cases) which encode for interacting capacity and accessibility, respectively.Concerning the stereo-electronic descriptors, the developed models confirm the key role of atomic charges and self-polarizability  and evidences the enhanced relevance of the atomic charge density the role of which in predicting chemical reactivity is well-documented in literature [As previously seen, terature . Among tSince both studies are based on the same MetaQSAR-based training sets and roughly involve the same set of descriptors, Interestingly, the second round of prediction which do not include the atom typing, provide, on average, worst performances which shows a certain degree of similarity with those reached by the MetaClass models. This confirms that atom typing has a very modest role in predicting the occurrence of a given metabolic reaction and both sets of models similarly depend on the included physicochemical and stereo-electronic descriptors. While showing lower MCC values, many developed models of the second round exhibit satisfactory performances thus indicating that the recognition of the sites of metabolism based on reactivity descriptors is yet possible and deserves further efforts to enhance the resulting performances, especially for those classes and subclasses which provided here unsatisfactory predictive models (see above).Indeed, and while considering the generally satisfactory results reported here, this study can be seen as an encouraging starting point which can be surely enhanced by extending the number and the informative richness of the considered descriptors. The descriptors utilized in this study were indeed chosen to cover a significant space of the  molecular properties while being computationally simple and not time-expensive. This choice was made by considering the high number of substrates included in the MetaQSAR-based datasets and to develop simple predictive models to be quickly applied to new molecules. Notwithstanding this, one may figure out that a wider and tailored set of descriptors could yield improved predictive models. For example, the observed relevance of various stereo-electronic descriptors  suggests that the inclusion of similar parameters computed by DFT methods, although computationally markedly more demanding, might have a beneficial effect. The role played in many models by molecular descriptors encoding for the interaction capacities  suggests that targeted docking simulations could describe the binding process in a more direct and informative way. The enrichment of the considered descriptors may involve also the atom typing by including extended atom types and/or fingerprints. Nevertheless, the enrichment of this kind of descriptors should be cautiously pursued since an increased role of atom typing could increase the number of false positives.(1)Redox reactions on carbon atoms are conveniently predicted even without atom typing; this outcome indicates that their reactive atoms mostly depend on the considered stereo-electronic descriptors .(2)Redox reactions involving nitrogen atoms (and to minor extent Sulphur atoms) are satisfactorily predicted only when using atom types, thus suggesting that their reactivity depends on different factors compared to carbon atoms.(3)Hydrolysis reactions yield markedly more accurate predictions when including atom types which reasonably allow an easy detection of the labile groups.(4)Conjugations with glucuronic acid are substantially unpredictable without atom types; this finding suggests that the reactivity of the involved centers depends on stereo-electronic factors not included in the considered descriptors.(5)Most reactions with glutathione can be successfully predicted even without atom types, a result which can be explained by considering that these conjugations depend on the here parameterized electrophilicity of the reactive centers.In more detail, the results of this study  can be summarized as follows:As mentioned above, the two sets of predictions  can be synergistically combined since the models including atom types can be used to exclude the atoms which cannot undergo the considered biotransformation, while the models without atom types should recognize the truly reactive centers.The study utilized the same first-generation metabolic reactions extracted from the MetaQSAR database  and alreAs described above, the predictive analyses involved all the classes and subclasses, including at least 50 instances. For each case, two predictive analyses were performed including or excluding the atom types among the utilized descriptors. The analyses including atom types were performed by using an ad-hoc script for the VEGA environment that: (a) extracts from MetaQSAR the substrates for a given class or subclass; (b) identifies within the substrates the reactive and non-reactive atoms and (c) calculates for the included substrates a set of atom- and ligand-based descriptors. For each considered class and subclass, the analyses comprised all collected atoms and involved the following tasks carried out by the above-mentioned script: (a) performing the feature selection to reduce the number of considered descriptors; (e) randomly under-sampling the NR atoms to obtain balanced datasets; (f) developing the corresponding predictive model by using the RF algorithm. Considering the very high number of NR atoms in all performed analyses, tasks (e) and (f) were repeated 100 times to minimize the randomness of the obtained results. Here, and in the analyses without atom types, the models were developed by using the RF algorithm, as implemented in the WEKA 3.8.6 software , by applTo assess the capacity to predict the reactivity of the sites of metabolism regardless of their atom types, the second set of predictions was developed by considering the NR atoms with the same atom type(s) of the reactive centers. For each analyses class and subclass, a specific dataset was manually collected by combining the reactive atoms with an equal number of randomly selected non-reactive atoms having the same atom type(s) of the reactive ones. The so-collected dataset undergo model generation and feature selection by adopting the same procedures described above for the first round of predictions.The present study describes the MetaSpot approach, which is based on the metabolic data extracted from the MetaQSAR database and allows the predictions of the reactive centers for almost all metabolic reactions. Apart from a few documented exceptions, all the models developed within the MetaSpot project provided satisfactory performances (even without atom typing), emphasizing the possibility of conveniently recognizing the reactive atoms. The MetaSpot project can be seen as the natural extension of the already published MetaClass study  since MeAs detailed in the discussion, this study can be seen as an encouraging starting point, and the reported models could be improved both by enriching the arsenal of the considered descriptors and by including structure-based approaches (such as docking simulations), which can simulate the recognition between the substrate and the involved enzymes. The predictive models could also be improved by extending and refining the collected metabolic data. Enriched metabolic data should maximize the chemical space covered by the collected reactions, thus extending the predictive power of the developed models. In addition, enriched metabolic data could be utilized to generate suitable external sets for a more precise validation and tuning of the selected predictive models.


Growing literature highlights the need to integrate hepatology and addiction care to improve outcomes for patients with alcohol use disorder and alcohol-associated liver disease. However, prospective data for this approach are lacking.We prospectively examined the efficacy of an integrated hepatology and addiction medicine approach on alcohol use and hepatology outcomes in inpatients with alcohol use disorder.An integrated approach improved the uptake of medical alcohol therapy, hepatic fibrosis screening, and viral hepatitis vaccination compared with a historical control of patients who received addiction medicine care alone. There were no differences in the rates of early alcohol remission. The integration of hepatology and addiction care may improve outcomes in patients with alcohol use disorder. A major obstacle in the treatment of patients with alcohol-associated liver disease (ALD) is early diagnosis, as many patients with ALD are diagnosed late in their disease course.t test with Welch correction, whereas categorical variables were compared using the Fisher exact test.This single-center, prospective study evaluated the performance of a novel multidisciplinary consultation group (ALivE plus addiction medicine) against a historical cohort of patients with AUD who received standard of care (SOC) in our hospital system. Starting in January 2020, primary inpatient medical services were provided the option to consult the ALivE service (which consisted of 1 hepatologist and a nurse practitioner) for patients with AUD admitted to the hospital with no known liver disease or evidence of current liver disease. These patients were evaluated by the ALivE service and underwent fibrosis staging with elastography, discussion of the importance of viral hepatitis vaccination, and education of the deleterious effects of alcohol on liver health. All patients seen by the ALivE team were also evaluated by addiction medicine.p < 0.001), leading to the identification of F2 or greater fibrosis by noninvasive testing in 25.8% (N = 66) of the ALivE cohort. We found that patients in the ALivE cohort had higher rates of AUD pharmacotherapy prescriptions at discharge compared with the SOC group . The rate of new AUD therapy  was higher in the ALivE group compared with the SOC group . With regard to remission data, 189 of the 256 patients seen by the ALiVE service had data available at the 6-month follow-up time point compared with 45 of the 63 patients in the SOC group. We did not see a difference in either early remission  or partial remission  between the ALiVE and SOC groups, respectively. As expected, given the involvement of a hepatologist in the patient’s care, the ALivE cohort had higher rates of hepatitis A  and hepatitis B  vaccination in nonimmune patients.In total, 256 patients were included in the ALivE group, whereas 63 patients were included in the SOC group Table . PatientIn this prospective cohort study, we found that the evaluation of patients with AUD without known liver disease by a hepatologist improved diagnostic and therapeutic care compared with the SOC. We found that hepatology evaluation increased liver fibrosis screening and advanced fibrosis identification, improved rates of AUD pharmacotherapy prescription, and improved rates of preventative hepatology care. The SOC at our hospital for patients with any substance use disorder is the evaluation by the addiction service, which provides education, behavior coaching, and substance use treatments. The findings of our study suggest that an integrated model of addiction medicine and hepatology could further improve care for patients with AUD in a multimodal capacity.Despite the evaluation by addiction medicine, an integrated consult approach with hepatology resulted in higher rates of AUD pharmacotherapy at the time of discharge. This finding is particularly important, given that data show an association between AUD pharmacotherapy and reduced odds of developing ALD in those without advanced fibrosis or having a decompensating hepatic event in those with underlying cirrhosis. The underutilization of AUD pharmacotherapy is well recognized,