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Liver transplantation in childhood has an excellent long-term outcome, but is associated with a long-term risk of infection. Measles is a vaccine-preventable infection, with case series describing severe courses with graft rejection, mechanical ventilation and even death in liver transplant recipients. Since about 30% of liver transplanted children receive liver transplants in their first year of life, not all have reached the recommended age for live vaccinations. On the contrary, live vaccines are contraindicated after transplantation. In addition, vaccination response is poorer in individuals with liver disease compared to healthy children. This retrospective, single-centre, cross-sectional study examines measles immunity in paediatric liver transplant recipients before and after transplantation. Vaccination records of 239 patients, followed up at Hannover Medical School between January 2021 and December 2022 were analysed. Twenty eight children were excluded due to stem cell transplantation, regular immunoglobulin substitution or measles vaccination after transplantation. More than 55% of all 211 children analysed and 75% of all those vaccinated at least once are measles seropositive after transplantation-48% after one and 84% after two vaccinations-which is less than in healthy individuals. Interestingly, 26% of unvaccinated children also showed measles antibodies and about 5-15% of vaccinated patients who were seronegative at the time of transplantation were seropositive afterwards, both possibly through infection. In multivariable Cox proportional hazards regression, the number of vaccinations (HR 4.30 [95% CI 2.09-8.83], p

The incidence of pediatric liver tumors in general has been rising over the last years and so is the number of children undergoing liver transplantation for this indication. To contribute to the ongoing improvement of pre- and post-transplant care, we aim to describe outcome and risk factors in our patient cohort. We have compared characteristics and outcome for patients transplanted for hepatoblastoma to other liver malignancies in our center between 1983 and 2022 and analysed influential factors on tumor recurrence and mortality using nominal logistic regression analysis. Of 39 children (16 f) who had transplants for liver malignancy, 31 were diagnosed with hepatoblastoma. The proportion of malignant tumors in the transplant cohort rose from 1.9% (1983–1992) to 9.1% in the current decade (p < 0.0001). Hepatoblastoma patients were transplanted at a younger age and were more likely to have tumor extent beyond the liver. Post-transplant bile flow impairment requiring intervention was significantly higher compared to our total cohort (48 vs. 24%, p > 0.0001). Hearing loss was a common side effect of ototoxic chemotherapy in hepatoblastoma patients (48%). The most common maintenance immunosuppression were mTor-inhibitors. Risk factors for tumor recurrence in patients with hepatoblastoma were higher AFP before transplant (AFPpre-LTX), a low ratio of AFPmax to AFPpre-LTX and salvage transplantation. Liver malignancies represent a rising number of indications for liver transplantation in childhood. Primary tumor resection can spare a liver transplant with all its long-term complications, but in case of tumor recurrence, transplantation might have inferior outcome. The rate of acute biopsy-proven rejections and biliary complications in comparison to our total transplant cohort needs further investigations.

Following paediatric solid organ liver transplantation, risk of infection is high, both in the short and long term. Even though an infection with hepatitis A virus (HAV) is often asymptomatic and self-limited in children, some case studies describe severe cases leading to death. Vaccinations offer simple, safe and cheap protection. However, data on vaccination rates against hepatitis A in children with liver disease are scarce. Moreover, the vaccine is only approved from the age of one year old. At the same time, up to 30% of children with liver disease are transplanted within the first year of life, so the window of opportunity for vaccination is limited. This retrospective, observational, single-centre study examines the HAV immunity in paediatric liver transplant recipients before and after the first year of transplantation. Vaccination records of 229 of 279 (82.1%) children transplanted between January 2003 and June 2021 were analysed. Of 139 eligible children aged ≥ 1 year old, only 58 (41.7%) were vaccinated at least with one HAV dose prior to transplantation. In addition, seven patients received the vaccine below one year of age. After one or two doses, 38.5% or 90.6% of 65 patients were anti-HAV-IgG positive, respectively. This percentage remained stable up to the first annual check-up. For children vaccinated only once, a shorter interval from vaccination to transplantation is a risk factor for lack of immunity. Thus, HAV immunisation should be started earlier in liver transplant candidates to improve immunity in this high-risk group.

Familial intrahepatic cholestasis 1 (FIC1) disease is a genetic disorder characterized by hepatic and gastrointestinal disease due to ATP8B1 deficiency, often requiring liver transplantation (LT). Extrahepatic symptoms, such as diarrhea, malabsorption, and failure to thrive, do not improve and instead may be aggravated after LT. We describe a patient with FIC1 disease who underwent LT at 2 years, 8 months of age. After LT, the child developed severe refractory diarrhea and failed to thrive. The response to bile acid resins was unsatisfactory, and the parents declined our recommendation for partial external biliary diversion (PEBD). Quality of life was extremely impaired, especially due to severe diarrhea, making school attendance impossible. Attempting to reduce the total bile acids, we initiated off-label use of the ileal bile acid transporter (IBAT) inhibitor Elobixibat (Goofice™), later converted to Odevixibat (Bylvay™). After six months of treatment, the patient showed less stool output, increased weight and height, and improved physical energy levels. The child could now pursue higher undergraduate education. In our patient with FIC1 disease, the use of IBAT inhibitors was effective in treating chronic diarrhea and failure to thrive. This approach is novel; further investigations are needed to clarify the exact mode of action in this condition.

Varicella is one of the most common vaccine-preventable infections after paediatric solid organ transplantation; thus, vaccination offers simple and cheap protection. However, children with liver disease often progress to liver transplantation (LT) before they reach the recommended vaccination age. As a live vaccine, varicella zoster virus (VZV) vaccination after transplantation is controversial; however, many case series demonstrate that vaccination may be safe and effective in paediatric liver transplant recipients. Only limited data exists describing long-term vaccination response in such immunocompromised patients. We investigated retrospectively vaccination response in paediatric patients before and after transplantation and describe long-term immunity over ten years, including the influence of booster-vaccinations. In this retrospective, single-centre study, 458 LT recipients were analysed between September 2004 and June 2021. Of these, 53 were re-transplantations. Patients with no available vaccination records and with a history of post-transplant lymphoproliferative disease, after hematopoietic stem cell transplantation and clinical chickenpox were excluded from this analysis (n = 198). In total, data on 207 children with a median annual follow-up of 6.2 years was available: 95 patients (45.9%) were unvaccinated prior to LT. Compared to healthy children, the response to vaccination, measured by seroconversion, is weaker in children with liver disease: almost 70% after one vaccination and 93% after two vaccinations. One year after transplantation, the mean titres and the number of children with protective antibody levels (VZV IgG ≥ 50 IU/L) decreased from 77.5% to 41.3%. Neither diagnosis, gender, nor age were predictors of vaccination response. Booster-vaccination was recommended for children after seroreversion using annual titre measurements and led to a significant increase in mean titre and number of protected children. Response to vaccination shows no difference from monotherapy with a calcineurin inhibitor to intensified immunosuppression by adding prednisolone or mycophenolate mofetil. Children with liver disease show weaker seroconversion rates to VZV vaccination compared to healthy children. Therefore, VZV-naïve children should receive basic immunization with two vaccine doses as well as those vaccinated only once before transplantation. An average of 2–3 vaccine doses are required in order to achieve a long-term seroconversion and protective antibody levels in 95% of children.

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.

(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983–2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983–1992) to 97.5%/86.5% (OR = 12.5; p < 0.0001/OR = 6.5; p < 0.0001) (2014–2020). Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation (log7.378/9.657; p < 0.0001) and indication of acute liver failure (log = 1.944/2.667; HR = 2.015/1.772; p = 0.0114/0.002) impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation (log = 1.755; HR = 1.744; p = 0.0176) and prolonged waiting times in high-urgency status (log = 2.588; HR = 1.073; p = 0.0026), whereas the indication of biliary atresia improved outcome (log = 1.502; HR = 0.575; p = 0.0315). Graft survival was additionally impaired by pre-existing portal vein thrombosis (log = 1.482; HR = 2.016; p = 0.0330). (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.

Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future.Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor.Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models.Discussion: We show for the first time that age and diagnosis are major independent determinants of cellular and soluble immune marker levels in children with end-stage liver disease. These results need to be considered for future research on predictive immune monitoring after pLTx.

BACKGROUND: Obesity is a risk factor for various types of infectious diseases and cancer. The increase in adipose tissue causes alterations in both adipogenesis and the production of adipocyte-secreted proteins (adipokines). Since natural killer (NK) cells are the host's primary defense against virus-infected and tumor cells, we investigated how adipocyte-conditioned medium (ACM) affects functions of two distinct human NK cell subsets. METHODS: Isolated human peripheral blood mononuclear cells (PBMCs) were cultured with various concentrations of human and murine ACM harvested on two different days during adipogenesis and analyzed by fluorescent-activated cell sorting (FACS). RESULTS: FACS analyses showed that the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), granzyme A (GzmA) and interferon (IFN)-γ in NK cells was regulated in a subset-specific manner. ACM treatment altered IFN-γ expression in CD56(dim) NK cells. The production of GzmA in CD56(bright) NK cells was differentially affected by the distinct adipokine compositions harvested at different states of adipogenesis. Comparison of the treatment with either human or murine ACM revealed that adipokine-induced effects on NK cell expression of the leptin receptor (Ob-R), TRAIL and IFN-γ were species-specific. CONCLUSION: Considering the growing prevalence of obesity and the various disorders related to it, the present study provides further insights into the roles human NK cell subsets play in the obesity-associated state of chronic low-grade inflammation.

This study presents the first quantitative assessment of weathering conditions in the Tajikistan depression throughout the last full glacial cycle. We employed geochemical and magnetic susceptibility analyses to investigate various weathering indices (WIs), with the CPA and FENG indices identified as the most suitable for this region. Our results confirm the formation of a robust pedocomplex, PS2, during the OIS5 interglacial phase, while primary loess deposition occurred during the interstadials. The presence of a weak paleosol, PS1, suggests that OIS3 was not significantly pronounced, and sediment transport and deposition continued during this period. Furthermore, we assessed the effectiveness of various climatic transfer functions, including some recently developed specifically for Chinese loess. These transfer functions have also shown promising applicability to the loess of Central Asia, producing realistic climate trends that are, however, still to be taken with caution. The MAT and mean annual precipitation generated with these functions show for the last interglacial period about 13°C and 665 mm, thus higher temperatures and lower precipitation than the current conditions of 10.8°C and 730 mm. These results indicate a significant increase (c. 15%) in both temperature and precipitation compared to the stadial periods.

Archaeological and palaeoenvironmental evidence from the Armenian Highlands and wider southern Caucasus region emphasises the significance of Marine Oxygen Isotope Stage 3 (c. 57–29 ka) as a crucial period for understanding hominin behaviours amidst environmental fluctuations. Ararat-1 cave, situated in the Ararat Depression, Republic of Armenia, presents potential for resolving emerging key debates regarding hominin land use adaptations during this interval, due to its well-preserved lithic artefacts and faunal assemblages. We present the first results of combined sedimentological, geochronological (luminescence and radiocarbon), archaeological and palaeoecological (macrofauna, microfauna and microcharcoal) study of the Ararat-1 sequence. We demonstrate sediment accumulation occurred between 52 and 35 ka and was caused by a combination of aeolian activity, cave rockfall and water action. Whilst the upper strata of the Ararat-1 sequence experienced post-depositional disturbance due to faunal and anthropogenic processes, the lower strata remain relatively undisturbed. We suggest that during a stable period within MIS 3, Ararat-1 was inhabited by Middle Palaeolithic hominins amidst a mosaic of semi-arid shrub, grassland, and temperate woodland ecosystems. These hominins utilised local and distant toolstone raw materials, indicating their ability to adapt to diverse ecological and elevation gradients. Through comparison of Ararat-1 with other sequences in the region, we highlight the spatial variability of MIS 3 environments and its on hominin land use adaptations. This demonstrates the importance of the Armenian Highlands for understanding regional MP settlement dynamics during a critical period of hominin dispersals and evolution.

Background Plant litter decomposition is a key process in carbon and nutrient cycling. Among the factors determining litter decomposition rates, the role of soil biota in the decomposition of different plant litter types and its modification by variations in climatic conditions is not well understood. Methods In this study, we used litterbags with different mesh sizes (45 µm, 1 mm and 4 mm) to investigate the effect of microorganisms and decomposer microarthropods on leaf and root litter decomposition along an altitudinal gradient of tropical montane rainforests in Ecuador. We examined decomposition rates, litter C and N concentrations, microbial biomass and activity, as well as decomposer microarthropod abundance over one year of exposure at three different altitudes (1,000, 2,000 and 3,000 m). Results Leaf litter mass loss did not differ between the 1,000 and 2,000 m sites, while root litter mass loss decreased with increasing altitude. Changes in microbial biomass and activity paralleled the changes in litter decomposition rates. Access of microarthropods to litterbags only increased root litter mass loss significantly at 3,000 m. The results suggest that the impacts of climatic conditions differentially affect the decomposition of leaf and root litter, and these modifications are modulated by the quality of the local litter material. The findings also highlight litter quality as the dominant force structuring detritivore communities. Overall, the results support the view that microorganisms mostly drive decomposition processes in tropical montane rainforests with soil microarthropods playing a more important role in decomposing low-quality litter material.

Northern Europe experienced cycles of hominin habitation and absence during the Middle Pleistocene. Fluvial gravel terrace sites in the east of Britain and north of France provide a majority of the data contributing to this understanding, mostly through the presence or absence of stone-tool artefacts. To date, however, relatively few sites have been radiometrically dated, and many have not been excavated in modern times, leading to an over-reliance on selectively sampled and poorly dated lithic assemblages. This includes Fordwich (Kent, UK), where over 330 bifaces were discovered through industrial quarrying in the 1920s. Here, we present the first excavation and dating of artefacts discovered in situ at Fordwich, alongside their technological analysis and relationship to those previously recovered. The site is demonstrated to retain deposits of Lower Palaeolithic artefacts, with 251 flakes, scrapers and cores identified to date. Infrared-radiofluorescence (IR-RF) dating of feldspar reveals 112 artefacts to have come from levels dating to at least 570 ± 36 to 513 ± 30 thousand years ago (ka) and are most plausibly assigned to an MIS 14 deposition, with artefacts produced during MIS 15 (approx. 560–620 ka). Indeed, these IR-RF samples provide minimum ages for artefacts. Combined with evidence from exposures linked to the original quarrying activities, a similar MIS 15 age is suggested for the more than 330 handaxe artefacts discovered in the 1920s. The remaining excavated artefacts come from levels dated to between 347 ± 22 and 385 ± 21 ka (MIS 10 or 11), with this later age interpreted to reflect post-MIS 14 deposition by substrate gullying and solifluction. These data demonstrate Fordwich to be one of the earliest Palaeolithic sites in northwestern Europe, and to retain the only large Acheulean handaxe assemblage directly dated to pre-MIS 13. Thus, Fordwich is determined to be a crucial piece of the pre-Anglian Palaeolithic puzzle in northern Europe.

The upper Unstrut River is located in Germany at the modern Central European climate boundary of Cfb and Dfb climate. The river drains a loess landscape, which has experienced important environmental changes throughout the last 12,000 years. To evaluate the impacts of these changes on floodplain evolution, a multi-proxy research program, consisting of 2D electrical resistivity tomography profiling (ERT), vibracoring, and sedimentological investigations, 14C and OSL dating were applied. From base to top the investigations the following fluvial deposits were revealed: (1) gravels embedded in a fine-grained sediment matrix (interpreted as fluvial bedload deposits); (2) silty sediment with pedogenic features (interpreted as overbank floodplain deposits); (3) peat and tufa deposits (interpreted as wetland deposits) intercalated by pedogenetically influenced silty sediments (interpreted as overbank deposits); (4) humic silty sediment with some pedogenic features (interpreted as overbank floodplain deposits); and (5) silty sediments (interpreted as overbank deposits). Radiocarbon and luminescence dates yielded the following periods for sediment formation: (1) Younger Dryas to Preboreal period (around 11.6 cal ka BP); (2) Preboreal to early Atlantic period (approx. 11.6 to 7.0 cal ka BP); (3) early Atlantic to late Subboreal period (approx. 7.3 to 3.4 cal ka BP); (4) late Subboreal to early Subatlantic period (2.9 to 2.3 cal ka BP); and (5) late Subatlantic period (approx. 1.0 to 0.6 cal ka BP). The results suggest that floodplain development during the latest Pleistocene and early Holocene (approx. 11.6 to 7.0 cal ka BP) was considerably controlled by climatic conditions and short-term climate variabilities, which caused gravel deposition and overbank sedimentation. Afterwards floodplain conditions varied between rather stable (peat and tufa development, initial soil formation) and active periods (deposition of overbank fines). In this context, active periods with increased sediment input prevailed from approx. 5.1 to 3.4 cal ka BP, 2.9 to 2.3 cal ka, and 1.0 to 0.6 cal ka BP, temporally corresponding well with increased land-use phases of the past. In conclusion this study demonstrates that the investigated Unstrut catchment has reacted very sensitively to natural and human-induced changes during the latest Pleistocene and Holocene. Consequently, this high vulnerability to external changes should be considered in future river predictions or river management.

The Armenian highlands encompasses rugged and environmentally diverse landscapes and is characterized by a mosaic of distinct ecological niches and large temperature gradients. Strong seasonal fluctuations in resource availability along topographic gradients likely prompted Pleistocene hominin groups to adapt by adjusting their mobility strategies. However, the role that elevated landscapes played in hunter-gatherer settlement systems during the Late Pleistocene (Middle Palaeolithic [MP]) remains poorly understood. At 1640 m above sea level, the MP site of Kalavan 2 (Armenia) is ideally positioned for testing hypotheses involving elevation-dependent seasonal mobility and subsistence strategies. Renewed excavations at Kalavan 2 exposed three main occupation horizons and ten additional low densities lithic and faunal assemblages. The results provide a new chronological, stratigraphical, and paleoenvironmental framework for hominin behaviors between ca. 60 to 45 ka. The evidence presented suggests that the stratified occupations at Kalavan 2 locale were repeated ephemerally most likely related to hunting in a high-elevation within the mountainous steppe landscape.