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While outcomes after liver transplantation have increased over the last two decades, this is primarily as a consequence of a reduction in early deaths and survival of those who survive the first 6 months has not significantly changed. Causes of premature death and graft loss include cardiovascular disease, renal impairment, malignancy and some infections. As the number of transplant recipients increase, care is being given by primary and secondary care clinicians. Management of the well patient is crucially dependent on careful assessment and where appropriate intervention, especially of cardiovascular risk - such as advice about avoidance of weight gain; management of hypertension, hyperlipidaemia and diabetes; and provision of appropriate lifestyle advice. Other interventions include surveillance for de novo malignancies, active management of immunosuppressive regimen with the need to tailor immunosuppression to the individual. Prompt investigation of abnormalities of liver function is essential. Immune-mediated graft damage still occurs but is less common as a cause for graft loss. Adherence is sometimes an issue, especially in teenagers and young adults, and should be considered and support given where needed. Immunisations (avoiding live and attenuated vaccines) should be encouraged. Recurrence of disease remains an issue, and some interventions (such as appropriate use of antiviral therapy for those grafted with viral hepatitis, use of ursodeoxycholic acid for those grafted for primary biliary cholangitis or long-term steroids for those grafted for autoimmune disease) may improve and maintain graft function. Close collaboration between recipient and the attending clinicians in primary, secondary and tertiary care and close attention to modifiable conditions will lead to improved outcomes., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9-transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied., Competing Interests: This study was supported by research funds from the National Institutes of Health (R01HL147968, R01 HL155344), the Veterans Administration (AN # 4345132), and the Wilkinson Foundation to Dr Mann. Dr Diwan was supported by grants from the National Institutes of Health (HL107594, HL143431, and NS094692) and the Department of Veterans Affairs (I01BX004235). Dr Finck was supported by grants from the National Institutes of Health (R01 HL119225, P30 DK05634). Dr Kovacs was supported by grants from the National Institutes of Health (S10 OD028597). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition., Competing Interests: None., (© 2022 The Authors.)

Background & Aims: Biliary complications (BC) following liver transplantation (LT) are responsible for significant morbidity. No technical procedure during reconstruction has been associated with a risk reduction of BC. The placement of an intraductal removable stent (IRS) during reconstruction followed by its endoscopic removal showed feasibility and safety in a preliminary study. This multicentric randomised controlled trial aimed at evaluating the impact of an IRS on BC following LT., Methods: This multicentric randomised controlled trial was conducted in 7 centres from April 2015 to February 2019. Randomisation was done during LT when a duct-to-duct anastomosis was confirmed with at least 1 of the stump diameters ≤7 mm. In the IRS group, a custom-made segment of a T-tube was placed into the bile duct to act as a stake during healing and was removed endoscopically 4 to 6 months post LT. The primary endpoint was the incidence of BC (fistulae and strictures) within 6 months post LT. The secondary criteria were complications related to the IRS placement or extraction, including endoscopic retrograde cholangio-pancreatography (ERCP)-related complications., Results: In total, 235 patients were randomised: 117 in the IRS group and 118 in the control group. BC occurred in 31 patients (26.5%) in the IRS group vs . 24 (20.3%) in the control group ( p  = 0.27), including 16 (13.8%) and 15 (12.8%) strictures, respectively. IRS migration occurred in 24 patients (20.5%), cholangitis in 1 (0.9%), acute pancreatitis in 2 (1.8%), and difficulty during endoscopic extraction in 19 (19.4%). No predictive factor for BC was identified., Conclusions: IRS does not prevent BC after LT and may require specific endoscopic expertise for removal., Trial Registration Number Clinicaltrialsgov: NCT02356939 (https://clinicaltrials.gov/ct2/show/NCT02356939?term=NCT02356939&draw=2&rank=1)., Lay Summary: Liver transplantation is a life-saving treatment for many patients with end-stage liver disease. However, it can be associated with complications involving the bile duct reconstruction. Herein, the placement of a specific stent called an intraductal removable stent was trialled as a way of reducing bile duct complications in patients undergoing liver transplantation. Unfortunately, it did not help preventing such complications., Competing Interests: The authors have declared no conflicts of interest in relation to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Background: Cardiovascular magnetic resonance (CMR) is the test of choice for diagnosis and risk stratification of myocardial inflammation in acute viral myocarditis. The objective of this study was to assess patterns of CMR inflammation in a cohort of acute myocarditis patients from Northern Africa, Asia, and the Middle East using unsupervised machine learning., Methods: A total of 169 racially and ethnically diverse adults ( ≥ 18 years of age) with CMR confirmed acute myocarditis were studied. The primary outcome was a combined clinical endpoint of cardiac death, arrhythmia, and dilated cardiomyopathy. Machine learning was used for exploratory analysis to identify patterns of CMR inflammation., Results: Our cohort was diverse with 25% from Northern Africa, 33% from Southern Asia, and 28% from Western Asia/the Middle East. Twelve patients met the combined clinical endpoint - 3 had arrythmia, 8 had dilated cardiomyopathy, and 1 died. Patients who met the combined endpoint had increased anterior (p = 0.034) and septal (p = 0.042) late gadolinium enhancement (LGE). Multivariable logistic regression, adjusted for age, gender, and BMI, found that patients from Southern Asia (p = 0.041) and the Middle East (p = 0.043) were independently associated with lateral LGE. Unsupervised machine learning and factor analysis identified two distinct CMR patterns of inflammation, one with increased LGE and the other with increased myocardial T1/T2., Conclusions: We found that anteroseptal inflammation is associated with worsened outcomes. Using machine learning, we identified two patterns of myocardial inflammation in acute myocarditis from CMR in a racially and ethnically diverse group of patients from Southern Asia, Northern Africa, and the Middle East., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Competing Interests: The authors have none to declare.

The coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously affected public health around the world. In-depth studies on the pathogenic mechanisms of SARS-CoV-2 is urgently necessary for pandemic prevention. However, most laboratory studies on SARS-CoV-2 have to be carried out in bio-safety level 3 (BSL-3) laboratories, greatly restricting the progress of relevant experiments. In this study, we used a bacterial artificial chromosome (BAC) method to assemble a SARS-CoV-2 replication and transcription system in Vero E6 cells without virion envelope formation, thus avoiding the risk of coronavirus exposure. Furthermore, an improved real-time quantitative reverse transcription PCR (RT-qPCR) approach was used to distinguish the replication of full-length replicon RNAs and transcription of subgenomic RNAs (sgRNAs). Using the SARS-CoV-2 replicon, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 facilitates the transcription of sgRNAs in the discontinuous synthesis process. Moreover, two high-frequency mutants of N protein, R203K and S194L, can obviously enhance the transcription level of the replicon, hinting that these mutations likely allow SARS-CoV-2 to spread and reproduce more quickly. In addition, remdesivir and chloroquine, two well-known drugs demonstrated to be effective against coronavirus in previous studies, also inhibited the transcription of our replicon, indicating the potential applications of this system in antiviral drug discovery. Overall, we developed a bio-safe and valuable replicon system of SARS-CoV-2 that is useful to study the mechanisms of viral RNA synthesis and has potential in novel antiviral drug screening., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction., Competing Interests: This study was supported by the American Heart Association (grant 18PRE33990001 to Mr Devarakonda), the Wright Center for Clinical and Translational Research Center (Wright Scholarship to Mr Devarakonda), and the National Institutes of Health (grants R01HL142281, R21AG053654, R01HL133167, and R35HL155651 to Dr Salloum). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

By the end of year 2019, the new virus SARS-CoV-2 appeared, causing the Coronavirus Disease 2019 (COVID-19), and spread very fast globally. A continuing need for diagnostic tools is a must to contain its spread. Till now, the gold standard method, the reverse transcription polymerase chain reaction (RT-PCR), is the precise procedure to detect the virus. However, SARS-CoV-2 may escape RT-PCR detection for several reasons. The development of well-designed, specific and sensitive serological test like enzyme immunoassay (EIA) is needed. This EIA can stand alone or work side by side with RT-PCR. In this study, we developed several EIAs including plates that are coated with either specially designed SARS-CoV-2 nucleocapsid or surface recombinant proteins. Each protein type can separately detect anti-SARS-CoV-2 IgM or IgG antibodies. For each EIAs, the cut-off value, specificity and sensitivity were determined utilizing RT-PCR confirmed Covid-19 and pre-pandemic healthy and other viruses-infected sera. Also, the receiver operator characteristic (ROC) analysis was performed to define the specificities and sensitivities of the optimized assay. The in-house EIAs were validated by comparing against commercial EIA kits. All in-house EIAs showed high specificity (98-99%) and sensitivity (97.8-98.9%) for the detection of IgG/IgM against RBD and N proteins of SARS-CoV-2. From these results, the developed Anti-RBD and anti-N IgG and IgM antibodies EIAs can be used as a specific and sensitive tool to detect SARS-CoV-2 infection, calculate the burden of disease and case fatality rates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies., Competing Interests: G.S. holds more than 5% of the total shares of KanonCure Inc., and receives compensation as a member of KanonCure Inc. The other author has no competing interests., (© 2021 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Objective: To present the clinical characteristics and outcome of transplant and nontransplant patients with invasive nocardiosis., Patients and Methods: We conducted a retrospective chart review of 110 patients 18 years and older diagnosed with culture-proven invasive nocardiosis (defined as the presence of clinical signs and/or radiographic abnormalities) between August 1, 1998, and November 30, 2018. Information on demographic, clinical, radiographic, and microbiological characteristics as well as mortality was collected., Results: One hundred ten individuals with invasive nocardiosis were identified, of whom 54 (49%) were transplant and 56 nontransplant (51%) patients. Most transplant patients were kidney and lung recipients. The overall mean age was 64.9 years, and transplant patients had a higher prevalence of diabetes and chronic kidney disease. A substantial proportion of nontransplant patients were receiving corticosteroids (39%), immunosuppressive medications (16%), and chemotherapy (9%) and had chronic obstructive pulmonary disease (20%), rheumatologic conditions (18%), and malignant neoplasia (18%). A higher proportion of transplant patients (28%) than nontransplant patients (4%) received trimethoprim-sulfamethoxazole prophylaxis. In both groups, the lung was the most common site of infection. Seventy percent of all Nocardia species isolated were present in almost equal proportion: N brasiliensis (16%), N farcinica (16%), N nova (15%), N cyriacigeorgia (13%), and N asteroides (11%). More than 90% of isolates were susceptible to trimethoprim-sulfamethoxazole, linezolid, and amikacin. There was no significant difference in mortality between the 2 groups at 1, 6, and 12 months after the initial diagnosis., Conclusion: The frequency of invasive Nocardia infection was similar in transplant and nontransplant patients and mortality at 1, 6, and 12 months was similar in both groups. Trimethoprim-sulfamethoxazole prophylaxis failed to prevent Nocardia infection., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by persistent pathologic activation of cytotoxic T lymphocytes, natural killer cells, and macrophages. We present details of a young patient who presented with high-grade fever, jaundice, and breathlessness. On investigations, he had hepatitis, anemia, neutropenia, and coagulopathy. He also had hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Bone marrow aspiration revealed histiocytosis, and transjugular liver biopsy revealed necrotizing granulomas positive for Mycobacterium tuberculosis on acid-fast bacilli staining. He was successfully managed with a combination of immunosuppressants and antitubercular therapy. Tuberculosis associated hemophagocytosis syndrome is rare and should be considered in patients with unexplained hemophagocytosis syndrome, especially in tuberculosis-endemic regions. Prompt recognition and treatment with antitubercular treatment and immunosuppressants are associated with good outcomes., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disorder with liver transplantation (LT) being the only definitive treatment in end-stage disease. Recurrence of PSC after LT is a significant concern which can lead to graft loss. The aim of this study is to find out the disease recurrence and long-term outcome after living donor liver transplantation (LDLT) in PSC., Methods: We conducted a retrospective review of all patients undergoing LDLT for PSC at our centre. Of 2268 adult LTs from August 2004 to July 2018, 32 (1.4%) patients underwent LDLT for PSC including 6 with PSC and autoimmune hepatitis overlap. The data were reviewed to look for PSC recurrence, complications, and overall survival. All patients received tacrolimus-based immunosuppression. Data are shown as number, percentage, median, and interquartile range (IQR)., Result: The mean age of 32 LDLT recipients was 44 ± 12 years (males 22, females 10). At the time of transplantation, the mean child's score was 9 ± 1.6 and model for end-stage liver disease score was 18.9 ± 6.4. Ulcerative colitis was seen in 7 patients and none had cholangiocarcinoma. Majority of patients (n = 29) received right lobe graft and all but 3 underwent hepaticojejunostomy for biliary reconstruction. PSC recurrence was seen in 6 (20%) patients during a median follow-up of 59 (29-101) months, after exclusion of 2 patients with early mortality. A total of five patients died during follow-up, and one of these deaths was due to PSC recurrence. There were 2 perioperative deaths due to sepsis and 3 deaths on follow-up (sepsis in 2 and PSC recurrence in 1)., Conclusion: LDLT can be performed in PSC with good overall long-term outcomes., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V.)

Background: There are few data on genetic relation of the donor and outcomes in living donor liver transplantation (LDLT) recipients. We compared outcomes of LDLT between recipients of genetically related and unrelated donors in a large single-center series., Methods: The study included 1372 adult, ABO-compatible, primary LDLT recipients, who received a graft from either a first-degree relative (parent, sibling, son, or daughter; n = 756) or unrelated donor (spouse or relative of the spouse; n = 616)., Results: The mean age of the recipients with a related donor was 50.2 ± 10.8 years compared with 47.3 ± 9.3 years for recipients with unrelated donors ( P  = 0.000). Chronic rejection was significantly more common in the genetically unrelated donor group than in the genetically related donor group (28 [4.5%] versus 9 [1.1%]; P  = 0.000) at a mean follow-up of 37 months (15-95 months). There were no significant differences in other outcomes between the 2 groups. The 12-month and 36-month survival between the unrelated and related groups was 87.6% versus 90%, and 86.3% versus 89.7% respectively ( P = 0.115). The multivariate analysis revealed genetically unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80-8.34, P  = 0.001) and history of acute cellular rejection (OR: 3.39, 95% CI: 1.68-6.81, P  = 0.001) as predictors of chronic rejection., Conclusion: Although chronic rejection was found to be more common in genetically unrelated donors, the patient survival after LDLT was similar., Competing Interests: The authors have none to declare., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Heart failure is an important, and growing, cause of morbidity and mortality. Half of patients with heart failure have preserved ejection fraction, for whom therapeutic options are limited. Here we report that cardiac bridging integrator 1 gene therapy to maintain subcellular membrane compartments within cardiomyocytes can stabilize intracellular distribution of calcium-handling machinery, preserving diastolic function in hearts stressed by chronic beta agonist stimulation and pressure overload. This study identifies that maintenance of intracellular architecture and, in particular, membrane microdomains at t-tubules, is important in the setting of sympathetic stress. Stabilization of membrane microdomains may be a pathway for future therapeutic development., (© 2020 The Authors.)

Mutations in the gene encoding for dystrophin leads to structural and functional deterioration of cardiomyocytes and is a hallmark of cardiomyopathy in Duchenne muscular dystrophy (DMD) patients. Administration of recombinant adeno-associated viral vectors delivering microdystrophin or ribonucleotide reductase (RNR), under muscle-specific regulatory control, rescues both baseline and high workload-challenged hearts in an aged, DMD mouse model. However, only RNR treatments improved both systolic and diastolic function under those conditions. Cardiac-specific recombinant adeno-associated viral treatment of RNR holds therapeutic promise for improvement of cardiomyopathy in DMD patients., (© 2019 The Authors.)

In metazoan genome, the mechanism of gene expression regulation between transcriptional regulatory elements and their target gene is spatiotemporal. Active promoters possess many specific chromosomal features, such as hypersensitive to DNaseI and enrichment of specific histone modifications. In this article, we proposed a novel method which possesses a high efficiency to find promoters in vitro . A promoter-trap library was constructed with totally 706 random mouse genomic DNA fragment clones, and 260 promoter-active fragments of the library were screened by transient transfection into 4T1 cells. To demonstrate the accuracy of this promoter finding method, 13 fragments with promoter activities were randomly selected for published DNase-seq and ChIP-seq data analysis, downstream transcripts prediction and expression confirmation. qRT-PCR results showed that six predicted transcription units were successfully amplified in different mouse tissues/cells or in reconstituted mouse mammary tumors. Our results indicate that this promoter finding method can successfully detect the promoter-active fragments and their downstream transcripts., Competing Interests: The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (© 2019 Published by Elsevier B.V.)

Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution., Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m 2 ), melphalan (140 mg/m 2 ) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1)., Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement., Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

Objectif: Décrire les méthodes actuelles d'évaluation et de prise en charge de l'anasarque fœtoplacentaire non immune en mettant l'accent sur les étiologies traitables ou récurrentes. RéSULTATS: Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque fœtoplacentaire non immune diagnostiquée en période prénatale. DONNéES: La littérature publiée a été récupérée au moyen de recherches menées dans PubMed, MEDLINE, CINAHL, et la Bibliothèque Cochrane en 2017 à l'aide de mots-clés (« non-immune hydrops fetalis », « fetal hydrops », « fetal therapy », « fetal metabolism »). Les articles retenus portaient sur des revues systématiques, des essais cliniques contrôlés, randomisés ou non, des études observationnelles et des études de cas importantes. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Les recherches ont été mis à jour régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en septembre 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique renseigne les lecteurs sur les causes de l'anasarque fœtoplacentaire non immune ainsi que sur son évaluation et sa prise en charge. Elle propose également une approche standardisée d'évaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en période prénatale et des étiologies génétiques récurrentes., Valeurs: La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. RECOMMANDATIONS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Individual patients with life-threatening or severely debilitating diseases can petition the U.S. Food and Drug Administration (FDA) through their physicians to have expanded access (EA) to drugs that are in clinical trials but have not reached full FDA approval (the "single-patient" investigational new drug [IND] application). Additionally, recent state and federal laws-so-called "right to try legislation"-allow patients to approach drug companies directly for access prior to FDA approval. While these pathways provide potential access for individual patients to investigational drugs, different EA pathways permit entire groups of certain patients to access investigational drugs prior to FDA approval. This review focuses on special categories of EA INDs intended for multiple patients-the intermediate-group IND and the widespread-treatment IND-as well as emergency authorization for use of investigational drugs and biological products (e.g., vaccines) in public health emergencies.

The probability of a Black African finding a matched unrelated donor for a hematopoietic stem cell transplant is minimal due to the high degree of genetic diversity amongst individuals of African origin. This problem could be resolved in part by the establishment of a public cord blood (CB) stem cell bank. The high prevalence of human immunodeficiency virus (HIV) amongst women attending antenatal clinics in sub-Saharan Africa together with the risk of mother-to-child transmission increases the risk of transplant transmissible infection. In addition to screening the mother in a period inclusive of 7 days prior to the following delivery, we propose that all CB units considered for storage undergo rigorous and reliable screening for HIV. The Ultrio-plus ® assay is a highly specific and sensitive test for detecting HIV, hepatitis-B and hepatitis-C viruses in peripheral blood. We validated the Ultrio-plus ® assay for analytical sensitivity in detecting HIV in CB at the level of detection of the assay. Until more comprehensive and sensitive methods are developed, the sensitivity and reliability of the Ultrio-plus ® assay suggest that it could be used for the routine screening of CB units in conjunction with currently recommended maternal screening to reduce the risk of transplant transmissible infection.

Introduction: Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales., Presentation of Case: A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem., Discussion: Non- Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover., Conclusion: A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor.

Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis (AIH) are still not full elucidated. Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response. We investigated 3 distinct polymorphic sites (+49A > G, CT60 G > A and -318C > T) of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology. A significant positive association with AIH susceptibility was found for the GG genotype in +49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls (28% vs 9%, p  = 0.003, OR = 3.93 [1.56-9.88]). The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients. CTLA4 genotyping in position -318 did not show any statistically significant difference in genotype or allele distribution. The CTLA4 gene polymorphism in position +49 is associated to AIH susceptibility in the Tunisian population. Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.