Sorghum bicolor (L.) Moench], hybrid cultivars for the biofuel industry are desired. Along with selection based on testcross performance, evaluation of the breeding population per se is also important for the success of hybrid breeding. In addition to additive genetic effects, non-additive  effects are expected to contribute to the performance of early generations. Unfortunately, studies on early generations in sorghum breeding programs are limited. In this study, we analyzed a breeding population for bioenergy sorghum, which was previously developed based on testcross performance, to compare genomic selection models both trained on and evaluated for the per se performance of the 3rd generation S0 individuals. Of over 200 ancestral inbred accessions in the base population, only 13 founders contributed to the 3rd generation as progenitors. Compared to the founders, the performances of the population per se were improved for target traits. The total genetic variance within the S0 generation progenies themselves for all traits was mainly additive, although non-additive variances contributed to each trait to some extent. For genomic selection, linear regression models explicitly considering all genetic components showed a higher predictive ability than other linear and non-linear models. Although the number and effect distribution of underlying loci was different among the traits, the influence of priors for marker effects was relatively small. These results indicate the importance of considering non-additive effects for dissecting the genetic architecture of early breeding generations and predicting the performance per se.In sorghum [ Sorghum bicolor (L.) Moench] is a promising bioenergy crop . Cytoplasmic male sterility (CMS) is also necessary for hybrid seed parents because sorghum is a predominantly self-pollinated crop  are suitable for hybridization. In a sorghum hybrid breeding program, only candidates with the suitability as hybrid parents are preselected in the advanced generations  before the evaluation based on testcross  showed a considerable level of dominance while others were primarily additive , breeding populations also have other complications  that need to be considered in dissecting the genetic architecture  was proposed to evaluate genetic potentials by the regression of target traits on genome-wide dense markers  and BayesA, are utilized for dealing with various genetic architectures of traits (reviewed by Gianola 2013). In particular, the number of QTL is an important factor in addition to the number of independent chromosome segments for selecting the appropriate prior . For example, e.g., heritability, marker density, and the training dataset size), and therefore the optimal settings for prior are generally unknown (Bayesian GP models can be applied for a genome-wide association study (GWAS) . In Bayeper se in a non-inbred (S0) generation of a bioenergy sorghum population that was selected based on testcross performance. The primary objectives of this research are: i) description of the genetic architecture of the S0 generation per se performance, ii) utilization of GP for evaluating the performance of the breeding population per se, and iii) comparison among models and priors for target traits. Finally, we discuss the importance and reliability of modeling non-additive effects for non-inbred and early inbreeding generations in plant breeding programs.The objective of this study is to give insights into the genetics of important agronomic performance 1 hybrid cultivars for bioenergy sorghum require both high biomass and high sugar contents. The mating design used to derive the sorghum breeding population is described in 1 hybrid.The long-term goal of our project is the breeding of bioenergy sorghum. Frd intermating generation derived from the base population (the 0th generation). To combine diverse genetic variations derived from the base population, intercrossing was performed in each generation. In theory, the maximum number of founders per family was eight in the 3rd generation. For selection, at least one tester was crossed with each breeding candidate to check the progeny performance. In the selection, total weight (TW) and the Brix value of culm juice (BR) of testcrosses were considered as the main target traits, although other traits were also considered secondarily (see Phenotypic data). The selection criteria were determined comprehensively because the decision of the best testcross across multiple traits was generally difficult .The breeding population used in this study corresponds to the 3th generation) was composed of 243 inbred accessions, which had been obtained from public genebanks (Table S1). For the next population (the 1st generation), we selected 29 accessions from the base population based on the progeny performance with each tester separately. Four accessions that were not tested in this project were added to the 29 accessions. Therefore, a total of 33 accessions was used as the parents for the 1st generation. We performed 23 intercrosses among the 33 accessions, which corresponds to the 1st generation (23 intra-population F1 hybrids). Of the 23 F1 hybrids, 9 F1 hybrids were selected for the next population (the 2nd generation). All crosses genetically segregate starting in the 2nd generation. The 2nd generation included a total of 11 families, which were produced by 10 intercrosses among 8 F1 hybrids (S0 progenies) in addition to a family derived from the selfing of an F1 hybrid (S1 progenies). In this study, we used all 11 families of the 2nd generation as the parents for the next population without selection. The next population (3rd) was derived from intercrosses among different families of the 2nd generation. A few exceptions were derived from crosses within the same family (full-sib mating). A total of 137 individuals (average of 12.5 sibs per family in the 2nd generation) was used as the parents for intercrossing, resulting in 260 full-sib families in the 3rd generation.A base population (the 0Intercrossing was limited to the combinations within the group that had been selected for performance on each tester. This means that a selected genotype (or family) for a particular tester was intercrossed with another genotype (family) selected for performance in combination with the same tester.per se were not directly used as parents for the breeding populations. For selection, we performed testcrosses with two testers with cytoplasmic male sterility (CMS), CMS-A and CMS-B. The 1st test population corresponds to the F1 hybrids between the two testers and the 0th generation. Based on the performance of the F1 hybrids, the parental inbred accessions were selected for each tester.Test populations were evaluated only for the selection of parents for the next breeding populations. In other words, test populations nd test population corresponds to the three-way crosses between each tester and the 1st generation. We created two sub-populations of selected F1s corresponding to the best families in combination with each of the two testers. Subsequent testcrossing on advanced generations involved the same tester used to initially select the breeding families. For example, when we selected multiple inbreds based on their testcross performance with the CMS-A tester in the 1st test population, we evaluated the testcross between CMS-A and the F1 hybrid among the selected inbreds in the 2nd test population. Because the 2nd test population genetically segregates, the progeny rows for each testcross family were grown and evaluated. Considering the testcross performance , we applied the family selection to the 2nd test population and selected families  for the next breeding population (the 2nd generation).The 20 plants of the 3rd generation per se (not as testcrosses) from June to September in 2017. The single experiment field was located at Corerepe, Sinaloa, Mexico . We germinated seedlings in a greenhouse for three weeks before transplanting to the field. During the field trial, we adjusted the amount of irrigated water using drip irrigation. The fertilizer level was the standard for high-biomass sorghum (N:P:K = 17:60:50 kg ha-1). The space between ridges was 1 m with 15-cm distances between individuals in the same ridge. We divided the field into two blocks for allocating each breeding family. A total of 260 breeding families was randomly assigned to each plot across two blocks without replication. For check plots, the ancestral accessions that contributed to the 3rd generation were incorporated into each block with at least a plot. In addition, 26 genotypes (F1 hybrids), which included 24 superior testcrosses generally selected from the 1st test population and two high-biomass varieties provided by EARTHNOTE Co. Ltd., were replicated within blocks. Each plot included five individuals. For the breeding families, all five individuals within a plot were measured for the phenotypes, resulting in 1,300 individuals . However, only 1,020 individuals  were used in this study due to missing data. For the ancestral accessions and checks, only two healthy individuals in a plot were measured. In this study, we evaluated six important traits for bioenergy sorghum . All traits had been considered for each selection, mainly focusing on the performance of TW and BR.We performed a field trial of the STo consider the field heterogeneity between the two experimental blocks, we calculated the adjusted phenotypic values using the following formula:d checks , bk is ti) was calculated as The adjusted phenotypic value of the RAINBOWR  in R  were used due to a procedural reason. Therefore, we obtained different marker datasets for the founder accessions and the breeding population, respectively. We treated each marker dataset independently for the analysis.DNA extraction and library preparation followed the procedure by Sbicolor_313_v3.0) (r2 ≥ 0.95 between two variant sites) on the same chromosome, only the first variant site in the VCF file (which was near the zero position on a chromosome) were kept. Finally, 6,410 (for the founder accessions) and 3,260 markers (the 3rd breeding population) remained for the following analyses, respectively.Each marker dataset was available through the following procedures. We mapped the RAD reads to the sorghum reference genome sequence (13_v3.0) . We carrPrincipal component analysis (PCA) on each marker dataset was independently carried out using the function “prcomp” in R.The Bayesian regression models used in this study can be classified into four categories: the additive linear model (A), the additive-dominance linear model (AD), the additive-dominance-epistasis linear model (ADE), and the Gaussian kernel model (GK). We adjusted marker genotype scores and calculated genomic relationship matrices using the natural and orthogonal interactions (NOIA) approach . In this study, we fitted the ADE model using the epistatic relationship matrices  were used to estimate Both additive and non-additive effects can be implicitly captured by the reproducing kernel Hilbert spaces (RKHS) regression based on a Gaussian kernel (GK) (Gianola and van Kaam 2008). The GK model can be written as  dataset .All Bayesian regression models were performed using Markov Chain Monte Carlo (MCMC) implementations in the R package BGLR . For theFor estimating genetic variance components, we calculated genotypic values in each MCMC sample after burn-in  between the adjusted phenotypic values  was performed using the R package agricolae , only 13 founders contributed to the ancestry of the 3rd generation (rd generation into 13 groups (G01–G13) based on their relationships to the founders. The genetic contribution of each founder in the ancestry ranged from 12.5 to 25.0% in the breeding families, except a family in G12 in which F170 and F247 each contributed 50.0%. G12 and G13 had been selected based on the testcross with CMS-A while we had selected the other groups for CMS-B. Only one founder (F210) was included in the ancestry of both subpopulations selected on the basis of performance with each tester. The remaining 13 founders in the 3rd generation represented a good sample of genetic variations of the base population , with different four priors for marker effects . In the Compared to the A models, the AD models estimated the genetic variances at larger values in all traits although the residuals were relatively small. Furthermore, genomic heritability was greatest in the ADE models. The differences among the four priors for marker effects  were generally minor for the estimation of genomic heritability.In addition to the total genetic variance, the variance components can be estimated in the AD and ADE models. In the AD models, the additive variance was larger than the dominance variance for all traits . The ratUsing the ADE model with BayesB, we identified the regions associated with the additive and dominance effects . Except e.g., the differences might be more distinct in CL than in the other traits). On the other hand, the influence of the priors for marker effects was relatively small across all predictions, although the difference among the priors seemed to depend on traits and models.We evaluated the prediction accuracy of the three linear models  and a non-linear model (GK) based on fivefold CV. The ADE models showed significant superiority to the A and AD models for all traits . Furtherrd generation population had improved trait performances per se compared to the founder accessions  showed a dominance association with CL, it was distant from the Dw1 locus , which might reflect their unreliability  cannot be inferred from the results  explained the property of various priors for marker effects in Bayesian regression models. Our results showed that the influences of the four priors  were generally small, although the underlying genetic architecture seemed to be different among traits , and 7. Although we could give light on the genetic architecture of early generations in a sorghum breeding program, the genetic architecture of a population is different in every generation with the change of the genotypic frequency . FurtherThe limitations of epistasis for selection might be another issue. For mate allocation, recombination fractions across the genome need to be considered . To expl


We present a new algorithm based on a deep learning method for model reconstruction from SAXS data. An auto-encoder for protein 3D models was trained to compress 3D shape information into vectors of a 200-dimensional latent space, and the vectors are optimized using genetic algorithms to build 3D models that are consistent with the scattering data. The program has been tested with experimental SAXS data, demonstrating the capacity and robustness of accurate model reconstruction. Furthermore, the model size information can be optimized using this algorithm, enhancing the automation in model reconstruction directly from SAXS data. The program was implemented using Python with the TensorFlow framework, with source code and webserver available from   •A convolutional neural network auto-encoder framework for 3D models is developed•The auto-encoder compresses protein shape information to 200 parameters•Accurate 3D models (both shape and radius) can be reconstructed from 1D SAXS data Computational Molecular Modeling; Algorithms; Computer Science Applications Small-angle X-ray scattering (SAXS) from protein molecules in solution is a powerful technique that provides information on molecular structures and dynamics . BecauseDespite the success in extracting structural information from SAXS profiles, reconstructing high-quality 3D models remains challenging. Several approaches have been proposed and implemented to build 3D density maps from SAXS data, including shape envelope approximation using spherical harmonics functions, polymer chain folding, dummy atom assembly, iterative phasing, and database searching methods. The spherical harmonics function approximation method is fast but limited by resolution . In the −1  models having cc values greater than 0.90  that have multiple conformations in the deposited dataset. For the majority of the testing models that have compact shapes, the auto-encoder works nicely in representing 3D shape information. The encoding-decoding test demonstrates that the 3D models are accurately reproduced after going through the encoding-decoding procedure, and the compressed 200-d vectors are sufficient to represent 3D molecular shapes. This lays the foundation for applying the auto-encoder method to reconstruct 3D models by optimizing compressed parameters to obtain models that fit to experimental SAXS data. Furthermore, the training dataset provides the distributions of latent variables, indicating that the valid values for these variables are distributed in limited ranges , and the atomic structure deposited along with the SAXS data was used for model quality assessment. The chi-scores of SAXS data comparison and the cc from the 3D model comparison are shown for each iteration. As shown in The reconstruction process was monitored based on the chi-score between model SAXS profile and the experimental data. As a retrospective check, the reconstructed models are also compared with the reference model by computing their correlation coefficients after optimal alignment. This is for the reconstruction of SASDA38.cc levels for visual inspections). At this level (cc = 0.70), the reconstructed models are consistent with the references in the overall shapes according to visual inspections. The models with a big cavity or flexible domains are challenging for the auto-encoder to compress the shape information to a 200-dimension vector, as discussed in the previous section. For models with rigid and compact structures, the auto-encoder and the SAXS-based reconstruction are very successful. Furthermore, random pairing the models was used as the control method, and the cc between randomly selected models were used to estimate a baseline for reconstruction performance assessment. Prior to the alignment and correlation coefficient computation, two models randomly selected from the 542 reference models were scaled to the same size. This procedure was repeated for 100,000 times to get the statistics of the cc values, which are scaled and shown with pink lines in cc value of the control method is 0.55 with a standard deviation of 0.16, suggesting that the expectation value of cc is 0.55 by random matching. The decodeSAXS algorithm performed much better than random matching. Among 542 reconstructed models, 86% showed cc > 0.55 and 54% models had cc > 0.70 in the case of the decodeSAXS using correct model radius.decodeSAXS method . Using the same dataset, the reconstruction algorithm was tested without providing the size information. The initial radius for each model in the first generation is a random positive number smaller than 300 (with the associated unit Å). The radius was taken as the 201st parameter and subject to the genetic algorithm for optimization. The optimized radii for 542 testing datasets are compared with the radii extracted from the reference models in decodeSAXS algorithm.In practice, the size information of the model to be reconstructed could not be accurately obtained in many cases, preventing successful model reconstructions. In such cases, the SASDA25). The computed model profiles in cc > 0.70).Because of the random initialization of the genetic algorithm, multiple reconstructions for the same SAXS dataset may lead to different models. Furthermore, the limited information contents in 1D SAXS profiles may also result in multiple 3D models that match to the experimental SAXS profile equally well. To test the model consistency, eight SAXS datasets were randomly chosen for multiple reconstructions. For each SAXS dataset, ten models were reconstructed by running the programs ten times with different initial models. Then the hierarchical clustering analyses were carried out using the correlation derived distance see . The clude novo model reconstruction method without using iterative model building. On the other hand, the present approach might be slow, but it can be easily expanded to other applications with an interface to convert decoded 3D models to experimental measurable information (SAXS profile in this case).3D model reconstruction from 1D SAXS data is challenging given the limited information embedded in the 1D profile. Prior knowledge, especially size information, has been required for model reconstruction. Here, using the deep learning method, the 3D models can be compressively represented using 200-dimension vectors. Based on the success in dimension reduction using the auto-encoder neural network methods, a model reconstruction method is implemented by optimizing parameters in the 200-d latent parameter space. More importantly, this new method does not require model size information and demonstrates its robustness in 3D model reconstructions. Currently, the 200-d vector and the SAXS profile are not directly related but related via the decoding part of the neural network to get the corresponding 3D model and subsequent calculate its SAXS profile. This work demonstrates that the deep learning methods have potential applications in the interpretation of X-ray data, with properly designed interfaces between the model and X-ray data. The calculation speed may not have clear advantages over the methods that construct 3D models in real space, owing to the extra decoding procedure. Nevertheless, the proposed method opens up a new avenue for model reconstruction. It is possible to improve the efficiency and accuracy of model reconstructions, by expanding the approach presented in this work. An ultimate method is to compress the latent space to match the SAXS data, so that the trained neural network can directly “translate” the SAXS information to 3D models. In such frameworks, there are information inputs from both 3D models and 1D SAXS data, and to train such neural networks, more complicated neural network architecture is desired. In a separate study, preliminary results show the possibility to encode a SAXS profile using low-dimensional vectors rather than computing from the decoded 3D models, and this feature will significantly reduce the computing time. Linking the 200-D parameter in this study and the latent space vector for SAXS data encoding will be another alternative toward a Neural network training and application can benefit from parallel processing of GPU; the speed gained from advanced hardware can facilitate the multiple reconstructions for model consistency examination. The computing time for model reconstruction is not the bottleneck in SAXS studies, considering that the sample preparation and experimental execution usually take much longer time. Furthermore, the auto-encoder is not limited to represent uniform density models; therefore, it is possible to expand the neural network to encode models with density variations from the uniform density approximation models.The progression of latent space parameters showed large variations of parameter values at the beginning stage of the optimization, and these parameters were converged to fixed values when the optimization progressed to 60–80 iterations. The linear interpolation between initial random values and the final optimized values can be decoded to 3D models as “intermediate models.” The interpolation of latent space parameters resulted a morphing of the decoded 3D models, from a roundish object to a model that matches SAXS data, revealing the relation between latent space parameters and real space models  and the final parameters, by varying the weighting factors. This is for the reconstruction of SASDA38.As the first demonstration for the deep learning method applied in the 3D model reconstruction from SAXS data, this work may open doors for potential applications of deep learning in understanding other types of experimental data, especially those that are insufficient to be directly converted to 3D models. For instance, imaging experimental data with one or a few 2D projection or scattering information could be analyzed in a similar approach to build 3D models. This method has demonstrated its capacity and robustness in building 3D models with diverse shapes from experimental data. As more high-throughput X-ray data are being collected, we anticipate increasing applications of such methods in data analysis.Owing to the low information content embedded in SAXS data, the present method is limited to the reconstruction of models with uniform density. In principle, the method can be expanded to reconstruct higher-resolution models to reflect density variations within molecular envelopes. This shall require more advanced neural network architecture to encode models with density variations.−1 in this study. Proper modeling of the hydration layer at molecular surfaces is desired to utilize the scattering signals at larger scattering angles.The maximum scattering angle used for model reconstruction is 0.2 ÅAll methods can be found in the accompanying


Ewing sarcomas are an uncommon group of malignant neoplasms. A multidisciplinary approach is highly recommended to reach a correct diagnosis, considering the clinical, radiological, and histopathological aspects. Since in up to 90% of cases, the translocation t   occurs resulting in a chimeric fusion transcript EWSR1-FLI-1. The pathologist has several tools in addition to conventional techniques (hematoxylin and eosin), such as immunohistochemistry, which plays a very important role in the differential diagnosis. We present a series of 15 cases of molecularly confirmed ES, in which we found a sensitivity of 100% for CD99 and 80% for PAX8 by immunohistochemistry. This indicates a high sensitivity; however, it is known that both CD99 and PAX8 are also expressed in other tumours. Therefore, molecular confirmation should be performed in all cases. Ewing sarcomas (ESs) are relatively uncommon and represent at least 6% of primary malignant bone tumours. It is the second most common sarcoma of the bone in children and young adults after osteosarcoma , 2.FLI1 gene on 11q24 results in a chimeric fusion transcript EWSR1-FLI-1 [There are currently several tools to approach the diagnosis of ES. A correct anamnesis and physical examination of the patient looking for signs or symptoms such as a rapidly growing mass mainly in the extremities, pain, and intermittent fever should be performed. The imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are essential to determine the size, the osteolytic or sclerotic signs, the extension, and ill-defined limits of these tumours. MRI is also vital to evaluate response to neoadjuvant therapy, direct surgical resection, and detect local recurrence or metastatic disease . The hisImmunohistochemistry (IHC) is a well-established tool, which is widely used to help identify a wide spectrum of specific pathological processes. It is also used in experimental research involving the bone and soft tissue. Besides descriptive analyses, multiparametric, semiquantitative scoring systems for evaluating different bone parameters represent a universal approach to include histopathologic information in biomedical research , 6.CD99 represents a surface glycoprotein encoded by the pseudo-autosomal MIC2 gene located in the short arm of the X and Y sex chromosomes . CD99 (MPaired box gene-8 protein (PAX8) is a nephric-lineage transcription factor and is a crucial transcription factor for organogenesis of the thyroid gland, kidney, and müllerian system . Its expSeveral studies have been published over the PAX8 expression in sarcomas such as rhabdomyosarcoma, malignant rhabdoid tumour, and clear cell sarcoma of the kidney . ExpressWe present a series of 15 cases of molecularly confirmed ES, trying to find the meaning of its immunoreactivity for CD99 and PAX8, to determine whether there is enough sensitivity to be useful in the diagnosis of these tumours.We have done a retrospective study of 15 cases diagnosed as ES in our department in the last six years (2014–2019).The inclusion criteria applied were  previousOnce obtained the tumoral tissue as trephine biopsy, core needle biopsy, or resection and after being processed in our laboratory of pathology , a battery of hematoxylin and eosin (H&E) stained slides was prepared in all cases .We designed an immunohistochemical panel that includes CD99 and PAX8 . Both hiAt the postanalytical stage, we applied a combined multiparametric, semiquantitative IHC scoring system, the immunoreactive score (IRS), which consists in a range of 0–12 as a product of multiplication of the positive cell proportion score (0–4) and the staining intensity score (0–3), resulting in one of the next: 0-1(negative), 2-3 (mild), 4–8 (moderate), and 9–12 (strongly positive) , 23, as μm sections of FFPE tumoral tissue were obtained from all the cases. A battery of H&E stained slide interlayer with unstained slides was prepared to identify the tumoral areas. Slide pretreatment for FISH was performed according to the standard recommendations by the manufacturer. The images were captured with a Leica DM 5500 B fluorescent microscope with a charge-coupled device camera (Leica Biosystems). The images were analysed by both a pathologist and a biologist using CytoVision software. At least 100 cells were scored for each slide. The presence of EWSR1 was reported only when >20% of the tumour cells showed split signals .Fluorescence in situ hybridization (FISH) using a Dual Color Break Apart Probe (Vysis EWSR1 Break Apart FISH Probe Kit), to detect the rearrangement of the EWSR1 gene, was performed in all cases. 3 In the 15 cases (100%), a radiological study with CT and MRI was performed before the biopsy procedure. After that, a complete extension study with positron emission tomography-computed tomography (PET-CT) was performed. The radiological size of the tumours ranges from 4 cm to 18 cm in the greatest diameter, with a mean of 10 cm. 8 cases (53.33%) presented bone tissue involvement by tumour at the time of diagnosis, and 100% of them showed osteolytic signs in the radiological study. The other 7 cases showed ill-defined limits in the radiological study, as shown in A small variability of histological patterns was found among all the cases. The vast majority of cases was composed of a uniform small and round cell with clear or lightly eosinophilic periodic acid-Schiff- (PAS-) positive cytoplasm and indistinct cytoplasmic membranes. The tumoral cells contained rounded nuclei with fine and homogeneous chromatin. Some cases showed areas with neuroectodermal differentiation (arrayed in rosettes as Homer Wright rosettes), as shown in In twelve cases (80%), PAX8 showed a nuclear mild to moderate pattern of immunoreactivity . All casEWSR1 gene rearrangement was present in all cases (100%) in different percentages of tumoral cells .ES represent at least 6% of primary malignant bone tumours being more common in children and young adults , 2. We rIn the group of patients analysed for this review, the age range was between 14 and 73 years with a mean of 31 years and a median of 24 years .The three bone regions most frequently affected by ES are the pelvic bones, especially the ilium, the diaphysis, or the metaphyseal-diaphyseal portion of long bones , and the chest wall (ribs). Radiologically, the lesions may be lytic, mixed lytic-sclerotic, or, rarely, predominantly sclerotic. CT and particularly MRI imaging are invaluable in further delineating the extent of disease not readily manifested on plain radiographs. Gallium scintigraphy and gadolinium-enhanced MRI images are the best for following the response to therapy . A radioImmunohistochemistry is still nowadays a useful tool for pathologists and oncologists because it gives information related to the tumoral oncogenesis. Immunohistochemistry is crucial for the differential diagnosis in metastatic cases of unknown origin. It can also be useful as a biomarker providing information about the susceptibility to specific therapies and helping us to determine the prognostic and therapeutic factors .We obtained similar results with respect to the immunoreactivity of CD99 in ES compared with other authors. Strong, diffuse membranous expression is seen in approximately 95% of ES . CD99 isThe immunoreactivity of PAX8 in ES has not been widely studied. Bui et al. had investigated the PAX8 staining pattern of primary renal and extrarenal ES/PNET to explore its potential diagnostic and prognostic role. They also have found a moderate (2+) and strong (3+) immunoreactivity for PAX8 in two cases of primary renal ES, respectively, and 14 of 22 (64%) extrarenal ES were also stained with PAX8. The intensity of staining in the latest varied from 1+ up to 3+. They proposed that the staining of ES/PNET with PAX8 is not dependent on the site of origin . Paul WeES is infrequent in general population. The correct diagnosis needs a multidisciplinary approach. The radiological examination plays a fundamental role due to the information provided by CT or MRI as the size, the exact situation, and some aggressiveness radiological criteria as tumoral necrosis or osteolytic damage. In our study, all the cases originated on long bones showed osteolytic behaviour.From the pathologist's point of view, the diagnosis of ES supposed a challenge because this requires the integration of the morphologic and microscopic criteria with the clinical and radiologic data. Immunohistochemistry supposed as a valuable tool that can help for diagnostic approaching and the differential diagnosis of ES.In the immunohistochemical analysis, we found that 100% and 80% of the cases showed intense CD99 and mild to moderate PAX8 immunoreactivity, respectively. This could be considered as a high sensitivity even when our sample was not so extended. Nevertheless, CD99 and PAX8 specificity is limited in ES because its immunoreactivity is commonly observed in many other tumours. A complete differential diagnosis is required to rule out other round cell tumours of mesenchymal, lymphoid, or epithelial origin that can also be immunoreactive for these markers. Immunohistochemical and molecular panels are necessary in almost all cases of ES to confirm the diagnosis.The ES diagnosis must be confirmed by molecular tests. FISH and RT-PCR as well as DNA sequencing by NGS should be performed if possible, in all cases.This way requires a deeper molecular investigation with a large prospective series to shed light about the implications of PAX8 in the oncogenesis of ES and its potential consequences on therapeutic response and prognosis.


Depression is a common mental health condition occurring across all ages, genders, and populations and is almost always multifaceted. It can manifest as a form of metabolic disorder, endocrine disorder, cardiovascular diseases, inflammatory disorders, deficiencies, or neurodegenerative disorders. Although there have been various treatment options available for the treatment of depression, it is still a sizable global health concern requiring more attention. This review article was produced by researching data and studies to prove a relationship between Vitamin B12 and depression. Numerous studies were reviewed, and based on these studies, it was concluded that supplementation of Vitamin B12 early enough can delay the onset of depression and improve the effect of anti-depressants when used in conjunction with Vitamin B12. Although other vitamins like Vitamin B6 and folate are known to have an impact on depression, we have primarily focused on Vitamin B12 in an attempt to offer the providers a foundation to address this concern with their patients prone to depression or have had a major depressive episode in their life. Over 264 million individuals suffer from depression across the world. Depression is one of the most commonly occurring mental health disorders occurring in adults and children . The WorThe American Academy of Pediatrics' most recent guidelines states that depression screening is recommended to begin at as low as 12 years of age. It is a well-known fact that depression can become a serious medical condition, if long-lasting, and can affect the quality of life, reduce overall productivity, and lead to extreme thoughts known as suicidal ideation [Depression is more prevalent in women and young adults aged 18-25 years of age , most liVitamin B12 is a water-soluble vitamin synthesized by the bacteria present in the human body. It is predominantly acquired by the intake of meat products, and thus individuals with a vegetarian or vegan diet tend to be naturally deficient. Deficiency of this particular vitamin can lead to fatigue, weakness, constipation, balance issues, mental fogginess, peripheral tingling, depression, and cognitive issues ,5.Numerous studies are being performed to determine the relationship between Vitamin B12 and depression, and if supplementation of Vitamin B12 can slow the progression of depression or prevent it. So far, there has not been concrete evidence that shows the positive effects of Vitamin B12 supplementation in patients with or prone to depression. However, some studies have shown positive effects on patients with depression when supplementation of Vitamin B12 is implemented. Some clinical studies have shown that higher Vitamin B12 levels in the body resulted in better outcomes in patients suffering from depressive and other mental health disorders , whereasDepression is a lifelong battle for the majority of the population across the world. Especially with the current situation in the world and the COVID-19 pandemic associated with lockdowns, loss of jobs, housing, and immigration statuses, the incidence of depression and other mental health disorders has significantly increased among children, adolescents, and adults, not being limited to a specific age group. This paper aims to find the effects of Vitamin B12 on depression with the help of other reviewed articles, in an attempt to allow providers to make evidence-based decisions to prevent and manage depression by merely supplementing individuals with Vitamin B12.Our review focuses on the effects of Vitamin B12 supplementation at the onset or during the prognosis of depression. A total of 35 studies and articles were reviewed for this review [Vitamin B12 and hyperhomocysteinemiaMicronutrients are known to affect the normal structure and functions of the brain. For this paper, we will be focusing on one specific micronutrient - Vitamin B12. Cyanocobalamin, also known as Vitamin B12, is one of the most important water-soluble vitamins. The primary functions of Vitamin B12 are appropriate red blood cell formation, neurological functioning, and DNA synthesis . DeficieVitamin B12 deficiency is reportedly known to cause mental disturbances in numerous individuals. However, there is little evidence to show the correlation between psychosis and Vitamin B12. Cobalamin is one of the essential elements for monoamine neurotransmitter synthesis in the brain. A study published in 2011 in the Academy of Psychosomatic Medicine included supplementation of Vitamin B12 and folate, which resulted in improved cognitive functioning among patients participating in the study. A borderline Vitamin B12 level of 75-95 pg/mL, as well as up to a normal level of 307 pg/mL, is known to cause neuropsychiatric symptoms in patients, and such symptoms may start manifesting even with such borderline deficiencies or low normal levels of Vitamin B12. The study does dispute if the effects were of the Vitamin B12 supplementation or anti-depressant medications; however, it concludes that supplementation did increase the overall response to the anti-depressants [HyperhomocysteinemiaHigher homocysteine levels are associated with a phenomenon called "methionine loading." A deficiency of Vitamin B12 along with B6 and folate usually prevents the conversion of homocysteine to methionine, increasing the levels of homocysteine. Hyperhomocysteinemia can also occur in patients with renal disorders or genetic alterations of methyl-tetrahydro-folate reductase or cystathionine beta-synthetase, which are required for the metabolism of homocysteine . Higher Vitamin B12 is interdependent with other micronutrients, mainly Vitamin B6 and folate. This interdependence affects multiple neuronal pathways that are not directly controlled by Vitamin B12. Neurotransmitters are required to conduct the signals from one neuron to another, with the help of pre- and post-synaptic junctions. The malfunctioning of any of these pathways can lead to depression . Lower VPathophysiology of depressionOver a decade ago, depression was commonly seen in adult and elderly patients but had become far more common among the younger population. According to the Journal of Psychological Medicine, the rates of depression have increased drastically among children as young as 12 years and older.Depression, once diagnosed, is clinically treated with anti-depressants and cognitive behavioral therapy (CBT). In patients where the anti-depressant regimen is not eliciting a response, an additional drug from a different pharmaceutical group has proved to have a significant effect ,20. HoweJournal of Nutrition in 2010, which discussed the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene in various ethnic groups. The study showed lesser scores on the Mini-Mental Status Exam (MMSE) and higher depression scores among patients with lower plasma levels of Vitamin B12 [A study performed in 2010 by Skarupski et al. included a sample US population of 35,053 older adults, and the results of this study stated that higher intakes of Vitamin B12 and B6 were associated with a lower risk of developing depressive symptoms by an average of 7.2 years . Accordiamin B12 .Daily supplementation of oral Vitamin B12 (100 mcg) and folic acid (400 mcg) has been shown to increase cognitive function in a randomized controlled trial performed by Walker et al. in 2012 . They prMelancholic depressive symptoms were more relatively associated with lower plasma Vitamin B12 levels. One such study reviewed concluded that Vitamin B12 deficiency played an important role in the pathogenesis of depressive symptoms . A randoThe total cyanocobalamin and methylcobalamin levels in patients with autism and schizophrenia were reported to be lower as compared to the age-matched control subjects. Although the association with the levels and depression was not performed, the study analyzed brain samples . It concOne-carbon metabolism has been extensively linked with psychiatric disorders among numerous studies. One such recent study published in 2020 comprised of 89 patients, mainly children and adolescents, and included a patient group that was already diagnosed with depression and a control group. They were subsequently tested for serum levels of Vitamin B12, homocysteine, and Vitamin D. The study utilized correlation analysis and showed a negative relationship between the severity of depressive symptoms and Vitamin B12, and associated hyperhomocysteinemia, concluding that low normal levels or deficiency of Vitamin B12 can become a significant contributing factor toward depression . Case-coAmong the numerous articles reviewed for this topic, the majority of them proposed that Vitamin B12 levels are related to the severity of depression. Although this topic lacks tangible and sizable data to prove the same, healthcare providers need to take into consideration the studies reviewed in this paper and utilize them to test the effects of Vitamin B12 supplementation in patients with neuropsychiatric disorders.LimitationsThe limitations of this topic are that the studies that have been reviewed for this paper have had relatively smaller sample population sizes. There is still a need for more research with a larger sample size to find more concrete evidence of the positive effects of Vitamin B12 on depression.In this article, we reviewed over 30 to 40 published articles and studies to understand the correlation between the supplementation of Vitamin B12 and the prognosis of depression. Based on the reviewed studies, it was found that although there is no concrete evidence showing positive effects of Vitamin B12 on depression or depressive symptoms, the lower levels of Vitamin B12 in the body are associated with a higher risk of developing depression. Routine testing for plasma Vitamin B12 levels can be recommended for patients across the board beginning at the adolescent age to prevent the population from developing depression or other forms of cognitive under-functioning, which may lead to depression. Low normal levels of Vitamin B12 should be recommended to be evaluated for symptoms of Vitamin B12 deficiency, including any neurological manifestations, as these symptoms can present even when the levels are within a normal range. However, additional studies with larger population groups should be done to formulate an evidence-based criterion for providers to adapt across the world.


The change in knee extension strength was significantly improved by 13% in the WPI + BIO group versus CHO on top of EMS, while WPI alone did not provide a significant benefit over CHO. On top of this, there was the largest improvement in gait speed (8%). The combination of EMS and this specific nutritional intervention could be considered as a new approach for the prevention of sarcopenia but more work is needed before this approach should be recommended. This trial was registered at the Japanese University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN000008382).Age-related sarcopenia is a progressive and generalized skeletal muscle disorder associated with adverse outcomes. Herein, we evaluate the effects of a combination of electrical muscle stimulation (EMS) and a whey-based nutritional supplement (with or without polyphenols and fish oil-derived omega-3 fatty acids) on muscle function and size. Free-living elderly participants with mobility limitations were included in this study. They received 2 sessions of EMS per week and were randomly assigned to ingest an isocaloric beverage and capsules for 12 weeks: (1) carbohydrate + placebo capsules (CHO,  The world population is aging rapidly . SarcopeOne well-known nutritional solution for sarcopenia is protein supplementation. An association between protein intake and muscle mass  or musclThe beneficial impact of resistance or endurance training on muscle mass and function is also highlighted in many studies ,22. HoweThus, a multimodal approach combining nutrition and exercise induced by EMS may provide an innovative treatment for limiting the development of sarcopenia with aging. Until now, no studies have been carried out investigating the combined approach of nutrition and EMS. Currently, we hypothesize that the effect of EMS could be improved with the consumption of a whey-based nutritional intervention with a specific blend of ingredients containing polyphenols and ω3 fatty acids (exhibiting antioxidant and anti-inflammatory activities) to further enhance the benefits of the whey-based nutritional intervention.−1. All participants included in the study were “free-living” people without any support or classified in Care support level 1, Care support level 2, Long-term care level 1 (LTC1) and Long-term care level 2 (LTC2) according to the LTCI system. This is a national system in Japan including everyone from age 65 and above used to determine the amount of services covered by the insurance  [The clinical study was performed at the Momoyama social welfare center for the elderly in Kyoto (Japan). The study protocol received the approval of the ethical committee from Kyoto University  and was conducted in accordance with the Declaration of Helsinki and in compliance with the Japanese ethical guidelines for clinical studies. Forty-one participants  with mobility limitations were recruited based on the following inclusion criteria: mobility limitations according to the long-term care insurance (LTCI) system of Japan, age between 60 and 90 years and gait speed below 1.5 m·services) ,35. Part2, regular exercise activity, history of neuromuscular impairments, currently participating or having participated in another clinical trial in the 4 weeks prior to the beginning of the study, consumption or planning to consume dietary supplements such as free amino acids, antioxidants or supplements specifically designed for malnourished elderly people, treatment adherence and serious chronic disease .Exclusion criteria were as follows: body mass index (BMI) > 25 kg/mAll participants received detailed information on the protocol and gave their  written informed consent to participate in the study.www.umin.ac.jp). The aim of this study was to assess the effects of a combination of EMS and a whey-based nutritional supplement (with or without polyphenols and fish oil-derived ω3 fatty acids) on muscle function and size in a physically compromised elderly population. The primary outcome measure of this study was the estimated change of the thickness of the thigh (rectus femoris) and calf (gastrocnemius) muscle using ultrasonography. In addition, gait speed, knee extension strength and nutritional assessment were evaluated. Safety measures including standard blood tests were assessed (described as follows). The study was a single center, parallel, double-blind, randomized-controlled trial registered in the Japanese UMIN  clinical trial registry (UMIN000008382 at ®) and sex at enrolment and was carried out using library blockrand in R by Nestlé clinical development unit. The treatment group to which a subject was allocated was concealed to the participants, the support staff, the investigators and Nestlé, except for the quality specialists at the clinical development unit.Participants were randomized (1:1:1) and assigned to one of three groups. Block randomization was stratified by age, Mini-Nutritional Assessment (MNA®95) + placebo capsules (WPI) or (3) beverage with 20 g of WPI + hard capsules containing rutin (500 mg/day) + fish oil-derived ω3 fatty acids/curcumin in soft capsules (1.5 g/day fish oil type NAD from Sofinol that provided 18% eicosapentaenoic acid (EPA) and 7% docosahexaenoic acid DHA and 500 mg/day curcumin with 95% curcuminoids) (WPI + BIO). Curcumin and rutin were supplied by Sankyo Ltd. . The dose of protein used in this study is based on results from a previous study showing that 0.4 g of protein/kg body weight/serving is required to maximally stimulate muscle protein synthesis [Participants were instructed to ingest dietary supplements consisting of one out of three experimental beverages together with 7 capsules  for 12 weeks on top of their twice weekly EMS treatment, as follows: (1) beverage with 20 g of carbohydrate  + placebo capsules containing dextrin and medium chain triglycerides (CHO), (2) beverage with 20 g of whey protein isolate . On the other days, participants drank the dietary supplement at the same time they were used to drinking it when receiving EMS. Participants were instructed to consume 7 capsules 3 times per day, 2 during breakfast, 3 during lunch and 2 during dinner for the duration of the study. Compliance was assessed by counting the left-over capsules at the end of the study. To help ensure the reliability of the capsule count, participants were asked to record the number of capsules ingested and asked to return any remaining pills at the end of the study.The electrical muscle stimulation procedures have been fully described elsewhere ,37. Brie®) to evaluate their nutritional state before starting the treatment and after 12 weeks. This allows for classifying participants as normal, at risk of malnutrition or malnourished. All measurements were performed according to a standardized manner and participants were instructed not to take any drinks with caffeine the night before the testing. Participants were asked to come fasted for the blood samples. All measurements were done in the morning two days after the final training sessions.Study endpoints were assessed before starting the treatment (W0) and again after 12 weeks (W12) for all variables except muscle morphology. All participants performed a Mini-Nutritional Assessment (MNAMuscle thickness of the rectus femoris (thigh) and gastrocnemius muscles  was assessed by ultrasonography at baseline, 4 weeks, 8 weeks and 12 weeks of the experimental intervention. Strong correlations have been reported between muscle thickness measured by B-mode ultrasound and site-matched skeletal muscle mass measured by MRI . TherefoPhysical performance was assessed at baseline and 12 weeks of the experimental intervention. Methods for muscle strength measurements were reported elsewhere ,41. BrieAs part of the physical performance evaluation, gait speed was determined with the 6 m walking time test (seconds). A 6 m straight path was marked with tape on the floor, and using a custom-made trigger-linked stop-watch, the participants were asked to walk normally as in daily life during assessments. Usual walking aids  were allowed. Gait speed was evaluated three times for each subject and averaged.Three minutes rest was provided between trials during the physical performance tests.Assessments of body composition  was conducted by bioelectrical impedance analysis . Bioelectrical impedance analysis (BIA) is an alternative device for evaluating body composition, and has been used in clinical settings, as well as community and population-based studies. Previous research examined BIA in various experimental conditions and demonstrated its validity, reliability and reproducibility among different ethnic groups . It was The full battery of biochemical, hematological and coagulation parameters were analyzed at the clinical laboratory from SRL group  including: red and white blood cell count, markers of inflammation , blood chemistry of CPK, HDL and LDL cholesterol, albumin, total protein, triglycerides and blood test of coagulation parameters  for safety control of the treatment.TM) at Nestlé, Lausanne.All data captured by the investigators were recorded on paper case report forms (CRF). Only blood biomarkers, ultrasonography and body composition results were generated as electronic files and were transmitted to the clinical data manager for loading and consolidation in the final database. All original CRF were sent to Nestlé and copies of all forms will remain at the study site. The CRF data was entered into a computer database  was calculated using an ordered polytomous model. Odds ratios and confidence intervals for being at risk or improvement of nutritional status from baseline to 12 weeks were estimated by a proportional odds model, taking advantage of ordered categories. The incidence of adverse events (the percentage of participants having experienced at least one adverse events) during the treatment period was compared between the three randomized groups by exact Chi-Square test. Treatment differences for blood measurements was estimated by robust regression, correcting for baseline on log-transformed data. A p value ≤ 0.05 was considered as being statistically significant. Data are expressed as means ± SEM.Statistical analyses were carried out with SAS version 9.3. The muscle thickness was analyzed using a mixed model for repeated measures, with baseline measurement, sex, age at randomization and time as covariates. For muscle strength, the overall treatment difference was estimated with the help of the LSMEANS statement using a linear mixed model correcting for baseline, age and with a sex–treatment interaction term. An ANCOVA correcting for baseline value, sex, age at randomization and treatment group was used to evaluate the effect on walking speed and body composition. The time effect for muscle strength and gait speed was estimated by Wilcoxon tests. The effect of intervention on nutritional status  in the CHO group, 15 subjects (100%) in the WPI group and 10 subjects (77%) in the WPI + BIO group) completed the study and were included in the statistical analysis. Per-protocol populations for analysis included participants who completed the final testing. The flow of study subjects is shown in p = 0.008 and p = 0.018, respectively) increased by 3% to 5% in all treatment groups. The size of the muscle was significantly higher in all groups after 12 weeks of intervention but no statistical difference was observed among CHO, WPI and WPI + BIO groups (no treatment by time interaction and treatment effect). The same effect was observed for the cross-sectional area (data not shown).Calf A and thip = 0.025), leading to a 13% improvement in muscle strength in the WPI + BIO group along the 12 weeks of treatment . WPI supplementation was not significantly different than CHO and WPI + BIO. In line with these results, there was a significant time effect only in the WPI + BIO group (p = 0.042).Muscle knee extension strength was significantly influenced by WPI + BIO supplementation . The +2.p = 0.032). By contrast, it was not significantly increased in either the CHO or WPI groups (around 3% increase from baseline). However, there was no significant treatment by time interaction or treatment difference between groups.Gait speed estimated using a 6 m walking time test  increaseThe body weight of the participants remained stable following the three separate nutritional interventions compared to baseline .WPI or WPI + BIO supplementations did not have any effect on total lean  and fat ® was not significantly affected by nutritional supplementations  in the CHO group, 26.7% (n = 4) in the WPI group and 23.1% (n = 3) in the WPI + BIO group.There were no whey protein, fish oil and polyphenols ingestion-related changes in red and white blood cell count, markers of inflammation , blood chemistry of CPK, HDL and LDL cholesterol, albumin, total protein and triglycerides at baseline and at week 12 (data not shown). Similarly, blood test of coagulation parameters  measured at baseline, 2, 6 and 12 weeks did not show significant group differences. There was no significant difference among groups for serious adverse events. The most commonly reported side effect for all participants who initiated the study was gastrointestinal symptoms, which was reported by 15.4% of the participants  fatty acids on top of whey protein combined with EMS treatment. Muscle thickness significantly increased in all groups but there were no statistical differences related to nutritional supplementation. By contrast, the change in muscle knee extension strength was significantly improved versus placebo in the WPI + BIO group with curcumin, rutin and ω3 on top of EMS. On top of this 13% increase in muscle strength, the largest improvement in gait speed (8%) was observed in the WPI + BIO group compared to the other groups. Despite the positive effect on muscle strength and gait speed, there were no significant changes in body composition and nutritional status.The muscle thickness of the leg of the participants was significantly improved by 3% to 5% in all treatment groups, suggesting that this effect could be due to EMS treatment only. The beneficial impact of resistance or endurance training on muscle mass and function is highlighted in many studies, suggesting that the potential anabolic response to exercise still remains despite the reduced metabolic response to nutrients generally observed in this population ,22. HoweIn our study, the WPI group did not demonstrate any benefit as compared to the CHO group. The short-term effects of whey protein were well studied and shown to stimulate postprandial muscle protein accretion in elderly adults . This is−1) improvement in gait speed, which is clinically meaningful. Previous studies show that clinically meaningful gait speed improvements (0.05 to 0.14 m·s−1) have been associated to better physical performance and survival rates [The main finding of the present study was a significant 13% change from baseline in muscle knee extension strength observed in the whey protein group supplemented with ω3, curcumin and rutin compared to the change in the carbohydrate group. WPI supplementation had the same effect as the CHO. On top of this effect of WPI + BIO, there was an 8%  in elderly woman after 90 days  and 6 moDifferent hypotheses can be postulated to explain the mechanism of action for the present results observed on muscle strength after WPI + BIO ingestion. First, muscle strength can be influenced not only by the quantity of the muscle , but also by the quality of the muscle and fiber types . It was Our study had some limitations: as a first proof of concept study, there was a small number of participants and the results need to be confirmed in a larger clinical study. In addition, we were not able to recruit equal amounts of males and females in each group. Moreover, we did not control or monitor dietary intake of our participants, although they were asked to maintain their habitual dietary intakes throughout the entire study period. This is a major limitation but there was no difference between groups for blood albumin and total protein level. Moreover, the MNA is assessing the nutritional status of the participants with questions related to the frequency of consumption of dairy products, eggs, meat, fish, vegetables, etc., and there was no difference between groups. MNA was used for randomization, thus limiting the risk of having important differences related to nutritional status. Lastly, we did not have a specific arm testing the WPI + BIO without EMS.In conclusion, we showed that the muscle size was increased in all groups and this could be explained by EMS treatment. WPI + BIO administration in combination with EMS elicits a significant increase of muscle knee extension strength and the largest improvement in gait speed (8%) after 12 weeks of treatment in elderly adults with limited mobility. This effect was not observed in the group supplemented with whey protein only. The functional improvement observed might therefore be related to physiological benefits related to a positive interaction between polyphenols, fish oil and protein. The underlying mechanism of action needs to be elucidated but such combinations of ingredients may help to manage the oxidative stress that could interfere with mitochondrial function or help to reverse the anabolic resistance. Thus, a multimodal approach combining such nutritional combination and exercise induced by EMS may provide an innovative treatment for limiting the development of sarcopenia with aging.


Type 1 autoimmune hepatitis (AIH) is a rare inflammatory disorder of the liver that may arise at any age, from infancy to adulthood. Long-standing autoimmune hepatitis may progress to cirrhosis and subsequent hepatocellular carcinoma (HCC). However, the true incidence of HCC in AIH patients is unknown as there is a paucity of published data. Currently, there are no established guidelines on screening patients with AIH for HCC. Without screening protocols, patients with AIH may present with late-stage HCC that may have been detected and treated earlier in the disease course. We describe a case of a patient with type 1 AIH who developed stage IIIB HCC in the absence of appropriate screening protocols with complex social determinants leading to barriers to access regular follow-up care.  Autoimmune hepatitis (AIH) is a disorder that is primarily characterized as chronic inflammation of the liver. Although the etiology of AIH is unknown and variable, several studies suggest that it may be environmentally triggered. This process results in the development and subsequent loss of tolerance to neoantigens that incite an inflammatory response throughout the hepatic system . The worAIH can be further classified into two subcategories, type 1 and type 2, determined by the type of circulating autoantibodies. Antinuclear antibody, anti-smooth muscle antibody, and anti-liver-kidney microsomal-1 antibodies are characteristic of type 1 AIH. Type 2 AIH is characterized by anti-liver cytosol antibody-1 or anti-liver-kidney-microsomal-1 antibody alone . AlthougPatients with AIH may present with a variety of clinical symptoms, ranging from an asymptomatic elevation in liver enzymes to acute liver failure. Clinical features of AIH include elevated liver enzymes , increased IgG or gamma-globulin levels or the presence of autoantibodies . AIH is One of the most significant complications of AIH is cirrhosis and subsequent hepatocellular carcinoma (HCC). The risk of developing HCC in patients with AIH has historically been assumed to be low. A systematic review by Tansel et al. demonstrated that while the risk of HCC in AIH patients appears lower than that of hepatitis B, C, or primary biliary cholangitis patients, 92 out of the 93 AIH patients had cirrhosis by the time of the HCC diagnosis . TherefoHepatocellular carcinoma is one of the top causes of cancer-related death in the United States. The incidence of HCC has tripled since the 1980s and the five-year survival rate is 18%. If HCC is not detected in a timely manner before metastasis, the five-year survival rate drops to 2% [We present a case of a patient with type 1 AIH who developed HCC 15 years after the initial diagnosis. This case highlights an important association between type 1 AIH and HCC. In addition, this case suggests a role for early screening in patients with AIH in order to prevent the progression of cirrhosis to HCC. A 35-year-old African American male with a 20-year history of type 1 AIH, liver cirrhosis, primary sclerosing cholangitis, and esophageal varices presented with a two-day history of confusion and bizarre behavior. He had been recently diagnosed with HCC and was taking lactulose and lenvatinib 12 mg daily two weeks prior to presentation. He was not able to titrate his bowel movements with lactulose at home due to chemotherapy-induced diarrhea, which resulted in missing two doses of lactulose. The patient was subsequently diagnosed with hepatic encephalopathy secondary to lactulose non-adherence in the setting of chemotherapy-induced diarrhea. During his hospital course, the patient was treated with lactulose and rifaximin, which resolved his encephalopathic symptoms. He is currently being evaluated for a liver transplant and is being monitored closely by his oncology team at a tertiary care center. Case backgroundThe patient was diagnosed with type 1 AIH at the age of 15 following a liver biopsy, which showed cirrhosis and inflammatory activity consistent with AIH. To manage recurrent AIH episodes, he was prescribed azathioprine, prednisone, and propranolol by a gastroenterologist at a tertiary care hospital. Unfortunately, due to complex social determinants of health including insurance coverage issues and unwanted medication side effects, he was mostly non-adherent to the management plan. Due to the patient’s multiple gastrointestinal comorbidities, a series of surveillance tests were prescribed in 2013, including an outpatient MRI, AFP monitoring, and surveillance abdominal ultrasounds every six months to screen for cholangiocarcinoma and primary liver cancer. However, insurance coverage challenges prevented the patient from maintaining consistent follow-up.Approximately one month prior to his hospital presentation with hepatic encephalopathy, he was diagnosed with HCC. This was determined after a workup for presentation with bilateral lower extremity and testicular swelling yielded the presence of a hepatic mass (4.91 by 3.93 mm) seen on MRI with a right portal vein thrombus  and bilirubin (6.7 mg/dL). Subsequent percutaneous needle biopsy of the liver confirmed the diagnosis of well-differentiated HCC, with biopsy positive for arginase-1 and negative for cytokeratin-7. Subsequent CT of the chest, abdomen, and pelvis with contrast for staging was performed one month after the initial diagnosis. While it demonstrated no evidence of metastatic disease, it did reveal progression of the hepatic mass to 5.15 by 3.83 mm (previously 4.91 by 3.93 mm) along with central invasion of the tumor  . This fuWe presented a case of HCC in the setting of a 20-year history of AIH with multiple complications. The patient failed to receive an individualized treatment regimen despite establishing care with a tertiary care hospital with a transplant center prior to his HCC diagnosis. Our patient’s barriers to healthcare access also contributed to the challenges he experienced while attempting to adhere to the extensive screening regiment prescribed to him. This case highlights the need for standardized screening guidelines for patients with AIH stratified by risk factors specific to the disease process. Additionally, clinicians should be aware of the complicated progression of this disease and mindful of the challenges patients may face in adhering to necessary surveillance screenings for HCC, due to complex social determinants of health.


Flow-diverter stents (FDS) are designed to maintain laminar flow in the parent artery and sidebranches and to promote thrombosis of the aneurysm. Although these devices were developed for use in intracranial circulation, FDS could be employed to treat aneurysms regardless of their location, when anatomic factors may limit the efficacy of classic endovascular techniques. The objective of this study is to describe the initial experience of a single center in the treatment of visceral artery aneurysms and pseudoaneurysms (VAA-VAP) with cerebral FDS, analyzing safety, efficacy and 1-year outcome. Between 2016 and 2018 six patients  underwent treatment with FDS of 4 VAA and 2 VAP located in renal (4), hepatic (1) and splenic arteries (1). Mean aneurysm diameter was 14.3 mm (range 8–22). All the aneurysms had sidebranches arising from the neck or had an unfavorable dome-to-neck ratio. Technical success, safety, efficacy and 1-year outcome were analyzed. Follow-ups (FU) with Color-Doppler US and CTA ranged from 12 to 36 (mean 20) months.n = 3) and at 12-month FUs. There was one sidebranch occlusion with evidence of a small area of kidney hypoperfusion at the 12-month FU, which was asymptomatic. In one patient, a reintervention was needed because CTA showed a severe in-stent stenosis, which was symptomatic. Mean hospitalization was 4.1 days.Technical success was achieved in all cases. There were no aneurysm rupture nor reperfusion after exclusion. Five out of six (83.3%) FDS were patent at each FU; all the aneurysms showed shrinkage with a mean dimensional reduction rate of 55.8%. Sac thrombosis was observed in 4 aneurysms at 1 (Treatment of morphologically complex VAA and VAP with cerebral FDS proved to be safe and efficient. Stronger evidence from larger populations are required. Visceral Artery Aneurysms (VAA) and Pseudoaneurysms (VAP) are rare clinical entities, which are diagnosed more and more frequently thanks to the increased use of cross-sectional imaging. Despite VAA and VAP are associated with a high incidence of rupture  are specifically designed to maintain laminar flow in the parent artery and sidebranches, while reducing flow velocity within the aneurysm, thus promoting thrombosis of the sac. Although these devices were primarily designed for use in intracranial circulation, cerebral FDS could hypothetically be employed to treat morphologically complex aneurysms, regardless of their location  and VAP (n = 2) with cerebral FDS between December 2016 and June 2018 were found. Three of the four VAA were incidentally diagnosed with CTA, and were located in the renal arteries (n = 2), the common hepatic artery (n = 1) and in a splenic artery branch (n = 1). One patient (Pt 2) was diagnosed with VAA after undergoing CTA for right flank pain; the remaining 3 aneurysms were asymptomatic. Two patients  presented with acute flank pain and uncontrollable hypertension: CTA revealed the presence of spontaneous dissections of segmental renal artery branches and circumscribed renal infarctions. Treatment was indicated in these cases because in the following days it was observed that the dissections had undergone morphological changes from stenotic to pseudoaneurysmal configurations.The database of patients with VAA and VAP treated in our department was retrospectively researched, and six patients who underwent treatment of VAA   are at high risk of rupture , under conscious sedation, after preoperative preparation with dual antiplatelet therapy (100 mg Aspirin and 75 mg clopidogrel) for 1 week. The renal aneurysms were treated via a transbrachial approach in three out of for cases, and via a transfemoral approach in the remaining case, because of the angulation of the renal arteries, while the treatment of the splenic and hepatic aneurysms was performed via a transfemoral approach. In all cases a 6 Fr guiding-catheter was used to catheterize the renal artery or the celiac trunk, a microcatheter was advanced into the target vessel on a 0.014″ guidewire , and finally a FDS was deployed  and the Surpass Streamline .The analyzed endpoints were technical success, safety, efficacy, and the 1-year outcome of the procedure. Technical success was defined as successful deployment of the FDS within the target artery, with documented stent and sidebranch patency at the end of the procedure. Safety was defined as freedom from minor (puncture site haematoma or pseudoaneurysm) or major complications . Efficacy was defined as stent and sidebranches patency and freedom from aneurysm rupture or reperfusion at 1, 6, and 12 months after intervention. The primary endpoint for outcome consisted of aneurysmal volumetric reduction and the secondary endpoint was sac occlusion at 1-year FU.Imaging follow-up was scheduled with pre-discharge and 1-month CD-US, followed by CTA scans at 6 and 12 months, and then on a yearly basis. Follow-up of pseudoaneurysms also included a CTA scan at 2 weeks. Follow-up ranged from 12 to 36 months (mean 20 months).Efficacy: Five out of six FDS (83.3%) were patent at each FU; no aneurysm ruptures nor reperfusion after exclusion were observed. Eight out of nine (88.9%) sidebranches covered by the flow diverters were patent at the last FU.Outcome: Sac shrinkage was observed in all cases with a mean dimensional reduction rate of 55.8% (ranging from 12.5 to 100%). Complete sac thrombosis was observed in two of the four VAA, and occurred respectively at 1 month in one case and at 12 months in another case , because of the recurrence of drug resistant hypertension 40 days after the procedure, a CTA was performed and revealed the presence of a severe in-stent stenosis. In this case because of the bilobate morphology of the VAP, from whose sac originated two sidebranches, it was required to use two partially overlapped FDS. The final angiographic control performed during the first intervention showed a mild in-stent stenosis at the level of the overlapping point, which was considered as not significant, and so a decision not to make an angioplasty was made, also in order to avoid foreshortening of the stents. Therefore, a second intervention was needed, for the correction of the stenosis by angioplasty: after that, the hypertension resolved in a few days. Both the flow diverter stents and the covered sidebranches were patent at the 12 months-FU CTA, which also confirmed the complete exclusion of the pseudoaneurysm  , which is a cobalt self-expandable stent specifically approved for visceral and peripheral artery aneurysm repair. Early reports showed encouraging results with stent patency rate of 89% and aneurysm exclusion rate of 84% at 1-year follow-up  techniques may be required, because FDS have low radial opening forces (Dmytriw et al. However, there are several clear advantages to using flow diversion techniques: the aneurysmal artery is treated at the neck, which is the point most at risk of future recurrence, sidebranches patency is preserved and, finally, the risk of incidental rupture associated with aneurysm sac catheterization and intrasaccular maneuvers are avoided.The exclusion of VAA and VAP may represent a challenge because of the technical difficulties associated with the treatment. Although there are relatively few reports as yet in the literature, endovascular repair of VAA and VAP with cerebral FDS seems to be a reliable option. Despite the greater amount of time required to obtain the shrinkage and the occlusion of the aneurysms, in comparison to traditional endovascular techniques, treatment with FDS in this series proved to be safe and efficient, and provided the possibility of overcoming some of the limits of the currently available techniques. Obviously, more robust evidence from larger population studies and prospective studies are required to reinforce these initial indications.Additional file 1