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Androgen deprivation therapy (ADT) has been the cornerstone of prostate cancer treatment. ADT delays cancer progression, alleviates cancer-related symptoms, and is associated with survival gains. Despite these established benefits, the extended duration of therapy comes with known side effects. Furthermore, research from the past decade has generated increased awareness for more potentially lethal cardiometabolic consequences of ADT. In this review, we explore the relationship between ADT and cardiometabolic effects. Current literature on this complex relationship remains conflicting, due to a variety of factors, including study design (randomized vs. observational), treatment decision-making, and patient factors. Looking to the future, a combination of well-designed, randomized controlled trials and high-quality, real-world evidence are needed to definitely establish any ADT cardiovascular safety signal and to evaluate the efficacy of potential screening and therapeutic interventions. Furthermore, a collaborative, integrated approach among all health care professionals is critical to accurately delineate patients' potential risk/benefit treatment options.

The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III-IV acute GVHD (but not grade I-II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient's ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant. Approximately 60% of nondiabetic patients experience hyperglycemia in the immediate post-transplant phase. Multiple risk factors have been identified related to development of new onset diabetes after transplant, and it is estimated that upward of 7%-30% of patients will develop new onset diabetes within the first year post-transplant. There are a number of medications studied in the kidney transplant population for diabetes management, and recent data and the risks and benefits of each regimen should be optimized. Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in parathyroid hormone levels. Parathyroidectomy and medical management are the options for treatment of secondary hyperparathyroidism, but there is no randomized, controlled trial providing clear recommendations for optimal management, and patient-specific factors should be considered. Obesity is the most common metabolic disorder affecting the transplant population in both the pre- and post-transplant phases of care. Not only does obesity have associations and interactions with comorbid illnesses, such as diabetes, dyslipidemia, and cardiovascular disease, all of which increase morbidity and mortality post-transplant, but it also is intimately inter-related with access to transplantation for patients with kidney failure. We review these metabolic disorders and their management, including data in patients with kidney transplants., (Copyright © 2020 by the American Society of Nephrology.)

Anchorage of a subset of cell surface proteins in eukaryotic cells is mediated by a glycosylphosphatidylinositol (GPI) moiety covalently attached to the carboxy-terminus of the protein moiety. Experimental evidence for the potential of GPI-anchored proteins (GPI-AP) of being released from cells into the extracellular environment has been accumulating, which involves either the loss or retention of the GPI anchor. Release of GPI-AP from donor cells may occur spontaneously or in response to endogenous or environmental signals. The experimental evidence for direct insertion of exogenous GPI-AP equipped with the complete anchor structure into the outer plasma membrane bilayer leaflets of acceptor cells is reviewed as well as the potential underlying molecular mechanisms. Furthermore, promiscuous transfer of certain GPI-AP between plasma membranes of different cells in vivo under certain (patho)physiological conditions has been reported. Engineering of target cell surfaces using chimeric GPI-AP with complete GPI anchor may be useful for therapeutic applications.

Objectives: Data on the relationship between tracheotomy and ventilator-associated pneumonia (VAP) in children is very limited. We planned to evaluate the effect of tracheotomy on VAP rates in children., Materials and Methods: We evaluated patients who underwent tracheotomy during follow-up at the pediatric intensive care unit (PICU) of our hospital. Patients who were diagnosed as VAP at least once and followed by a mechanical ventilation (MV) for at least 30 days before and after tracheotomy were included in our study. The underlying diagnoses of the patients and the number of VAP diagnosis, VAP rates (VAP number x1000/day of MV) before and after tracheotomy were recorded. Logistic regression analysis was used to compare VAP rates before and following a tracheotomy., Results: There were a total of 47 patients including 28 (59.6%) girls and 19 (40.4%) boys in our study. The duration of MV before tracheotomy was 74.9 ± 48.9 (31-295) days and after tracheotomy, it was 103.3 ± 102.8 (30-586) days. The number of VAP before tracheotomy was 0.9 ± 1.2 (0-8) and after tracheotomy, it was 0.6 ± 0.6 (0-3). The VAP rate before tracheotomy was 5.9 ± 6.3 (0-26.5) and the VAP rate after tracheotomy was 3.2 ± 3.8 (0-11.4). Ventilator-associated pneumonia rates were lower following tracheotomy (OR:0.91,95%CI:0.826-0.981,p = 0.017)., Conclusion: Tracheotomy decreased the VAP rate in children receiving long-term mechanical ventilatory support., Competing Interests: Declaration of competing interest None (All authors confirm that)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The burden imposed by cardiometabolic diseases remains a principal health care system concern. Integration of mobile health (mHealth) interventions is helpful for telemonitoring of these patients, which enables patients to be more active and take part in their treatment, while being more conscious and gaining more control over the outcomes. However, little is known about the degree to which users engage, and the extent to which this interaction matches the usage pattern for which mHealth interventions were designed., Objective: The aim of this study was to describe the characteristics and results of studies on mHealth solutions that measured the effects of interventions with patient engagement in the context of chronic cardiometabolic diseases., Methods: A critical review of systematic reviews was conducted to recover data on interventions focused on the engagement of patients with chronic cardiometabolic diseases using mHealth technologies. Articles (from January 1, 2010) were searched in the Medlars Online International Literature Medline (Medline/Pubmed), Embase, Cochrane Library, PsycINFO, and Scielo databases. Only studies that quantified a measure of engagement by patients with cardiometabolic disease were included for analysis. The Critical Appraisal Skills Programme (CASP) was used to determine included studies considering the quality of the data provided. The Scottish Intercollegiate Guidelines Network (SIGN) checklist was used to assess the quality of the evidence according to the methodology used in the studies reviewed. Engagement was defined as the level of patient implication or participation in self-care interventions. Engagement measures included number of logs to the website or platform, frequency of usage, number of messages exchanged, and number of tasks completed., Results: Initially, 638 papers were retrieved after applying the inclusion and exclusion criteria. Finally, only three systematic reviews measuring engagement were included in the analysis. No reviews applying a meta-analysis approach were found. The three review articles described the results of 10 clinical trials and feasibility studies that quantified engagement and met the inclusion criteria assessed through CASP. The sample size varied between 6 and 270 individuals, who were predominantly men. Cardiac disease was the principal target in the comparison of traditional and mHealth interventions for engagement improvement. The level of patient engagement with mHealth technologies varied between 50% and 97%, and technologies incorporating smartphones with a reminder function resulted in the highest level of engagement., Conclusions: mHealth interventions are an effective solution for improving engagement of patients with chronic cardiometabolic diseases. However, there is a need for advanced analysis and higher-quality studies focused on long-term engagement with specific interventions. The use of smartphones with a single app that includes a reminder function appears to result in better improvement in active participation, leading to higher engagement among patients with cardiometabolic diseases., (©Kamila J Cheikh-Moussa, Jose Joaquin Mira, Domingo Orozco-Beltran. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 08.04.2020.)

Mesenchymal stromal cells (MSC) have become a popular treatment modality in equine orthopaedics. Regenerative therapies are especially interesting for pathologies like complicated tendinopathies of the distal limb, osteoarthritis, osteochondritis dissecans (OCD) and more recently metabolic disorders. Main sources for MSC harvesting in the horse are bone marrow, adipose tissue and umbilical cord blood. While the acquisition of umbilical cord blood is fairly easy and non-invasive, extraction of bone marrow and adipose tissue requires more invasive techniques. Characterization of the stem cells as a result of any isolation method, is also a crucial step for the confirmation of the cells' stemness properties; thus, three main characteristics must be fulfilled by these cells, namely: adherence, expression of a series of well-defined differentiation clusters as well as pluripotency. EVs, resulting from the paracrine action of MSCs, also play a key role in the therapeutic mechanisms mediated by stem cells; MSC-EVs are thus largely implicated in the regulation of proliferation, maturation, polarization and migration of various target cells. Evidence that EVs alone represent a complex network 0involving different soluble factors and could then reflect biophysical characteristics of parent cells has fuelled the importance of developing highly specific techniques for their isolation and analysis. All these aspects related to the functional and technical understanding of MSCs will be discussed and summarized in this review.

It is well demonstrated that physical activity can improve the control of diseases such as diabetes, or dyslipidemia. Introduction of regular and frequent physical activity is also part of the useful measures in the management of excess weight. It is therefore surprising that the prescription of physical activity for the treatment of these diseases is still not part of the curriculum of medical studies, and that reimbursement remains very scarce. This article summarizes the state of scientific knowledge in the field and outlines their clinical application., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The gut microbiota that inhabit our gastrointestinal tract are well known to play an important role in maintaining human health in many aspects, including facilitating the digestion and absorption of nutrients, protecting against pathogens and regulating immune system. Gut microbiota dysbiosis is associated with a lot of diseases, such as inflammatory bowel disease, allergy, obesity, cardiovascular and neurodegenerative diseases and cancers. With the increasing knowledge of the microbiome, utilization of probiotic bacteria in modulating gut microbiota to prevent and treat a large number of disorders and diseases has gained much interest. In recent years, aided by the continuous development of tools and techniques, engineering probiotic microbes with desired characteristics and functionalities to benefit human health has made significant progress. In this paper, we summarize the recent advances in design and construction of probiotics as living diagnostics and therapeutics for probing and treating a series of diseases including metabolic disorders, inflammation and pathogenic bacteria infections. We also discuss the current challenges and future perspectives in expanding the application of probiotics for disease treatment and detection. We intend to provide insights and ideas for engineering of probiotics to better serve disease therapy and human health.

Browning of white adipose tissue (WAT) has been recognized as an important strategy for the treatment of obesity, insulin resistance, and diabetes. Enoyl coenzyme A hydratase 1 (ECH1) is a widely known enzyme involved in lipid metabolism. However, whether and how ECH1 is implicated in browning of WAT remain obscure. Adeno-associated, virus-mediated genetic engineering of ECH1 in adipose tissue was used in investigations in mouse models of obesity induced by a high-fat diet (HFD) or browning induced by cold exposure. Metabolic parameters showed that ECH1 overexpression decreased weight gain and improved insulin sensitivity and lipid profile after 8 wk of an HFD. Further work revealed that these changes were associated with enhanced energy expenditure and increased appearance of brown-like adipocytes in inguinal WAT, as verified by a remarkable increase in uncoupling protein 1 and thermogenic gene expression. In vitro, ECH1 induced brown fat-related gene expression in adipocytes differentiated from primary stromal vascular fractions, whereas knockdown of ECH1 reversed this effect. Mechanistically, ECH1 regulated the thermogenic program by inhibiting mammalian target of rapamycin signaling, which may partially explain the potential mechanism for ECH1 regulating adipose browning. In summary, ECH1 may participate in the pathology of obesity by regulating browning of WAT, which probably provides us with a new therapeutic strategy for combating obesity.

Purpose: This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies., Recent Findings: All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren's syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.

The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson's disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1 -deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease., Competing Interests: The authors declare no conflict of interest. B.S. and L.C.P. are members of the EASL Consortium for Regenerative Hepatology.

Although the beneficial effects of probiotics in the prevention or treatment of metabolic disorders have been extensively researched, the precise mechanisms by which probiotics improve metabolic homeostasis are still not clear. Given that probiotics usually exert a comprehensive effect on multiple metabolic disorders, defining a concurrent mechanism underlying the multiple effects is critical to understand the function of probiotics. In this study, we identified the SIRT1-dependent or independent PGC-1α pathways in multiple organs that mediate the protective effects of a strain of Lactobacillus plantarum against high-fat diet-induced adiposity, glucose intolerance, and dyslipidemia. L. plantarum treatment significantly enhanced the expression of SIRT1, PPARα, and PGC-1α in the liver and adipose tissues under HFD-fed condition. L. plantarum treated mice also exhibited significantly increased expressions of genes involved in bile acid synthesis and reverse cholesterol transport in the liver, browning and thermogenesis of adipose tissue, and fatty acid oxidation in the liver and adipose tissue. Additionally, L. plantarum treatment significantly upregulated the expressions of adiponectin in adipose tissue, irisin in skeletal muscle and subcutaneous adipose tissue (SAT), and FGF21 in SAT. These beneficial changes were associated with a significantly improved HFD-induced alteration of gut microbiota. Our findings suggest that the PGC-1α-mediated pathway could be regarded as a potential target in the development of probiotics-based therapies for the prevention and treatment of metabolic disorders., Competing Interests: Hyunchae Joung, Byoung-Kook Kim, and In Suk Choi, who are employees of Chong Kun Dang Bio Research Institute, declare conflict of interest as they have collaborated in gut microbiota analysis and this study was funded by Chong Kun Dang Bio Research Institute. The other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Changes in the global economy resulted in sedentary lifestyle and excessive calorie intake, increasing the incidence of metabolic diseases, which subsequently became a universal public concern. The difficulties of managing chronic diseases did not dampen researchers' enthusiasm for studying new therapeutics or adjuvant treatments. Cordyceps spp. is a kind of traditional Chinese herbal medicine; however, our understanding of this medicine remains at an initial stage. Recently, an increasing number of studies have demonstrated the potential of Cordyceps as a therapeutic agent for the effective treatment of metabolic-related disorders by exerting a variety of activities, including but not limited to anti-inflammatory, immunoregulatory, hypoglycemic, renoprotective and cardiovascular-protective effects. This article reviews the potential efficacy and underlying mechanisms of Cordyceps and its major bioactive ingredients in metabolic syndrome and its associated comorbidities., (© 2019 John Wiley & Sons, Ltd.)

Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer's disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system., Competing Interests: The authors declare no conflict of interest.

Interleukin 17A (IL-17A) is one of the currently known six members of the IL-17 cytokine family and is implicated in immune responses to infectious pathogens and in the pathogenesis of inflammatory autoimmune diseases like psoriasis. Psoriatic skin is characterized by high expression of IL-17A and IL-17F, which act on immune and non-immune cell types and strongly contribute to tissue inflammation. In psoriatic lesions, IL-17A, IL-17E, and IL-17F are involved in neutrophil accumulation, followed by the formation of epidermal micro abscesses. IL-17A together with other Th17 cytokines also upregulates the production of several chemokines that are implicated in psoriasis pathogenesis. IL17A-targeting antibodies show an impressive clinical efficacy in patients with psoriasis. Studies have reported an improvement of at least 75% as measured by the psoriasis area and severity index (PASI) in >80% of patients treated with anti-IL-17A therapy. Psoriasis skin manifestations, cardiovascular as well as metabolic disease in psoriasis appear to share pathogenic mechanisms evolving around IL-17A and its proinflammatory role. Thus, anti-IL-17A therapy not only improves skin manifestations of psoriasis, but also cardiovascular inflammation as well as metabolic factors and different domains of psoriatic arthritis (PsA) including peripheral arthritis, enthesitis, dactylitis, and axial involvement. This review summarizes the biological role of IL-17A, before reviewing currently available data on its role in the physiology and pathophysiology of the skin, as well as the cardiovascular and the metabolic system. In conclusion, clinical recommendations for patients with moderate to severe psoriasis based on the current available data are given., (Copyright © 2020 von Stebut, Boehncke, Ghoreschi, Gori, Kaya, Thaci and Schäffler.)

Background: The liver has a critical role in the metabolism of glucose and lipids. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection leads to a spectrum of liver disease including chronic hepatitis, cirrhosis and hepatocellular carcinoma. Metabolic syndrome (MetS) has a rising incidence owing to an epidemic of type 2 diabetes mellitus (T2DM) and obesity. Non-alcoholic fatty liver disease is a liver manifestation of MetS and has become the most common cause of chronic liver disease worldwide., Aim: To summarise the interplay among hepatitis viruses, MetS and its components., Methods: We searched the literature about HBV, HCV infection, MetS, fatty liver and its components from PubMed., Results: With respect to the viral replication cycle, lipids are important mediators between viral entry and hepatocyte in HCV infection, but not in HBV infection. Thus, HCV infection is inversely associated with hyperlipidaemia and lipid rebound occurs following sustained viral response induced by interferon-based therapy or direct antiviral agents. In addition, HCV infection is positively associated with insulin resistance, hepatic steatosis, MetS and the risk of T2DM and atherosclerosis. In contrast, HBV infection may protect infected subjects from the development of MetS and hepatic steatosis. Accumulating evidence suggests that HBV infection is inversely associated with lipid metabolism, and exhibits no conclusive association with insulin resistance or the risk of T2DM and arteriosclerosis., Conclusions: In patients with viral hepatitis and concurrent metabolic diseases, a multidisciplinary approach should be given rather than simply antiviral treatment., (© 2019 John Wiley & Sons Ltd.)

The article is mainly devoted to such representatives of gut microbiota as lactic acid bacteria and bifidobacteria, with minor accent on less frequently used or new probiotic microorganisms. Positive effects in treatment and prevention of diseases by different microbial groups, their metabolites and mechanisms of action, management and market of probiotic products are considered., (Copyright © 2019 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.

The donkey evolved under harsh and arid environmental conditions, developing unique energy-efficiency traits, with an efficiency to rapidly mobilize fat in situations of increased energy demands or when food is scarce. This evolution has led to an inherent predisposition of donkeys to obesity, dyslipidemias, insulin dysregulation/metabolic syndrome, pituitary pars intermedia dysfunction, and endocrinopathic laminitis. Marked differences have been described in hormone dynamics and testing protocols for the diagnosis of these endocrine and metabolic diseases in donkeys compared with horses, underlining the necessity of a species-specific approach in order to avoid misdiagnosis, unnecessary or inadequate treatments, and additional costs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The large number of monogenic metabolic disorders originating in the liver poses a unique opportunity for development of gene therapy modalities to pursue curative approaches. Various disorders have been successfully treated via liver-directed gene therapy, though most of the advances have been in animal models, with only limited success in clinical trials. Pre-clinical data in animals using non-viral approaches, including the Sleeping Beauty transposon system, are discussed. The various advances with viral vectors for liver-directed gene therapy are also a focus of this review, including retroviral, adenoviral, recombinant adeno-associated viral, and SV40 vectors. Genome editing techniques, including zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats (CRISPR), are also described. Further, the various controversies in the field with regards to somatic vs. germline editing using CRISPR in humans are explored, while also highlighting the myriad of preclinical advances. Lastly, newer technologies are reviewed, including base editing and prime editing, which use CRISPR with exciting adjunctive properties to avoid double-stranded breaks and thus the recruitment of endogenous repair mechanisms. While encouraging results have been achieved recently, there are still significant challenges to overcome prior to the broad use of vector-based and genome editing techniques in the clinical arena. As these technologies mature, the promise of a cure for many disabling inherited metabolic disorders is within reach, and urgently needed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Inborn errors of metabolism (IEM) are rare diseases caused by mutations in genes encoding enzymes or carriers. Qualitative or quantitative protein deficiency induces both an accumulation of precursor metabolites and a lack of products downstream of the blockade. Pregnancy in patients with IEM is a condition likely to promote metabolic decompensation. In this review, we presented liver symptoms described during pregnancy in a context of hepatic IEM. In particular, we detailed clinical and biological abnormalities specifically occurring in tyrosinemia type I, Wilson disease, and main urea cycle defects. In the case of hepatic IEM, depending on the deficit, pregnant women have an increased risk of pre-eclampsia and HELLP syndrome, as well as hyperammonemia. Wilson disease, and principal urea cycle defects. Multidisciplinary consultation is essential for the optimal management of pregnant women with IEM as well as newborns.

Background: Continuous renal replacement therapies (CRRTs) either as continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHD) are used frequently in critically ill children. Many clinical variables and technical issues are known to affect the result. The factors that could be modified to increase the survival of renal replacement are sought. As a contribution, we present the data on 104 patients who underwent CRRT within a 7-year period., Materials and Method: A total of 104 patients admitted between 2009 and 2016 were included in the study. The demographic information, admittance pediatric risk of mortality (PRISM) scores, indication for CRRT, presence of fluid overload, CRRT modality, durations of CRRT, and pediatric intensive care unit (PICU) stay were compared between survivors and nonsurvivors., Results: The overall rate of survival was 51%. Patients with fluid overload had significantly increased rate of death, CRRT duration, and PICU stay. Multiorgan dysfunction syndrome as the indication for CRRT was significantly related to decreased survival when compared to acute renal failure and acute attacks of metabolic diseases. The CRRT modality was not different between survivors and nonsurvivors. Standardized mortality ratio of the group was calculated to be 0.8., Conclusion: The CRRT in critically ill patients is successful in achieving fluid removal and correction of metabolic imbalances caused by organ failures or attacks of inborn errors of metabolism. It has a positive effect on expected mortality in high-risk PICU patients. To affect the outcome, follow-up should be focused on starting therapy in early stages of fluid overload. Prospective studies defining relative importance of risk factors causing mortality can assist in building up guidelines to affect the outcome.

Background: Energy expenditure prediction equations are used to estimate energy intake based on general population measures. However, when using equations to compare with a disease cohort with known metabolic abnormalities, it is important to derive one's own equations based on measurement conditions matching the disease cohort., Objective: We aimed to use newly developed prediction equations based on a healthy pediatric population to describe and predict resting energy expenditure (REE) in a cohort of pediatric patients with thyroid disorders., Methods: Body composition was measured by DXA and REE was assessed by indirect calorimetry in 201 healthy participants. A prediction equation for REE was derived in 100 healthy participants using multiple linear regression and z scores were calculated. The equation was validated in 101 healthy participants. This method was applied to participants with resistance to thyroid hormone (RTH) disorders, due to mutations in either thyroid hormone receptor β or α (β: female n = 17, male n = 9; α: female n = 1, male n = 1), with deviation of REE in patients compared with the healthy population presented by the difference in z scores., Results: The prediction equation for REE = 0.061 * Lean soft tissue (kg) - 0.138 * Sex (0 male, 1 female) + 2.41 (R2 = 0.816). The mean ± SD of the residuals is -0.02 ± 0.44 kJ/min. Mean ± SD REE z scores for RTHβ patients are -0.02 ± 1.26. z Scores of -1.69 and -2.05 were recorded in male (n = 1) and female ( n = 1) RTHα patients., Conclusions: We have described methodology whereby differences in REE between patients with a metabolic disorder and healthy participants can be expressed as a z score. This approach also enables change in REE after a clinical intervention (e.g., thyroxine treatment of RTHα) to be monitored., (Copyright © American Society for Nutrition 2019.)

In recent years, an important secretory role of brown adipose tissue (BAT) has emerged, which is consistent, to some extent, with the earlier recognition of the important secretory role of white fat. The so-called brown adipokines or 'batokines' may play an autocrine role, which may either be positive or negative, in the thermogenic function of brown adipocytes. Additionally, there is a growing recognition of the signalling molecules released by brown adipocytes that target sympathetic nerve endings (such as neuregulin-4 and S100b protein), vascular cells (e.g., bone morphogenetic protein-8b), and immune cells (e.g., C-X-C motif chemokine ligand-14) to promote the tissue remodelling associated with the adaptive BAT recruitment in response to thermogenic stimuli. Moreover, existing indications of an endocrine role of BAT are being confirmed through the release of brown adipokines acting on other distant tissues and organs; a recent example is the recognition that BAT-secreted fibroblast growth factor-21 and myostatin target the heart and skeletal muscle, respectively. The application of proteomics technologies is aiding the identification of new members of the brown adipocyte secretome, such as the extracellular matrix or complement system components. In summary, BAT can no longer be considered a mere producer of heat in response to environment or dietary challenges; it is also an active secretory tissue releasing brown adipokines with a relevant local and systemic action. The identification of the major brown adipokines and their roles is highly important for the discovery of novel candidates useful in formulating intervention strategies for metabolic diseases.

The probiotic Akkermansia muciniphila (A. muciniphila) is an intestinal bacterium that was first identified in human feces in 2004. Its specialization in mucin degradation makes it a key microorganism that maintains intestinal mucosal barrier function. As an unique representative strain of the phylum Verrucomicrobia that can be cultured in vitro, A. muciniphila is much easier to detect by metagenomic analysis of intestinal flora. In the past few years, A. muciniphila has been getting increasing attention for the positive correlation between its intestinal colonization and host homeostatic metabolism. In this review, we summarize the relationship between A. muciniphila and host health and diseases, especially focusing on metabolic diseases and related mechanisms, as well as the natural food and drug-derived substrates affecting its colonization in the host, expecting to provide evidence and clues for the development of drugs targeting A. muciniphila., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Nutritional supplements may improve development of infants born small (preterm or small for gestational age [SGA]) but may increase the risk of later metabolic disease. We conducted a systematic review and meta-analysis to assess the effects of macronutrient supplements for infants born small on later development and metabolism., Methods and Findings: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to April 1, 2019, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and assessed post-discharge outcomes. Co-primary outcomes were cognitive impairment and metabolic risk, evaluated in toddlers (<3 years), childhood (3 to 8 years), and adolescence (9 to 18 years). Two reviewers independently extracted data. Quality was assessed using the Cochrane Risk of Bias tool, and data were pooled using random-effect models. Twenty-one randomised and one quasirandomised trial of variable methodological quality involving 3,680 infants were included. In toddlers born small, supplementation did not alter cognitive impairment (relative risk [RR] 1.00; 95% confidence interval [CI] 0.67 to 1.49; P = 0.99), and there were no differences in cognitive scores (mean difference [MD] 0.57; 95% CI -0.71 to 1.84; P = 0.38) or motor scores (MD 1.16; 95% CI -0.32 to 2.65; P = 0.12) between supplemented and unsupplemented groups. However, fewer supplemented children had motor impairment (RR 0.76; 95% CI 0.62 to 0.94; P = 0.01). In subgroup analyses, supplementation improved cognitive scores in boys (MD 5.60; 95% CI 1.07 to 10.14; P = 0.02), but not girls born small (MD -2.04; 95% CI -7.04 to 2.95; P = 0.42), and did not alter cognitive or motor scores in the subgroup of children born SGA. In childhood, there was no difference in cognitive impairment (RR 0.81; 95% CI 0.26 to 2.57; P = 0.72) or cognitive scores (MD 1.02; 95% CI -1.91 to 3.95; P = 0.50) between supplemented and unsupplemented groups. There were also no differences in blood pressure, triglyceride, and low-density lipoprotein (LDL) concentrations (all P > 0.05). However, supplemented children had lower fasting glucose (mmol/L: MD -0.20; 95% CI -0.34 to -0.06; P = 0.005) and higher high-density lipoprotein (HDL) concentrations (mmol/L: MD 0.11; 95% CI 0.02 to 0.19; P = 0.02). In subgroup analyses, there was no evidence of differences in blood pressure between supplemented and unsupplemented groups in boys or girls born small, or in SGA children. In adolescence, there was no difference between supplemented and unsupplemented groups in blood pressure, triglycerides, LDL and HDL concentrations, fasting blood glucose, insulin resistance, and fasting insulin concentrations (all P > 0.05). Limitations include considerable unexplained heterogeneity, low to very low quality of the evidence, and limited data beyond early childhood., Conclusions: In this systematic review and meta-analysis of randomised trials, we found no evidence that early macronutrient supplementation for infants born small altered later cognitive function, although there was some evidence that supplementation may decrease motor impairment in toddlers. Contrary to the findings from observational studies, evidence from randomised trials suggests that early macronutrient supplementation for infants born small improves some metabolic outcomes in childhood., Prospero Registration: CRD42019127858., Competing Interests: The authors have declared that no competing interests exist.

In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all of these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Indeed, liver-directed gene therapy trials for hemophilia A and B have demonstrated the potential of gene therapy to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. Herein, we review the advances and limitations of gene therapy for such disorders, covering therapeutic strategies based on gene addition and gene editing and the exciting clinical results obtained with the use of ribonucleic acid as therapeutic molecules.

Objective: Obesity induced metabolic dysregulation results in cluster of chronic conditions mainly hyperglycemia, hyperinsulinemia, dyslipidemia, diabetes, cardiovascular complications and insulin resistance. To investigate the effect of i.m. injection of human adipose tissue derived mesenchymal stem cells and its secretome in correcting obesity induced metabolic dysregulation in high fat diet fed obese model of mice and understand its mechanism of action., Subjects: We injected human adipose tissue derived mesenchymal stem cells (ADMSCs) suspension (CS), conditioned medium (CM) and the cell lysate (CL) intramuscularly in high fat diet (HFD)-induced C57BL/6 mice. Metformin was used as a positive control. ADMSCs were traced in vivo for its bio distribution after injection at different time points., Results: ADMSCs-treated mice exhibited remarkable decrease in insulin resistance as quantified by HOMA-IR and triglyceride glucose index with concomitant decrease in oxidized LDL and IL6 as compared with the untreated control. CS injection showed improvement in glucose tolerance and reduction in fatty infiltration in the liver, macrophage infiltration in adipose and hypertrophy of the islets resulting from HFD. Upregulation of miRNA-206, MyoD and increase in protein content of the skeletal muscle in CS-treated mice indicates plausible mechanism of action of ADMSCs treatment in ameliorating IR in HFD mice., Conclusion: Of all the three treatments, CS was found to be the best. ADMSCs were found to have migrated to different organs in order to bring about the correction in dysregulated metabolism induced by obesity. Our results open up a novel treatment modality for possible therapeutic usage in human subjects by employing autologous or allogeneic ADMSCs for the better management of obesity induced metabolic dysregulation.

With few effective treatments available, the global rise of metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, seems unstoppable. Likely caused by an obesogenic environment interacting with genetic susceptibility, the pathophysiology of obesity and metabolic diseases is highly complex and involves crosstalk between many organs and systems, including the brain. The vagus nerve is in a key position to bidirectionally link several peripheral metabolic organs with the brain and is increasingly targeted for neuromodulation therapy to treat metabolic disease. Here, we review the basics of vagal functional anatomy and its implications for vagal neuromodulation therapies. We find that most existing vagal neuromodulation techniques either ignore or misinterpret the rich functional specificity of both vagal efferents and afferents as demonstrated by a large body of literature. This lack of specificity of manipulating vagal fibers is likely the reason for the relatively poor beneficial long-term effects of such therapies. For these therapies to become more effective, rigorous validation of all physiological endpoints and optimization of stimulation parameters as well as electrode placements will be necessary. However, given the large number of function-specific fibers in any vagal branch, genetically guided neuromodulation techniques are more likely to succeed., (© 2019 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of The New York Academy of Sciences.)

Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.

Purpose: In this review, we summarize current evidence on the gut microbiome and microbial metabolites in relation to obesity and obesity-associated metabolic disorders. Special emphasis is given on mechanisms interconnecting gut microbiome and microbial metabolites with metabolic disorders as well as on potential preventive and therapeutic perspectives with a "bench to bedside" approach., Recent Findings: Recent data have highlighted the role of gut dysbiosis in the etiology and pathogenesis of metabolic disorders, including obesity, metabolic syndrome, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Overall, most studies have demonstrated a reduction in gut microbiome diversity and richness in obese subjects, but there is still much debate on the exact microbial signature of a healthy or an obese gut microbiome. Despite the controversial role of an altered gut microbiome as a cause or consequence of obesity in human studies, numerous animal studies and certain human studies suggest beneficial metabolic effects of certain microbial intestinal metabolites, such as butyrate, that could be used in the prevention and treatment of obesity and its comorbidities. More randomized controlled trials and larger prospective studies including well-defined cohorts as well as a multi-omics approach are warranted to better identify the associations between the gut microbiome, microbial metabolites, and obesity and its metabolic complications.

Purpose of Review: Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism includes intrinsic and extrinsic pathways and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism., Recent Findings: Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism. We highlight important questions for future basic research that will help improve translational research and provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.

Dyslipidemia is a global health problem and a high risk factor for atherosclerosis, which can lead to serious cardiovascular disease (CVD). Existing studies have shown inconsistent effects of turmeric and curcuminoids on blood lipids in adults. We performed this systematic review and meta-analysis to evaluate the effects of turmeric and curcuminoids on blood triglycerides (TG), total cholesterol (TC), LDL cholesterol, and HDL cholesterol. We searched the English databases of the Web of Science, PubMed, Ovid (including EMBASE and MEDLINE), Scopus, and the Cochrane Library and 2 Chinese databases, Wanfang Data and China National Knowledge Infrastructure, for randomized controlled trials (RCTs) that studied the effects of turmeric and curcuminoids on blood TG, TC, LDL cholesterol, and HDL cholesterol in subjects with metabolic diseases. With random-effects models, separate meta-analyses were conducted by using inverse-variance. The results are presented as the mean difference with 95% CIs. Evidence from 12 RCTs for TG, 14 RCTs for TC, 13 RCTs for LDL cholesterol, and 16 RCTs for HDL cholesterol showed that turmeric and curcuminoids could lower blood TG by -19.1 mg/dL (95% CI: -31.7, -6.46 mg/dL; P = 0.003), TC by -11.4 mg/dL (95% CI: -17.1, -5.74 mg/dL; P < 0.0001), and LDL cholesterol by -9.83 mg/dL (95% CI: -15.9, -3.74 mg/dL; P = 0.002), and increase HDL cholesterol by 1.9 mg/dL (95% CI: 0.31, 3.49 mg/dL; P = 0.02). In conclusion, turmeric and curcuminoids can significantly modulate blood lipids in adults with metabolic diseases. However, these findings should be interpreted cautiously because of the significant heterogeneity between included studies (I2 > 50%). There is a need for further RCTs in future., (Copyright © American Society for Nutrition 2019.)

Background: People with mental illness are at an increased risk for developing cardio-metabolic disorders. Routine screening following pharmacotherapy is however unacceptably low in sub-Saharan African countries with less than 1% adequately screened. It is unknown whether this is due to a lack of adequate competences., Objectives: The aim of this pilot study was to assess the barriers, attitudes, confidence, and knowledge of nurses regarding metabolic health, prevention and treatment in Uganda., Methods: Twenty-eight nurses (39% female, 30.9±6.9 years) completed the Metabolic - Barriers, Confidence, Attitudes and Knowledge Questionnaire and the physical activity prescription rate item of the Exercise in Mental Illness Questionnaire., Results: More than 75% had a positive attitude towards metabolic screening and intervention and more than 50% were confident in providing smoking cessation advice, and physical activity and nutritional counseling. However, 57% stated that their heavy workload prevented them from doing health screening and promotion activities. There was a negative correlation (ρ=-0.54, P=0.003) between the frequency of physical activity prescription and the perception of the inability of patients to change., Conclusion: The present findings suggest that nurses are generally supportive of metabolic health screening and intervention but their high workload prevents them from implementing metabolic health interventions., (© 2019 Vancampfort et al.)

Background: The prevalence of obesity and metabolic diseases continues to rise globally. The increased consumption of unhealthy energy-rich diets that are high in fat and sugars results in oxidative stress and inflammation leading to hypothalamic dysfunction, which has been linked with these diseases. Conversely, diets rich in polyphenols, which are phytochemicals known for their antioxidant and anti-inflammatory properties, are associated with a reduced risk for developing metabolic diseases., Scope of Review: This review provides an overview of the effects of polyphenols against diet-induced hypothalamic dysfunction with respect to neural inflammation and mitochondrial dysfunction. Results show that polyphenols ameliorate oxidative stress and inflammation within the hypothalamus, thereby improving leptin signaling and mitochondrial biogenesis. Furthermore, they protect against neurodegeneration by decreasing the production of reactive oxygen species and enhancing natural antioxidant defense systems., Major Conclusions: The potential of polyphenols as nutraceuticals against hypothalamic inflammation, mitochondrial dysfunction, and neurodegeneration could hold tremendous value. With hypothalamic inflammation increasing naturally with age, the potential to modulate these processes in order to extend longevity is exciting and warrants exploration. The continued escalation of mental health disorders, which are characterized by heightened neuronal inflammation, necessitates the furthered investigation into polyphenol therapeutic usage in this regard., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: Patient portals are online electronic medical record applications that allow patients greater control of their own health and encourage meaningful interaction with their healthcare providers. The uptake of this technology is commonplace throughout developed healthcare economies and is on the Northern Ireland Electronic Healthcare Record (NIECR) roadmap., Aim: To assess patients' perceptions and proposed provision of a patient portal in endocrinology outpatients., Methods: Patients (n=75) attending three endocrinology outpatient clinics were eligible to participate. After discussion at clinic, invited patients were contacted via e-mail to complete a confidential and anonymised online survey. There were a total of 23 questions in the survey which included a mix of free text and categorical responses. The survey duration was conducted over a 6-month period., Results: The survey response rate was 51/75 (68%), M33:F18. 46/51 (90%) had access to smart phones, 45/51 (88%) used the internet daily. 31/51 (60%) of respondents were aged between 18-45, 20/51 (40%) were aged ≥ 45 years. 50/51 (98%) reported they would use the technology if available. 47/51 (92%) felt engaging with a patient portal would enhance communication with their doctor and improve understanding of their medical issues. Reported perceived applications of use included; remote access and advice for test results and medical questions, arranging appointments, requesting prescriptions and health promotion. 90% of respondents said they would be content to access results even if abnormal. Possible barriers to adoption of this technology included data protection and understanding medical terminology., Conclusions: The overall response to the provision of this technology was positive, although concerns regarding data protection remain prevalent. Perceived benefits included enhanced doctor-patient communication, optimizing workflow and improving patient engagement., Competing Interests: Provenance: externally peer reviewed, (Copyright © 2019 Ulster Medical Society.)

Maternal cardiometabolic disorders, such as gestational diabetes mellitus, pre-eclampsia, obesity, and dyslipidemia, are the most common conditions that predispose offspring to risk for future cardiometabolic diseases, needing appropriate therapeutic approach. The implications of microbiota in the pathophysiology of maternal cardiometabolic disorders are progressively emerging and probiotics may be a simple and safe therapeutic strategy for maternal cardiometabolic management. In this review, we argue the importance of cardiometabolic dysfunction during pregnancy and/or lactation on the offspring risk for cardiometabolic disease in later life. In addition, we comprehensively discuss the microbial diversity observed in maternal cardiometabolic disorders and we present the main findings on probiotic intervention as a potential strategy for management of maternal cardiometabolic disorders. Current data reveal that gut microbiota may be transmitted from mother to offspring. Whether targeting microbiota with probiotic intervention during the periconceptional period prevents or delays the onset of cardiometabolic disorders in adult offspring should be tested in future clinical trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The health-promoting effects of physical activity to prevent and treat metabolic disorders are numerous. However, the underlying molecular mechanisms are not yet completely deciphered. In recent years, studies have referred to the liver as an endocrine organ, since it releases specific proteins called hepatokines. Some of these hepatokines are involved in whole body metabolic homeostasis and are theorized to participate in the development of metabolic disease. In this regard, the present review describes the role of Fibroblast Growth Factor 21, Fetuin-A, Angiopoietin-like protein 4, and Follistatin in metabolic disease and their production in response to acute exercise. Also, we discuss the potential role of hepatokines in mediating the beneficial effects of regular exercise and the future challenges to the discovery of new exercise-induced hepatokines.

Synthetic biology builds programmed biological systems for a wide range of purposes such as improving human health, remedying the environment, and boosting the production of valuable chemical substances. In recent years, the rapid development of synthetic biology has enabled synthetic bacterium-based diagnoses and therapeutics superior to traditional methodologies by engaging bacterial sensing of and response to environmental signals inherent in these complex biological systems. Biosynthetic systems have opened a new avenue of disease diagnosis and treatment. In this review, we introduce designed synthetic bacterial systems acting as living therapeutics in the diagnosis and treatment of several diseases. We also discuss the safety and robustness of genetically modified synthetic bacteria inside the human body.

Non-integrative AAV-mediated gene therapy in the liver is effective in adult patients, but faces limitations in pediatric settings due to episomal DNA loss during hepatocyte proliferation. Gene targeting is a promising approach by permanently modifying the genome. We previously rescued neonatal lethality in Crigler-Najjar mice by inserting a promoterless human uridine glucuronosyl transferase A1 (UGT1A1) cDNA in exon 14 of the albumin gene, without the use of nucleases. To increase recombination rate and therapeutic efficacy, here we used CRISPR/SaCas9. Neonatal mice were transduced with two AAVs: one expressing the SaCas9 and sgRNA, and one containing a promoterless cDNA flanked by albumin homology regions. Targeting efficiency increased ~26-fold with an eGFP reporter cDNA, reaching up to 24% of eGFP-positive hepatocytes. Next, we fully corrected the diseased phenotype of Crigler-Najjar mice by targeting the hUGT1A1 cDNA. Treated mice had normal plasma bilirubin up to 10 months after administration, hUGT1A1 protein levels were ~6-fold higher than in WT liver, with a 90-fold increase in recombination rate. Liver histology, inflammatory markers, and plasma albumin were normal in treated mice, with no off-targets in predicted sites. Thus, the improved efficacy and reassuring safety profile support the potential application of the proposed approach to other liver diseases.

Newly revealed links between inflammation, obesity, and cardiometabolic syndrome have created opportunities to try previously unexplored therapeutic modalities in these common and life-risking disorders. One potential modulator of these complex disorders is the gut microbiome, which was described in recent years to be altered in patients suffering from features of cardiometabolic syndrome and to transmit cardiometabolic phenotypes upon transfer into germ-free mice. As a result, there is great interest in developing new modalities targeting the altered commensal bacteria as a means of treatment for cardiometabolic syndrome. Fecal microbiota transplantation (FMT) is one such modality in which a disease-associated microbiome is replaced by a healthy microbiome configuration. So far clinical use of FMT has been overwhelmingly successful in recurrent Clostridium difficile infection and is being extensively studied in other microbiome-associated pathologies such as cardiometabolic syndrome. This review will focus on the rationale, promises and challenges in FMT utilization in human disease. In particular, it will overview the role of the gut microbiota in cardiometabolic syndrome and the rationale, experience, and prospects of utilizing FMT treatment as a potential preventive and curative treatment of metabolic human disease.