Loneliness, Psychological Well-being, Depression, and Social Participation in the Older Persons: Rural and Urban Differences.

INTRODUCTION: The purpose of this study is to compare the loneliness, psychological well- being, depression, and social participation of elderly people living in Turkish society between rural and urban areas. The sample group of the study, in which a correlational survey model was used, consisted of 610 elderly adults. METHOD: The study population consists of two groups: the first group consists of individuals over 65 years of age living in the city (Istanbul) (n= 291), and the second group consists of individuals over 65 years of age living in rural areas (rural areas of Ordu) (n= 319). Socio-demographic Information Form, Loneliness in the Elderly Scale, Geriatric Depression Scale, Psychological Well-Being in the Elderly Scale, and Social Inclusion Scale were applied online. Statistical analyses of the study were conducted using SPSS 27.00, and the Independent Samples t-test and ANOVA test were used. RESULTS: According to the findings of this study, statistically significant results were found in psychological well-being, social inclusion, social relations, loneliness and depression, and place of residence. It was observed that the social isolation and social acceptance levels of those living in urban areas were higher than those living in rural areas. Social, loneliness, and depression scores of those living in the village/town were found to be higher than those living in the city centre. Furthermore, the social relationship scores of those living in the village/town were found to be higher than those living in the city centre. CONCLUSION: The increasing elderly population worldwide has become an issue that requires global measures. Place of residence is one of the factors thought to affect older people's health and well- being. It is thought that the study data will contribute to new policies that will ensure the protection and promotion of elderly health and those working in this field. In addition, the study, which provides information about Turkish culture, will also enable intercultural comparisons.

Selective cytotoxic effects of nitrogen-doped graphene coated mixed iron oxide nanoparticles on HepG2 as a new potential therapeutic approach.

New selective therapeutics are needed for the treatment of hepatocellular carcinoma (HCC), the 7th most common cancer. In this study, we compared the cytotoxic effect induced by the release of pH-dependent iron nanoparticles from nitrogen-doped graphene-coated mixed iron oxide nanoparticles (FexOy/N-GN) with the cytotoxic effect of nitrogen-doped graphene (N-GN) and commercial graphene nanoflakes (GN) in Hepatoma G2 (HepG2) cells and healthy cells. The cytotoxic effect of nanocomposites (2.5-100 ug/ml) on HepG2 and healthy fibroblast (BJ) cells (12-48 h) was measured by Cell Viability assay, and the half maximal inhibitory concentration (IC50) was calculated. After the shortest (12 h) and longest incubation (48 h) incubation periods in HepG2 cells, IC50 values of FexOy/N-GN were calculated as 21.95 to 2.11 µg.mL-1, IC50 values of N-GN were calculated as 39.64 to 26.47 µg.mL-1 and IC50 values of GN were calculated as 49.94 to 29.94, respectively. After 48 h, FexOy/N-GN showed a selectivity index (SI) of 10.80 for HepG2/BJ cells, exceeding the SI of N-GN (1.27) by about 8.5-fold. The high cytotoxicity of FexOy/N-GN was caused by the fact that liver cancer cells have many transferrin receptors and time-dependent pH changes in their microenvironment increase iron release. This indicates the potential of FexOy/N-GN as a new selective therapeutic.

Prognostic Biomarkers in Kidney Transplantation: A Systematic Review and Critical Appraisal.

SIGNIFICANCE STATEMENT: Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. METHODS: We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood ( n =821, 71.8%), intragraft ( n =169, 14.8%), or urine ( n =81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8-35.5) between 2005 and 2012 and 57.5 (IQR, 53.3-59.8) between 2013 and 2022 ( P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96-629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS: Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival.

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

The role of salivary galectin-3 and galectin-9 levels in plaque-induced gingivitis and periodontitis.

Background: This study aimed to compare the salivary galectin-3 and galectin-9 levels in periodontitis, gingivitis, and periodontally healthy patients. Methods: This study included 75 non-smokers who were systemically healthy. The clinical periodontal parameters of each participant were recorded. Individuals with periodontal health, gingivitis, and Stage II or Stage III Grade B periodontitis were allocated to the corresponding study groups (n = 25 each). Saliva samples were obtained from all individuals after they abstained from drinking and eating 1 h before sample collection. The galectin-3 and galectin-9 levels in the saliva were analyzed using enzyme-linked immunosorbent assay. One-way analysis of variance, student's t-test, Spearman correlation, and logistic regression were used for statistical analyses. Results: The galectin-3 and galectin-9 levels were significantly higher in the periodontitis and gingivitis groups than in the healthy group (p < 0.001). The highest galectin-3 and galectin-9 levels were observed in the gingivitis group (p < 0.05). Overall, the galectin-3 levels were significantly higher than the galectin-9 levels in all the groups (p < 0.001). Conclusions: The salivary galectin-3 and galectin-9 levels were high in patients with periodontitis and gingivitis, suggesting that they could be potential biomarkers for periodontal diseases.

An automated histological classification system for precision diagnostics of kidney allografts.

For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795 .

Human alveolar progenitors generate dual lineage bronchioalveolar organoids.

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280+/EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3ß inhibitor, CHIR99021. By RNA-seq profiling of GSK-3ß knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction.

How schools in Germany shape and impact the lives of adolescent refugees in terms of mental health and social mobility.

Schools are relevant settings for supporting refugee adolescents' mental health. As education and migration are important social determinants of health, we aim to integrate the qualitative findings of our mixed-methods study into a broader discussion regarding the role of schools and the potential effects on refugee adolescents' lives and mental health, as well as the impact of the COVID-19 pandemic. In this article, we present the findings of school-based actors' (i.e., teachers and school psychologists) perception of refugee adolescents' access to mental health care. The interviews highlight the importance of schools and social activities as main stabilizers and sources of support for refugee adolescents' mental health and the role trusting school-parent relationships play in mental health care help-seeking. Our data indicate that schools lack the resources to properly address these needs. However, these structural gaps are rooted into historical segregation and discrimination in the German educational system and left unaddressed, can increase stigma and intergenerational social inequalities, especially in connection to the COVID-19 pandemic. We conclude our article with a set of recommendations that could be relevant and implemented across different contexts to strengthen the role of the school setting in promoting the mental health and well-being of refugee adolescents.

Antithrombin supplementation for prevention of vascular thrombosis after pediatric liver transplantation.

AIMS: After liver transplantation (LT), synthesis of coagulation factors by the graft recovers faster for pro thrombotic than anti thrombotic factors, resulting in a potential pro thrombotic imbalance. We studied the thrombotic and hemorrhagic complications in our pediatric LT series, providing supplementation of fresh frozen plasma (FFP) and/or antithrombin (AT) in the prophylactic antithrombotic regimen. METHODS: This was a retrospective observational single center study. All isolated pediatric LTs performed between 1/11/2009 and 31/12/2019 (n = 181) were included. Postoperatively, in addition to low molecular weight heparin, 22 patients (12%) received FFP (10 ml/kg twice daily for 10 days), 27 patients (15%) were given FFP (reduced duration) and AT (50-100 IU/kg/day if AT activity remained <70%), and 132 (73%) received AT only. Complications, outcome, and coagulation profiles in postoperative days 0-10 were analyzed. RESULTS: In all three treatment groups, AT activity normalized by day 4 while prothrombin remained <70% of normal until day 9. Hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), and hemorrhagic complications occurred in 2.8%, 3.3%, and 3.9% of LTs. One- and 5-year patient and graft survival were 88% (±2.4% Standard Error) and 84% (±2.5%), and 86% (±2.6%) and 84% (±2.7%), respectively, without difference between groups. HAT were associated with low AT on days 0 and 1, and PVT with low AT on day 0. CONCLUSIONS: Low antithrombin activity after LT was associated with postoperative thromboses. FFP and/or AT supplementation allowed early normalization of AT activity, while thrombotic or hemorrhagic complications were rare, suggesting efficient and safe management of post-LT coagulopathy.

Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.

Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Cold Ischemia Time and Graft Fibrosis Are Associated with Autoantibodies after Pediatric Liver Transplantation: A Retrospective Cohort Study of the European Reference Network TransplantChild.

The reported prevalence of autoantibodies (AAB) (ANA, SMA, LKM, SLA) after pediatric liver transplantation (pLTX) varies considerably from 26-75%, but their clinical impact on outcome is uncertain. We aimed to study the prevalence of AAB after pLTX, their association with donor-, transplant-, and recipient-characteristics, and their relation to outcome. In our multicenter retrospective study, we aimed to clarify conflicting results from earlier studies. Six ERN TransplantChild centers reported data on 242 patients, of whom 61% were AAB positive. Prevalence varied across these centers. Independent of the interval between pLTX and AAB analysis, a one-hour increase in CIT resulted in an odds ratio (OR) of 1.37 (95% CI 1.11-1.69) for SMA positivity and an OR of 1.42 (95%CI 1.18-1.72) for ANA positivity. Steroid-free immunosuppression (IS) versus steroid-including IS (OR 5.28; 95% CI 1.45-19.28) was a risk factor for SMA positivity. Liver enzymes were not associated with ANA or SMA positivity. We did not observe an association of rejection activity index with ANA or SMA. However, the liver fibrosis score in follow-up biopsies was associated with ANA titer and donor age. In conclusion, this first multicenter study on AAB after pLTX showed high AAB prevalence and varied widely between centers. Longer CIT and prednisolone-free-IS were associated with AAB positivity, whereas AAB were not indicative of rejection, but instead were associated with graft fibrosis. The detection of AAB may be a marker of liver fibrosis and may be taken into consideration when indications for liver biopsy and immunosuppressive regimes, or reduction of immunosuppression in long-term follow-up, are being discussed. Prospective immunological profiling of pLTX patients, including AAB, is important to further improve our understanding of transplant immunology and silent graft fibrosis.

Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum.

INTRODUCTION: Amyloid beta (Aß), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. METHODS: Within 248 Aß-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aß-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging-based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline. RESULTS: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aß, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aß-tau-atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aß, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. DISCUSSION: These findings emphasize that treatments that remove Aß and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.

Do Parental and Peer Support Protect Adjustment in the Face of Ethnic Discrimination? A Comparison between Refugee Youth and Youth of Immigrant Descent.

Applying a risk and protection perspective, this study paid special attention to the protective roles of parental and peer support in the face of perceived ethnic discrimination (PED) at school. Responding to the inconsistent findings of previous research, the survey study provides greater clarity regarding the interactions between PED at school, social support and positive adjustment (self-esteem, self-efficacy, optimism and school integration). The sample comprised 104 ethnic-minority youth (Mage = 17.73, SD = 3.29, 61% female), including refugee youth (n = 55) and second- and third-generation youth of immigrant descent (n = 49). Structural equation models across the whole sample confirmed peer support as a significant moderator, indicating that ethnic-minority youth who received low peer support were less optimistic when facing PED. In multi-group models, we tested whether results differ across refugee youth and youth of immigrant descent. Results revealed between-group differences concerning the moderating roles of parental and peer support: For youth of immigrant descent, while more PED was associated with lower self-esteem when receiving low parental support, we found a positive association between PED and optimism when receiving high parental support. Based on the findings that refugee youth were shown to be less optimistic when obtaining low peer support, the main interaction effect for peer support on optimism seemed to be driven by refugee youth. The results of our cross-sectional study highlight the importance of identifying specific social support factors for specific adjustment outcomes and also the importance of differentiating between minority groups. Further, the findings offer practical implications for the educational sector in terms of programs focusing on the development of peer-support networks to especially promote refugee youth resilience and resettlement in Germany.

Impact of the COVID-19 pandemic on publication dynamics and non-COVID-19 research production.

BACKGROUND: The COVID-19 pandemic has severely affected health systems and medical research worldwide but its impact on the global publication dynamics and non-COVID-19 research has not been measured. We hypothesized that the COVID-19 pandemic may have impacted the scientific production of non-COVID-19 research. METHODS: We conducted a comprehensive meta-research on studies (original articles, research letters and case reports) published between 01/01/2019 and 01/01/2021 in 10 high-impact medical and infectious disease journals (New England Journal of Medicine, Lancet, Journal of the American Medical Association, Nature Medicine, British Medical Journal, Annals of Internal Medicine, Lancet Global Health, Lancet Public Health, Lancet Infectious Disease and Clinical Infectious Disease). For each publication, we recorded publication date, publication type, number of authors, whether the publication was related to COVID-19, whether the publication was based on a case series, and the number of patients included in the study if the publication was based on a case report or a case series. We estimated the publication dynamics with a locally estimated scatterplot smoothing method. A Natural Language Processing algorithm was designed to calculate the number of authors for each publication. We simulated the number of non-COVID-19 studies that could have been published during the pandemic by extrapolating the publication dynamics of 2019 to 2020, and comparing the expected number to the observed number of studies. RESULTS: Among the 22,525 studies assessed, 6319 met the inclusion criteria, of which 1022 (16.2%) were related to COVID-19 research. A dramatic increase in the number of publications in general journals was observed from February to April 2020 from a weekly median number of publications of 4.0 (IQR: 2.8-5.5) to 19.5 (IQR: 15.8-24.8) (p < 0.001), followed afterwards by a pattern of stability with a weekly median number of publications of 10.0 (IQR: 6.0-14.0) until December 2020 (p = 0.045 in comparison with April). Two prototypical editorial strategies were found: 1) journals that maintained the volume of non-COVID-19 publications while integrating COVID-19 research and thus increased their overall scientific production, and 2) journals that decreased the volume of non-COVID-19 publications while integrating COVID-19 publications. We estimated using simulation models that the COVID pandemic was associated with a 18% decrease in the production of non-COVID-19 research. We also found a significant change of the publication type in COVID-19 research as compared with non-COVID-19 research illustrated by a decrease in the number of original articles, (47.9% in COVID-19 publications vs 71.3% in non-COVID-19 publications, p < 0.001). Last, COVID-19 publications showed a higher number of authors, especially for case reports with a median of 9.0 authors (IQR: 6.0-13.0) in COVID-19 publications, compared to a median of 4.0 authors (IQR: 3.0-6.0) in non-COVID-19 publications (p < 0.001). CONCLUSION: In this meta-research gathering publications from high-impact medical journals, we have shown that the dramatic rise in COVID-19 publications was accompanied by a substantial decrease of non-COVID-19 research. META-RESEARCH REGISTRATION: https://osf.io/9vtzp/ .

Under-Vaccination in Pediatric Liver Transplant Candidates with Acute and Chronic Liver Disease-A Retrospective Observational Study of the European Reference Network TransplantChild.

Infection is a serious concern in the short and long term after pediatric liver transplantation. Vaccination represents an easy and cheap opportunity to reduce morbidity and mortality due to vaccine-preventable infection. This retrospective, observational, multi-center study examines the immunization status in pediatric liver transplant candidates at the time of transplantation and compares it to a control group of children with acute liver disease. Findings show only 80% were vaccinated age-appropriately, defined as having received the recommended number of vaccination doses for their age prior to transplantation; for DTP-PV-Hib, less than 75% for Hepatitis B and two-thirds for pneumococcal conjugate vaccine in children with chronic liver disease. Vaccination coverage for live vaccines is better compared to the acute control group with 81% versus 62% for measles, mumps and rubella (p = 0.003) and 65% versus 55% for varicella (p = 0.171). Nevertheless, a country-specific comparison with national reference data suggests a lower vaccination coverage in children with chronic liver disease. Our study reveals an under-vaccination in this high-risk group prior to transplantation and underlines the need to improve vaccination.

Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection : A Retrospective Cohort Study.

BACKGROUND: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. OBJECTIVE: To assess the potential effect of donor or recipient HED on liver transplant rejection. DESIGN: Retrospective cohort study. SETTING: Liver transplant units. PATIENTS: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. MEASUREMENTS: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. RESULTS: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. LIMITATION: The DSAs were measured only in children. CONCLUSION: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. PRIMARY FUNDING SOURCE: Institut National de la Santé et de la Recherche Médicale.

Heterologous expression of 8-demethyl-tetracenomycin (8-dmtc) affected Streptomyces coelicolor life cycle.

Heterologous hosts are highly important to detect the expression of biosynthetic gene clusters that are cryptic or poorly expressed in their natural hosts. To investigate whether actinorhodin-overproducer Streptomyces coelicolor ∆ppk mutant strain could be a possible prototype as a heterologous expression host, a cosmid containing most of the elm gene cluster of Streptomyces olivaceus Tü2353 was integrated into chromosomes of both S. coelicolor A3(2) and ∆ppk strains. Interestingly, it was found that the production of tetracyclic polyketide 8-demethyl-tetracenomycin (8-DMTC) by recombinant strains caused significant changes in the morphology of cells. All the pellets and clumps were disentangled and mycelia were fragmented in the recombinant strains. Moreover, they produce neither pigmented antibiotics nor agarase and did not sporulate. By eliminating the elm biosynthesis genes from the cosmid, we showed that the morphological properties of recombinants were caused by the production of 8-DMTC. Extracellular application of 8-DMTC on S. coelicolor wild-type cells caused a similar phenotype with the 8-DMTC-producing recombinant strains. The results of this study may contribute to the understanding of the effect of 8-DMTC in Streptomyces since the morphological changes that we have observed have not been reported before. It is also valuable in that it provides useful information about the use of Streptomyces as hosts for the heterologous expression of 8-DMTC.

COVID-19-related medical research: a meta-research and critical appraisal.

BACKGROUND: Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles. METHODS: The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools. RESULTS: Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37-337). CONCLUSIONS: Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/5zjyx/.

Adenosine kinase deficiency: Three new cases and diagnostic value of hypermethioninemia.

Adenosine kinase (ADK) deficiency is characterized by liver disease, dysmorphic features, epilepsy and developmental delay. This defect disrupts the adenosine/AMP futile cycle and interferes with the upstream methionine cycle. We report the clinical, histological and biochemical courses of three ADK children carrying two new mutations and presenting with neonatal cholestasis and neurological disorders. One of them died of liver failure whereas the other two recovered from their liver damage. As the phenotype was consistent with a mitochondrial disorder, we studied liver mitochondrial respiratory chain activities in two patients and revealed a combined defect of several complexes. In addition, we retrospectively analyzed methionine plasma concentration, a hallmark of ADK deficiency, in a cohort of children and showed that methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases. ADK deficiency is a cause of neonatal or early infantile liver disease that may mimic primary mitochondrial disorders. In this context, an elevation of methionine plasma levels over twice the upper limit should not be considered as a nonspecific finding. ADK deficiency induced-liver dysfunction is most often transient, but could be life-threatening.