Increased‐risk donor (IRD) organs make up a significant proportion of the deceased organ donor pool but may be declined by patients on the waiting list for various reasons. We conducted a survey of patients awaiting a liver transplant to determine the factors leading to the acceptance of an IRD organ as well as what strategies could increase the rate of acceptance. Adult liver transplant candidates who were outpatients completed a survey of 51 questions on a 5‐point Likert scale with categories related to demographics, knowledge of IRDs, and likelihood of acceptance. A total of 150 transplant candidates completed the survey (age 19‐80 years). Male patients constituted 67.3%. Many patients (58.7%) had postsecondary education. Only 23.3% of patients had a potential living donor, and 58/144 (40.3%) were not optimistic about receiving an organ in the next 3 months. The overall IRD organ acceptance rate was 41.1%, whereas 26.2% said they would decline an IRD organ. Women were more likely to accept an IRD organ (54.3% versus 34.7%; P = 0.02). Those who had a college education or higher tended to have lower IRD organ acceptability (28.3% versus 47.4%; P = 0.07). Acceptability also increased as the specified transmission risk of human immunodeficiency virus or hepatitis C virus decreased ( P < 0.001). Patients were also more likely to accept an IRD organ if they were educated on the benefits of IRD organs (eg, knowledge that an IRD organ was of better quality increased overall acceptance from 41.1% to 63.3%; P < 0.001). Our survey provides insight into liver transplant candidates who would benefit from greater education on IRD organs. Strategies targeting specific educational points are likely to increase acceptability.
Recurrent hepatocellular carcinoma (HCC) develops in 15–20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.
This study aims to determine whether children with ADHD and learning disabilities (LD) have a significant history of obstetrical complications when compared to children with ADHD but without LD. Methods: Sixty-four children aged 6 to 12 years diagnosed with ADHD were assessed for a history of obstetrical complications using the Kinney medical and gynecological questionnaire. Learning ability was appraised using the Wide-Range Achievement Test (WRAT-R) for anglophone students and the "Test de Rendement Français" for francophone students. Results: Children with ADHD and a learning disability in mathematics had a higher rate of neonatal complications of great severity (p = 0.01) than children with ADHD and no disability in mathematics. Children with ADHD and a learning disability in reading also had a preponderance of neonatal complications of high severity (p = 0.02) compared to their peers with ADHD and no learning disability in reading. Children with ADHD and learning disability tend to have a significant history of neonatal complications, which validates the theory that complications in early life could adversely affect a child's academic ability later in life. This further confirms the importance of the perinatal and postnatal periods in CNS development of brain regions essential for mathematics and reading ability.
To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis.PubMed and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationally-predicted annotations for significant association of genes to curated molecular pathways.From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and cAMP-mediated signalling.Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome.
Post-transplant diabetes mellitus (PTDM) compromises long-term survival in liver transplant (LT) recipients. The aim of this study was to determine incidence of PTDM after LT and risk factors associated with it. A literature search was conducted, and prospective studies that reported on the incidence of PTDM in LT adult patients on tacrolimus, sirolimus, or cyclosporine were included. We performed random effects meta-analyses for the incidence of PTDM stratified by immunosuppressant and time period. Of 9817 articles identified, 26 studies were included in the qualitative analysis and 21 studies were eligible for the quantitative analysis representing 79 559 LT recipients in 32 separate treatment arms. The proportion of patients who developed PTDM by two-three years was 0.15 (95% CI: 0.10-0.24) for cyclosporine, 0.23 (95% CI: 0.14-0.36) for tacrolimus, and 0.27 (95% CI: 0.23-0.30) for sirolimus. CONCLUSION: Our results showed that sirolimus-based immunosuppression was associated with a higher incidence of PTDM than tacrolimus or cyclosporine at two-three years. However, there were only two studies that compared all three drugs which is a limitation of the study and requires more studies with patients on sirolimus. Recipient factors increasing the risk of PTDM are older age, male sex, and high BMI.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and encompasses a spectrum from simple steatosis to steatohepatitis (NASH). There is currently no approved pharmacologic therapy against NASH, partly due to an incomplete understanding of its molecular basis. The goal of this study was to determine the key differentially expressed genes (DEGs), as well as those genes and pathways central to its pathogenesis. We performed an integrative computational analysis of publicly available gene expression data in NASH from GEO (GSE17470, GSE24807, GSE37031, GSE89632). The DEGs were identified using GEOquery, and only the genes present in at least three of the studies, to a total of 190 DEGs, were considered for further analyses. The pathways, networks, molecular interactions, functional analyses were generated through the use of Ingenuity Pathway Analysis (IPA). For selected networks, we computed the centrality using igraph package in R. Among the statistically significant predicted networks (p-val < 0.05), three were of most biological interest: the first is involved in antimicrobial response, inflammatory response and immunological disease, the second in cancer, organismal injury and development and the third in metabolic diseases. We discovered that HNF4A is the central gene in the network of NASH connected to metabolic diseases and that it regulates HNF1A, an additional transcription regulator also involved in lipid metabolism. Therefore, we show, for the first time to our knowledge, that HNF4A is central to the pathogenesis of NASH. This adds to previous literature demonstrating that HNF4A regulates the transcription of genes involved in the progression of NAFLD, and that HNF4A genetic variants play a potential role in NASH progression.
Treatment options for obstructive sleep apnea include positive airway pressure and alternatives such as behavioral interventions, oral appliances, nasal expiratory positive airway pressure, negative pressure interventions, and surgical procedures. Certain drugs are also promising. An important aspect of the treatment includes troubleshooting the reasons for poor adherence to positive airway pressure treatment, discussing alternatives based either on individual preference or on phenotypic characterization of the sleep apnea, and managing expectations.
