Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults ...with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10
, 10
or up to 10
cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.
Although school-based programmes for the identification of children and young people (CYP) with mental health difficulties (MHD) have the potential to improve short- and long-term outcomes across a ...range of mental disorders, the evidence-base on the effectiveness of these programmes is underdeveloped. In this systematic review, we sought to identify and synthesise evidence on the effectiveness and cost-effectiveness of school-based methods to identify students experiencing MHD, as measured by accurate identification, referral rates, and service uptake.
Electronic bibliographic databases: MEDLINE, Embase, PsycINFO, ERIC, British Education Index and ASSIA were searched. Comparative studies were included if they assessed the effectiveness or cost-effectiveness of strategies to identify students in formal education aged 3-18 years with MHD, presenting symptoms of mental ill health, or exposed to psychosocial risks that increase the likelihood of developing a MHD.
We identified 27 studies describing 44 unique identification programmes. Only one study was a randomised controlled trial. Most studies evaluated the utility of universal screening programmes; where comparison of identification rates was made, the comparator test varied across studies. The heterogeneity of studies, the absence of randomised studies and poor outcome reporting make for a weak evidence-base that only generate tentative conclusions about the effectiveness of school-based identification programmes.
Well-designed pragmatic trials that include the evaluation of cost-effectiveness and detailed process evaluations are necessary to establish the accuracy of different identification models, as well as their effectiveness in connecting students to appropriate support in real-world settings.
Background
This scoping review aimed to overview studies that used administrative data linkage in the context of child maltreatment to improve our understanding of the value that data linkage may ...confer for policy, practice, and research.
Methods
We searched MEDLINE, Embase, PsycINFO, CINAHL, and ERIC electronic databases in June 2019 and May 2020 for studies that linked two or more datasets (at least one of which was administrative in nature) to study child maltreatment. We report findings with numerical and narrative summary.
Results
We included 121 studies, mainly from the United States or Australia and published in the past decade. Data came primarily from social services and health sectors, and linkage processes and data quality were often not described in sufficient detail to align with current reporting guidelines. Most studies were descriptive in nature and research questions addressed fell under eight themes: descriptive epidemiology, risk factors, outcomes, intergenerational transmission, predictive modelling, intervention/service evaluation, multi-sector involvement, and methodological considerations/advancements.
Conclusions
Included studies demonstrated the wide variety of ways in which data linkage can contribute to the public health response to child maltreatment. However, how research using linked data can be translated into effective service development and monitoring, or targeting of interventions, is underexplored in terms of privacy protection, ethics and governance, data quality, and evidence of effectiveness.
The liver performs multiple functions within the human body. It is composed of numerous cell types, which play important roles in organ physiology. Our study centers on the major metabolic cell type ...of the liver, the hepatocyte, and its susceptibility to damage during drug overdose. In these studies, hepatocytes were generated from a renewable and genetically defined resource. In vitro-derived hepatocytes were extensively profiled and exposed to varying levels of paracetamol and plasma isolated from liver-failure patients, with a view to identifying noncoding microRNAs that could reduce drug- or serum-induced hepatotoxicity. We identified a novel anti-microRNA, which reduced paracetamol-induced hepatotoxicity and glutathione depletion. Additionally, we identified a prosurvival role for anti-microRNA-324 following exposure to plasma collected from liver failure patients. We believe that these studies represent an important advance for the field, demonstrating the power of stem cell-derived systems to model human biology "in a dish" and identify novel noncoding microRNAs, which could be translated to the clinic in the future.
The liver performs vital functions within the human body and is composed of numerous cell types. The major metabolic cell type of the liver, the hepatocyte, is susceptible to damage during drug overdose. In these studies, hepatocytes were generated from a renewable resource and exposed to varying levels of paracetamol, with a view to identifying interventions that could reduce or attenuate drug-induced liver toxicity. A novel noncoding RNA that reduced paracetamol-induced hepatocyte toxicity was identified. These findings may represent an important advance for the field.
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Summer Gut Syndrome (SGS) is caused by various Vibrio bacterial species and can have negative effects on aquaculture farms worldwide. In New Zealand, SGS is caused by Vibrio harveyii ...infecting King Salmon (Oncorhynchus tshawytscha). To find leads for the prevention of SGS, we screened the inhibitory effects of 16 strains of Shewanella upon V. harveyii growth in competitive solid phase cultures. The detailed investigation of Shewanella halifaxensis IRL548 revealed 2-benzyl-4-chlorophenol (1), a known, commercially available antibacterial agent, as the major bioactive component. Synthesis of a small library of congeners to confirm the natural product identity and to provide a structure–activity relationship for the observed activity was also completed. Compound 1 exhibits moderate activity against two pathogenic microorganisms.
Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce ...inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in-human trial (MAcrophages Therapy for liver CirrHosis MATCH trial).
We outline the development and validation phases of GMP production. This includes use of the CliniMACS Prodigy cell sorting system to isolate CD14+ cells; optimizing macrophage culture conditions, assessing cellular identity, product purity, functional capability and determining the stability of the final cell product.
The GMP-compliant macrophage products have a high level of purity and viability, and have a consistent phenotypic profile, expressing high levels of mature macrophage markers 25F9 and CD206 and low levels of CCR2. The macrophages demonstrate effective phagocytic capacity, are constitutively oriented to an anti-inflammatory profile and remain responsive to cytokine and TLR stimulation. The process validation shows that the cell product in excipient is remarkably robust, consistently passing the viability and phenotypic release criteria up to 48 hours after harvest.
This is the first report of validation of a large-scale, fully Good Manufacturing Practice–compliant, autologous macrophage cell therapy product for the potential treatment of cirrhosis. Phenotypic and functional assays confirm that these cells remain functionally viable for up to 48 h, allowing significant flexibility in administration to patients.
Abstract Background aims Macrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to ...determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis. Methods Infusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-β, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases MMP-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice–compatible technique. Results There was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 108 and 2.5 ± 0.56 × 108 , respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 108 ± 0.38 × 108 , with more than 90% viability and 0.65 × 108 ± 0.16 × 108 , respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin IL-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences. Conclusions Macrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy.
Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive ...function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.
Ehrlichia chaffeensis (Rickettsiales: Anaplasmatacae), an understudied bacterial pathogen emerging in the eastern United States, is increasing throughout the range of its vector, the lone star tick ...Amblyomma americanum, L. (Acari: Ixodidae). To mitigate human disease risk, we must understand what factors drive E. chaffeensis prevalence. Here, we report patterns of E. chaffeensis prevalence in southeastern Virginia across 4 yr and ask how seasonal weather patterns affect variation in rates of E. chaffeensis occurrence. We collected A. americanum nymphs at 130 plots across southeastern Virginia in 2012, 2013, 2015, and 2016, and used polymerase chain reaction and gel electrophoresis to test for the presence of E. chaffeensis DNA. Prevalence estimates varied among years, ranging from 0.9% to 3.7%, and persistence of E. chaffeensis occurrence varied across space, with some sites never testing positive, and one site testing positive every year. Using generalized linear mixed-effects models, we related E. chaffeensis occurrence to temperature, humidity, vapor–pressure deficit, and precipitation during seasons up to 21 mo prior to sampling. Surprisingly, all support was lent to a positive effect of temperature during the previous fall and winter (i.e., prior to the nymphs' hatching), which we hypothesize to influence reservoir host population dynamics through changes to mortality or natality. Although further work is necessary to truly elucidate the mechanisms at play, our study shows E. chaffeensis distribution to be very dynamic across multiple dimensions, demanding broad concerted monitoring efforts that can consider both space and time.
Advances in celiac disease Moore, Joanna K; West, Susanna Ra; Robins, Gerry
Current opinion in gastroenterology
27, Številka:
2
Journal Article
Recenzirano
To critically summarize recent research in celiac disease.
There are new serological markers with potential use not only in the diagnosis of celiac disease but also as important follow-up tools. As ...our understanding of celiac disease increases with further isolation of nonhuman leukocyte antigen genes and clarification of the intracellular pathways that underlie its pathogenesis, there are new modalities which will not only allow improved risk stratification of individuals but also facilitate the development of novel therapeutic agents.
Small bowel biopsy remains the gold standard for both diagnosis and monitoring. A gluten-free diet currently remains the only treatment option, with potential other options being discovered such as glutenases for predigestion of gluten.
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