Eosinophilic esophagitis: absolute eosinophilic count, peak eosinophilic count, and potential biomarkers of eosinophilic degranulation products-an in-depth systematic review.

Background: Eosinophilic esophagitis is a chronic inflammatory disorder, often relapsing. There is an increasing need to develop new alternative diagnostic and monitoring methods on a critical basis, which will provide samples through none or minimally invasive procedures. This study aims to identify and document the types and roles of potential biomarkers in eosinophilic esophagitis released by eosinophils as well as the potential relationship to the peak eosinophilic count and the degree of degranulation of in situ eosinophils (DGE/DGE + NDGE: degranulated eosinophils/degranulated eosinophils and non-degranulated eosinophils). Methods: This is the first in-depth systematic review study using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) parameters involving a literature search of academic databases (PubMed, Scopus, Medline, Google Scholar, and Cochrane Database, 2011-2022) targeting specifically the eosinophilic counts and ratio, and the eosinophilic degranulation products as potential biomarkers. Data were extracted from ten selected studies and presented on a spreadsheet. Results: The studies show the ability to detect eosinophilic and non-eosinophilic degranulation products, and absolute eosinophilic count in samples, including blood and urine, thereby serving as potential surrogates in making the diagnosis or monitoring disease progression in the future. There is an obvious paucity of studies that correlate potential biomarkers to the degree of degranulation of in situ eosinophils. Conclusions: A few minimally invasive methods and biomarkers may be suggested as alternative tools in diagnosing and monitoring eosinophilic esophagitis. While there is no consensus on the clinical usefulness of these biomarkers, our critical evaluation may suggest that the eosinophilic degranulation ratio (DGE/DGE + NDGE: degranulated eosinophils/degranulated eosinophils and non-degranulated eosinophils) in the esophagus may be critical for evaluating properly these biomarkers. An increasing trend may culminate in the potential clinical use of these biomarkers evaluated not only with the peak eosinophilic count, but also with the degranulation score upon regulatory bodies' approval to monitor eosinophilic esophagitis in the future. We strongly advocate for the necessity to score the esophageal biopsies with both a peak eosinophilic count and a score of the degranulated eosinophils.

Double Trouble: How Microbiome Dysbiosis and Mitochondrial Dysfunction Drive Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are closely related liver conditions that have become more prevalent globally. This review examines the intricate interplay between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH. The combination of these two factors creates a synergistic situation referred to as "double trouble", which promotes the accumulation of lipids in the liver and the subsequent progression from simple steatosis (NAFLD) to inflammation (NASH). Microbiome dysbiosis, characterized by changes in the composition of gut microbes and increased intestinal permeability, contributes to the movement of bacterial products into the liver. It triggers metabolic disturbances and has anti-inflammatory effects. Understanding the complex relationship between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH is crucial for advancing innovative therapeutic approaches that target these underlying mechanisms.

Sudden cardiac death and post-traumatic stress disorder: More research is needed.

Sudden cardiac death is an event which is traumatic for the individuals, who survive and their relatives. Very few research is concentrated on these survivals and the symptoms arising from post-traumatic stress disorders. In this journal, Birk et al. report on twelve eligible cardiac arrest survivors contacted, of which ten were enrolled. The authors report on heart rate variability biofeedback, which is, according to the authors, a promising non-pharmacologic approach for reducing anxiety. The intervention was comprised of daily sessions of diaphragmatic paced breathing and real-time monitoring of cardiac activity guided by a smartphone app and heart rate monitor. Ninety percent of the patients had good scores for intervention acceptability and feasibility, and 80 % reported good scores for its appropriateness and usability for reducing fear. Trait anxiety decreased significantly pre-to-post intervention. We comment on this finding highlighting other studies targeting sudden cardiac death and supporting that more research with very large randomized clinical trials is needed.

Liver Biopsy Handling of Metabolic-Associated Fatty Liver Disease (MAFLD): the Children's Hospital of Eastern Ontario grossing protocol.

Metabolic-(non-alcoholic) associated fatty liver disease (MAFLD/NAFLD) has increasingly become a worldwide epidemic. It has been suggested that renaming NAFLD to MAFLD is critical in identifying patients with advanced fibrosis and poor cardiovascular outcomes. There are concerns that the progression to non-alcoholic steatohepatitis (NASH) may become a constant drive in the future healthcare of children and adolescents. There is a necessity to tackle the emerging risk factors for NASH-associated hepatocellular carcinoma (HCC). In this narrative review, we present the current protocol of liver biopsy separated between pre-analytical, analytical, and post-analytical handling. Genetic association investigations have identified single nucleotide polymorphisms implicated in the progression of MAFLD-HCC, many of which seem to belong to the lipid metabolism pathways. PNPLA3 rs738409 variant, TM6SF2 rs58542926 variant, MBOAT7 rs641738 variant, and GCKR variants seem to be significantly associated with NAFLD disease susceptibility. In disclosing the current comprehensive protocol performed at the Children's Hospital of Eastern Ontario, Ottawa, ON, Canada, we support the most recent Kulkarni-Sarin's pledge to rename NAFLD to MAFLD. Grossing of the liver biopsy is key to identifying histologic, immunophenotypical, and ultrastructure data and properly preserving tissue for molecular genomics data.

Handling a biopsy with fatty liver disease Fatty liver disease is increasing worldwide. There is a necessity to tackle the emerging risk factors for the development of liver cancer following years of fatty liver disease. In this paper, we show our protocol at the Children's Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada.

Investigating the Role of Non-Coding RNA in Non-Alcoholic Fatty Liver Disease.

Non-coding RNAs (ncRNAs) are RNA molecules that do not code for protein but play key roles in regulating cellular processes. NcRNAs globally affect gene expression in diverse physiological and pathological contexts. Functionally important ncRNAs act in chromatin modifications, in mRNA stabilization and translation, and in regulation of various signaling pathways. Non-alcoholic fatty liver disease (NAFLD) is a set of conditions caused by the accumulation of triacylglycerol in the liver. Studies of ncRNA in NAFLD are limited but have demonstrated that ncRNAs play a critical role in the pathogenesis of NAFLD. In this review, we summarize NAFLD's pathogenesis and clinical features, discuss current treatment options, and review the involvement of ncRNAs as regulatory molecules in NAFLD and its progression to non-alcoholic steatohepatitis (NASH). In addition, we highlight signaling pathways dysregulated in NAFLD and review their crosstalk with ncRNAs. Having a thorough understanding of the disease process's molecular mechanisms will facilitate development of highly effective diagnostic and therapeutic treatments. Such insights can also inform preventive strategies to minimize the disease's future development.

Carney complex: A clinicopathologic study on a single family from several Canadian provinces.

Carney syndrome is an autosomal dominant complex involving endocrinopathy, mucocutaneous hyperpigmentation, and different tumors, including cardiac myxomas. We report on a single family with several members affected with Carney syndrome. Family and individual medical histories were investigated in several Canadian provinces. The histology slides were also reviewed. Four family members (two young women, both sisters, their mother, and maternal grandmother) were found to harbor Carney syndrome. Everyone was presented with multiple and recurrent atrial myxomas of the heart, requiring multiple open cardiac surgeries. Breast myxomas and cutaneous hyperpigmentation were also revealed in one of the sisters and their mother. Interestingly, genetic testing was positive for the female family members and negative for the father and brother. We cannot rule out that the brother may have had a new mutation or harboring a mosaic. The young woman's brother did not have cardiac myxoma but developed a unilateral Sertoli cell tumor of testis. Carney syndrome is a rare complex multisystemic genetic disorder, including multiple and recurrent cardiac myxomas. We strongly suggest that reporting familial Carney syndrome is still critical in the 21st century to augment the awareness of this situation among clinicians and pathologists.

MASLD and aspartame: are new studies in the horizon?

Fatty liver disease has been on the rise in the past few decades, and there is no hope that it will stop. The terminology change that has been recently proposed may not be sufficient to advocate for a reduction of steatogenic foods and a change in lifestyle. A course change may be supported by the recent labeling of aspartame sweetener as a possible carcinogenic compound by the International Association for Research on Cancer (IARC), an agency of the World Health Organization (WHO). Aspartame sweeteners and other edulcorating molecular compounds besides colorings may trigger liver cancer other than fatty liver disease, despite limited data supporting it. An essential bias in human cohort studies is indeed the exclusion of all confounding factors, which may be barely impossible for human studies. In this perspective, we suggest that the activation of the NOD-like receptor-enclosing protein 3 (NLRP3) inflammasome and the stimulation of the tumor suppression gene TP53 may be critical in the progression from fatty liver to liver inflammation and liver cancer. Aspartame reduces a transcriptional coactivator, precisely the peroxisomal proliferator-initiated receptor-γ (gamma) coactivator 1-α (alpha) (or PGC1α). This coactivator upregulates mitochondrial bioformation, oxidative phosphorylation, respiratory capacity, and fatty acid ß-oxidation. Aspartame acts in this way, probably through the activation of TP53. These events have been accountable for the variations in the lipid outline in serum and total lipid storage as well as for the impairment of gluconeogenesis in the liver, as supported by the downregulation of the gluconeogenic enzymes in experimental animals, and may be relevant in humans as well.

Analysis of risk factors for community-acquired Clostridioides difficile diarrhea in children: a case-control study in Chenzhou, China.

Background: Most previous studies on Clostridium difficile infection (CDI) mainly focused on adults with underlying diseases or critical illnesses. However, the number of CDI cases in children has also significantly increased, especially the growth of community-acquired CDI, which has attracted attention. This study was conducted to examine the toxin gene characteristics and the risk factors associated with community-acquired CDI (CA-CDI) in children with diarrhea. Methods: Children with diarrhea before admission or within 48 hours of hospitalization were included in the study. Stool samples were collected from children with community-acquired diarrhea who were treated at the Children's Hospital of the First People's Hospital of Chenzhou, China from June of 2021 to June of 2022. Fluorescence real-time polymerase chain reaction was utilized to detect Clostridioides difficile (CD) toxins A (tcdA) and B (tcdB) genes as well as binary toxin gene A (cdtA) and B (cdtB) in the specimens cultured for CD. Each child with CA-CDI was matched with four control children of the same sex, age, and place of residence. Necessary clinical data were extracted from the hospital's electronic medical record system. Then, a multivariate conditional logistic regression analysis was applied to identify potential risk factors for CA-CDI. Results: Sixteen (8.3%) of the 193 stool specimens who tested positive for CD were selected for the case group, and their matching 64 control patients were in the study cohort. The breakdown of the CD genotypes of the 16 positive cases were follows: 14 (tcdA+ and tcdB+) (7.25%) and 2 (tcdA+ and tcdB-) (1.04%). The cdtA and cdtB binary toxin genes were negative in all. The results of multivariate conditional logistic regression analysis identified antibiotic use within the previous month [odds ratio (OR) =5.13; 95% confidence interval (CI): 1.65-15.91] and non-breastfeeding (OR =4.89; 95% CI: 1.11-21.53) as independent risk factors for CDI in pediatric patients experiencing community-acquired diarrhea. Conclusions: Children who had been treated with antibiotics and not breastfed were more susceptible to CDI. Therefore, in order to prevent and to control the spread of CD infection, being prudent to the aforementioned high-risk factors is strongly advocated in clinical practice.

Stillbirth Investigations: An Iconographic and Concise Diagnostic Workup in Perinatal Pathology.

Introduction Stillbirth is a dramatic event for the parents, health care team, and anyone close to the expectant parents. Multidisciplinary team (MDT) meetings are essential to improve communication in health care. We review the most frequent findings discussed at MDT meetings. Methods A PubMed search was conducted through December 2021 since the inception (1965) using clinical queries with the key terms "stillbirth" AND "investigation" AND "pathology" AND "human." The search strategy included reviews, meta-analyses, randomized controlled trials, clinical trials, and observational studies. This systematic review is based on, but not limited to, the search results. It is the experience of more than 30 years of pediatrics, obstetrics, and pathology staff. Results Two hundred and six articles were screened and complemented through the perusal of congressional activities and personal communications. Pathological findings following perinatal death can be divided into macroscopic, histologic, and placental findings. The placenta is crucial in fetal medicine and is key in determining the cause of stillbirth in a substantial number of events. Perinatal lung disease is essential to evaluate the response of newborns to extrauterine life and address newborns' outcomes appropriately. Conclusions Stillbirth remains one of the less explored areas of medicine, and we can determine the cause in a limited number of cases. Nevertheless, placental pathology is critical in the etiology discovery pathway. Accurate investigations and discussion of photography-supported findings are vital in promoting communication at MDT meetings.

Congenital segmental dilatation of the intestine: an in-depth review.

OBJECTIVE: Congenital segmental dilatation of the intestine (CSDI) is a rare gastrointestinal condition. We conducted a scoping review through MEDLINE and Google Scholar, collecting data from 1959 through August 2020 to better understand this peculiar disease. METHODS: The clinical and pathological features of 150 patients were reviewed. RESULTS: The mean age was 25.9 days, and 61.3% of patients were male. An antenatal diagnosis was made in 15.3% of patients. Predominant symptoms included abdominal distension (83.9%) and vomiting (61.3%). Pallor and anemia were associated with ileal CSDI. The most common sites of the lesion were the ileum (56%) and colon (27.3%). Associated anomalies occurred in 57.3% of the patients, of which the most common included other abnormalities of the digestive system (69.8%), abdominal wall (19.8%), and cardiovascular system (11.6%). Resection and anastomosis was performed in 83.3% of patients. Postoperative complications occurred in 10%. Normal ganglion cells were commonly found (97.3%), while muscle layer hypertrophy and atrophy were found in 14.7% and 13.3% of the patients, respectively. Abnormal interstitial cells of Cajal were identified in four patients. Death occurred in 12.7% of patients. Demise was significantly associated with the duodenal location of CSDI (Mantel-Cox test, p = 0.002). CONCLUSION: CSDI remains poorly understood, and mortality is associated chiefly with its duodenal location. Further research is needed, and biorepositories should be promptly set up to study this disease in the future better.

What is currently known about the topic? CSDI is a sporadic condition, which can represent a challenge for neonatologists.What new information is contained in this article? Pallor and anemia are found explicitly in ileal CSD, and the duodenal location of CSDI is associated with the highest mortality rate.

COVID-19 vaccination-related autoimmune hepatitis-a perspective.

Autoimmune hepatitis (AIH) is the inflammation of the liver with clear-cut interface hepatitis and piecemeal necrosis located at the boundary between portal areas and periportal hepatocytes, and characterized by autoimmunity to hepatocytes with an increase in the antinuclear antibody. After the disastrous SARS-CoV-2 pandemic flagellated several countries, several vaccines have been commercialized and have become a ground for social responsibility. The mRNA vaccines, issued by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273), do not use prebuilt viruses to supply the antigen in the subject's body and are not perfect but have been useful in tackling the pandemic. Nevertheless, both myocarditis and AIH have been reported as side effects of the vaccination programs in addition to thromboembolic events. Here, we explore this topic and give a data-based perspective, gathering a comparison between the titin protein of the sarcomere and myocarditis. The isolation of a Drosophila gene using the serum from a patient with autoimmune scleroderma recognized an epitope on chromosomes (condensed mitotic form) in both human cultured cells and early Drosophila embryos. It revealed that this gene encodes a Drosophila homolog of the vertebrate titin (D-Titin). Moreover, anti-titin antibodies have been found in a subset of patients with myasthenia gravis, a neuromuscular junction disease that is mostly associated with autoimmune antibodies, such as the anti-acetylcholine receptor antibody. The co-existence of myasthenia gravis and autoimmune hepatitis is rare, and a cohort of patients with myasthenia gravis anti-titin antibodies seems to be highly relevant. In consideration of these data and the number of patients who may not be symptomatic, we postulated that autoimmune phenomena may not be exceedingly rare, following the administration of mRNA technology-based vaccines, and a balance between pros and cons in administrating boosters is critical.

LipidR - a Commentary on a Lipidomics Software Platform Useful for Potential Liquid Biopsies Data Analysis.

LipidR is a recent software platform that uses R. This commentary briefly reviews the data published in the literature using this new tool for data mining and analyzing lipidomics datasets. This software is maintained by the R Foundation specifically for Statistical Computing. The R language is widely used among statisticians and data miners for developing statistical software and data analysis. LipidR is a novel open-source R package with enormous functionalities. LipidR filled three significant gaps in lipidomics. First, LipidR has the potential to mine public lipidomics datasets more efficiently and effectively. Second, the deconstructing function of the lipid name is unique to LipidR. Third, the adjustment for confounding factors, which is required for complex clinical lipidomic profiles, is implemented in LipidR. We expect LipidR will be crucial in analyzing lipidomic profiles of liquid biopsies in the near future.

Computer-assisted diagnostics.

Healthcare is at the edge of a profound renovation or collapse due to the rapid inflow of machine learning protocols and procedures able to optimize several processes. Clinical trials are key for the progress of science and the correct interpretation of data. Rickard et al., in this journal, report that data on misidentification rates in medical trials are scarce. In five trials involving more than 800 blood or histology specimens examined, data clarification forms (DCFs) were issued for 21% of instances, and 67% were related to sample identification. The authors suggest that a suitable number of de- recognized data points is critical. Moreover, a formalized process involving the specimen accession employed in routine care is key to mitigate recognition errors and their potential profound impact on clinical research and outcome. We fully agree with the authors and their report is highly relevant today that we face transformation in healthcare. We suggest that 3D barcoding may mitigate several issues on misidentification.

Pediatric Hepatic Angiosarcoma (PHAS) and Vinyl Chloride-A Ghost of the Past May Loom over East Palestine, OH, and beyond: A Critical Commentary.

Road accidents are not infrequent everywhere in the world, but when they involve poisonous and dangerous chemical compounds, they represent a hazard and an issue for public health. In this commentary, we briefly review a recent East Palestine event and one of the chemicals primarily involved with a predisposition to initiate a carcinogenetic process. The author reviewed, as a consultant, numerous chemical compounds for the International Agency for Research on Cancer, a trusted agency of the World Health Organization. Something is looming over the territories of East Palestine, Ohio, United States, draining water from the soil. We speculate that there is a dark and opprobrious fate for this area of the United States due to the potential increase in cases of pediatric hepatic angiosarcoma, which will also be revised in this commentary.

Pediatric Echinococcosis of the Liver in Austria: Clinical and Therapeutical Considerations.

Echinococcosis is considered a neglected disease in most European countries. However, migratory flows of populations, long-term stays in endemic areas, uninterrupted tourism (travel to Echinococcus-endemic countries), traveling dogs and dog translocations from endemic areas, and inappropriate hygiene practices are potential factors that alarm public health officials. Identifying a cyst-like mass in the liver or lung of an individual with a travel history of likely exposure to sheepdogs in an area where the parasite Echinococcus (E.) granulosus (sive cysticus) is endemic advocates for a prompt preliminary diagnosis of cystic echinococcosis (CE), no matter the age of the affected individuals. Routine imaging techniques, including ultrasonography, computed tomography (CT) scans, and magnetic resonance imaging (MRI) scans, are used to detect cysts. After a cyst has been discovered, serologic investigations are used to confirm the diagnosis. Typically, alveolar echinococcosis (AE) is found in older individuals. Yet young people are also affected because frequent oral exploration of the environment is a regular behavior for infants and toddlers. In this review, therapeutic considerations for pediatric echinococcosis-drug-based benzimidazole therapy; AE: atypical liver resection, the resection of individual or multiple segments, a right or left hemi-hepatectomy, or an extended hemi-hepatectomy; CE: PAIR-technique, cyst excision, liver segment(s) resection (laparoscopically or conventionally)-are revised following experience in one of the most affected regions of Europe. In addition, we performed a systematic review using three databases (i.e., PubMed, EMBASE, and Scopus) to evaluate the quality of evidence in published studies on pediatric echinococcosis.

Over supplementation with vitamin B12 alters microbe-host interactions in the gut leading to accelerated Citrobacter rodentium colonization and pathogenesis in mice.

BACKGROUND: Vitamin B12 supplements typically contain doses that far exceed the recommended daily amount, and high exposures are generally considered safe. Competitive and syntrophic interactions for B12 exist between microbes in the gut. Yet, to what extent excessive levels contribute to the activities of the gut microbiota remains unclear. The objective of this study was to evaluate the effect of B12 on microbial ecology using a B12 supplemented mouse model with Citrobacter rodentium, a mouse-specific pathogen. Mice were fed a standard chow diet and received either water or water supplemented with B12 (cyanocobalamin: ~120 µg/day), which equates to approximately 25 mg in humans. Infection severity was determined by body weight, pathogen load, and histopathologic scoring. Host biomarkers of inflammation were assessed in the colon before and after the pathogen challenge. RESULTS: Cyanocobalamin supplementation enhanced pathogen colonization at day 1 (P < 0.05) and day 3 (P < 0.01) postinfection. The impact of B12 on gut microbial communities, although minor, was distinct and attributed to the changes in the Lachnospiraceae populations and reduced alpha diversity. Cyanocobalamin treatment disrupted the activity of the low-abundance community members of the gut microbiota. It enhanced the amount of interleukin-12 p40 subunit protein (IL12/23p40; P < 0.001) and interleukin-17a (IL-17A; P < 0.05) in the colon of naïve mice. This immune phenotype was microbe dependent, and the response varied based on the baseline microbiota. The cecal metatranscriptome revealed that excessive cyanocobalamin decreased the expression of glucose utilizing genes by C. rodentium, a metabolic attribute previously associated with pathogen virulence. CONCLUSIONS: Oral vitamin B12 supplementation promoted C. rodentium colonization in mice by altering the activities of the Lachnospiraceae populations in the gut. A lower abundance of select Lachnospiraceae species correlated to higher p40 subunit levels, while the detection of Parasutterella exacerbated inflammatory markers in the colon of naïve mice. The B12-induced change in gut ecology enhanced the ability of C. rodentium colonization by impacting key microbe-host interactions that help with pathogen exclusion. This research provides insight into how B12 impacts the gut microbiota and highlights potential consequences of disrupting microbial B12 competition/sharing through over-supplementation. Video Abstract.