The Impact of Donor and Recipient Genetic Variation on Outcomes After Solid Organ Transplantation:a Scoping Review and Future Perspectives

At the outset of solid organ transplantation, genetic variation between donors and recipients was recognized as a major player in mechanisms such as allograft tolerance and rejection. Genome-wide association studies have been very successful in identifying novel variant-trait associations, but have been difficult to perform in the field of solid organ transplantation due to complex covariates, era effects, and poor statistical power for detecting donor-recipient interactions. To overcome a lack of statistical power, consortia such as the International Genetics and Translational Research in Transplantation Network have been established. Studies have focused on the consequences of genetic dissimilarities between donors and recipients and have reported associations between polymorphisms in candidate genes or their regulatory regions with transplantation outcomes. However, knowledge on the exact influence of genetic variation is limited due to a lack of comprehensive characterization and harmonization of recipients' or donors' phenotypes and validation using an experimental approach. Causal research in genetics has evolved from agnostic discovery in genome-wide association studies to functional annotation and clarification of underlying molecular mechanisms in translational studies. In this overview, we summarize how the recent advances and progresses in the field of genetics and genomics have improved the understanding of outcomes after solid organ transplantation

A combination of fecal calprotectin and human beta-defensin 2 facilitates diagnosis and monitoring of inflammatory bowel disease

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies. We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing. Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing-based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC approximate to 0.7). HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data

The effect of delayed primary treatment initiation on adverse events and recurrence in older head and neck cancer patients

Background and purpose: As a result of rapid tumor growth in head and neck squamous cell carcinoma (HNSCC), delay in treatment initiation can result in tumor progression and inferior outcome. Especially older and frail patients are prone to develop adverse events. The aim of this study was to assess the effect of delay on development of adverse events and recurrence in older HNSCC patients. Materials and methods: This cohort study with prospectively collected data included all newly diagnosed, curatively treated HNSCC patients (>60 years) between 2015 and 2017. Time-to-treatment interval and geriatric domains were assessed. Adverse events were defined as postoperative complications (ClavienDindo classification) and acute radiation-induced toxicity (Common Terminology Criteria of Adverse Events). Multivariable regression models were performed, using adverse events and recurrence as outcome variables. Results: A total of 245 patients were included. Median time-to-treatment was 26 days for surgery patients and 40 days for radiotherapy patients (p < 0.001). Delayed treatment initiation was not associated with postoperative complications or acute radiation-induced toxicity. Delay was significantly associated with recurrence risk within two years after treatment initiation in a model adjusted for stage and tumor location in patients treated with initial surgery (HR:4.1, 95%CI:1.2- 14.0, p = 0.024). For patients treated with radiotherapy, delay was not significantly associated with recurrence risk. Conclusion: Delayed treatment initiation was independently associated with increased recurrence risk in patients treated with initial surgery. Delay was not associated with short-term adverse events. These findings highlight the importance of establishing fast-track care pathways to minimize delays and improve especially long-term outcome. (c) 2022 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 173 (2022) 154-162 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Donor tobacco smoking is associated with postoperative thrombosis after primary liver transplantation

Background: Thrombosis after liver transplantation is a leading cause of graft loss, morbidity, and mortality. Several known recipient- and surgery-related characteristics have been associated with increased risk of thrombosis after transplantation. Potential donor-related risk factors, however, remain largely undefined. Objectives: We aimed to identify risk factors for early post-transplantation thrombosis ('90 days) and to determine the impact of early postoperative thrombosis on long-term graft and patient survival. Patients/Methods: A post hoc analysis was performed of an observational cohort study including all primary, adult liver transplantations performed between 1993 and 2018. Donor-, recipient-, and surgery-related characteristics were collected. Competing risk model analyses and multivariable regression analyses were performed to identify risk factors for developing early post-transplant thrombosis and graft failure. Results: From a total of 748 adult liver transplantations, 58 recipients (7.8%) developed a thrombosis after a median of 7 days. Post-transplantation thrombotic events included 25 hepatic artery thromboses, 13 portal vein thromboses, and 22 other thrombotic complications. Donor history of smoking was independently associated with early postoperative thrombosis (odds ratio [OR] 2.42; 95% confidence interval [CI], 1.29-4.52). Development of early post-transplant thrombosis was independently associated with patient mortality (hazard ratio [HR] 3.61; 95% CI 1.54-8.46) and graft failure (HR 5.80, 95% CI 3.26-10.33), respectively. Conclusion: Donor history of smoking conveys a more than two-fold increased risk of thrombosis after liver transplantation, independent of other factors. Post-transplant thrombosis was independently associated with decreased patient and graft survival

Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-alpha biologicals and an Infliximab-biosimilar

Introduction TNF-alpha-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-alpha antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. Aim To determine the neutralizing capacity of first- and second generation anti-TNF-alpha antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). Methods TNF-alpha neutralization was measured using a quantitative TNF-alpha sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF kappa B response element. All available anti-TNF-alpha drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-alpha-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab(2)-fragment, biosimilar CT-P13 (Inflectra) and ADA. Results TNF-alpha strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of firstgeneration anti-TNF-alpha drugs were required to neutralize TNF-alpha compared to the secondgeneration anti-TNF-alpha drugs. Serum of IBD patients with proven ATI blocked TNF-alpha-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA. Conclusion The second-generation anti-TNF-alpha drugs show increased TNF-alpha-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn's disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) &lt; 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR &lt; 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR &lt; 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet-inflammation relationship

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty

Variations in the slope of the psychometric functions for speech intelligibility: a systematic survey

Although many studies have looked at the effects of different listening conditions on the intelligibility of speech, their analyses have often concentrated on changes to a single value on the psychometric function, namely, the threshold. Far less commonly has the slope of the psychometric function, that is, the rate at which intelligibility changes with level, been considered. The slope of the function is crucial because it is the slope, rather than the threshold, that determines the improvement in intelligibility caused by any given improvement in signal-to-noise ratio by, for instance, a hearing aid. The aim of the current study was to systematically survey and reanalyze the psychometric function data available in the literature in an attempt to quantify the range of slope changes across studies and to identify listening conditions that affect the slope of the psychometric function. The data for 885 individual psychometric functions, taken from 139 different studies, were fitted with a common logistic equation from which the slope was calculated. Large variations in slope across studies were found, with slope values ranging from as shallow as 1% per dB to as steep as 44% per dB (median = 6.6% per dB), suggesting that the perceptual benefit offered by an improvement in signal-to-noise ratio depends greatly on listening environment. The type and number of maskers used were found to be major factors on the value of the slope of the psychometric function while other minor effects of target predictability, target corpus, and target/masker similarity were also found

The timing of ostomy closure in infants with necrotizing enterocolitis: a systematic review

Item does not contain fulltextPURPOSE: The optimal timing of ostomy closure is a matter of debate. We performed a systematic review of outcomes of early ostomy closure (EC, within 8 weeks) and late ostomy closure (LC, after 8 weeks) in infants with necrotizing enterocolitis. METHODS: PubMed, EMbase, Web-of-Science, and Cinahl were searched for studies that detailed time to ostomy closure, and time to full enteral nutrition (FEN) or complications after ostomy closure. Patients with Hirschsprung's disease or anorectal malformations were excluded. Analysis was performed using SPSS 17 and RevMan 5. RESULTS: Of 778 retrieved articles, 5 met the inclusion criteria. The median score for study quality was 9 [range 8-14 on a scale of 0 to 32 points (Downs and Black, J Epidemiol Community Health 52:377-384, 1998)]. One study described mean time to FEN: 19.1 days after EC (n = 13) versus 7.2 days after LC (n = 24; P = 0.027). Four studies reported complication rates after ostomy closure, complications occurred in 27% of the EC group versus 23% of the LC group. The combined odds ratio (LC vs. EC) was 1.1 [95% CI 0.5, 2.5]. CONCLUSION: Evidence that supports early or late closure is scarce and the published articles are of poor quality. There is no significant difference between EC versus LC in the complication rate. This systematic review supports neither early nor late ostomy closure

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base