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Ex vivo lung perfusion (EVLP) is a preservation method for donor lungs, which keep lungs viable in a physiological environment outside of a body for a short period of time. EVLP is established clinically for lung transplantation. Experimental applications for EVLP are e.g. lung cancer research or medical device development and testing. For preservation, a lung is ventilated artificially in an organ chamber and perfused antegrade through the pulmonary artery. Here we introduce a thermoregulation system for an experimental EVLP system to be used for translational research approaches as well as for training medical staff. To implement physiological culture conditions that are a prerequisite for lung preservation and tissue homeostasis, a thermoregulation is needed to rewarm the explanted lung tissue (storage temperature 4°C). Technically, the EVLP system must be thermally insulated, so loss of caloric is avoided. For monitoring, temperature sensors are integrated within the lung, in the organ chamber and in the afferent perfusate tube, whereby the measured values determine the thermoregulation. Initial tests using thermal packs (cooled to 4-6°C) placed on a heating mat, as a part of the perfusion circuit, showed that the perfusate temperature falls to 34°C, but restores after approximately 60 minutes (36.5°C), whereby the thermal pack is warmed. With this setup longer perfusion times should be obtained rather than without thermoregulation due to normothermic perfusion of the lung.

The sensitivity of terrestrial environments to past changes in heat transport is expected to be manifested in Holocene climate proxy records on millennial to seasonal timescales. Stalagmite formation in the Okshola cave near Fauske (northern Norway) began at about 10.4 ka, soon after the valley was deglaciated. Past monitoring of the cave and surface has revealed stable modern conditions with uniform drip rates, relative humidity and temperature. Stable isotope records from two stalagmites provide time-series spanning from c. 10 380 yr to AD 1997; a banded, multi-coloured stalagmite (Oks82) was formed between 10 380 yr and 5050 yr, whereas a pristine, white stalagmite (FM3) covers the period from ∼7500 yr to the present. The stable oxygen isotope (δ18Oc), stable carbon isotope (δ13Cc), and growth rate records are interpreted as showing i) a negative correlation between cave/surface temperature and δ18Oc, ii) a positive correlation between wetness and δ13Cc, and iii) a positive correlation between temperature and growth rate. Following this, the data from Okshola show that the Holocene was characterised by high-variability climate in the early part, lowvariability climate in the middle part, and high-variability climate and shifts between two distinct modes in the late part. A total of nine Scandinavian stalagmite δ18Oc records of comparable dating precision are now available for parts or most of the Holocene. None of them show a clear Holocene thermal optimum, suggesting that they are influenced by annual mean temperature (cave temperature) rather than seasonal temperature. For the last 1000 years, δ18Oc values display a depletion-enrichment-depletion pattern commonly interpreted as reflecting the conventional view on climate development for the last millennium. Although the δ18Oc records show similar patterns and amplitudes of change, the main challenges for utilising high-latitude stalagmites as palaeoclimate archives are i) the accuracy of the age models, ii) the ambiguity of the proxy signals, and iii) calibration with monitoring data. [ABSTRACT FROM AUTHOR]

Abstract Background MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages. Methods To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation. Results Intratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 ± 136.7 vs. 242.2 ± 102.2 pg/ml, p < 0.05), KC (1796.2 ± 436.1 vs. 1138.2 ± 310.2 pg/ml, p < 0.05) and neutrophils (total number of neutrophils, 3.33 ± 0.93 × 104 vs. 1.90 ± 0.61 × 104, p < 0.05) in our mouse model. Conclusion MIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.

Purpose: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy., Methods: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship., Results: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( P trend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m 2 , the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer., Conclusion: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m 2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Adequate privacy protection is crucial for implementing modern AI algorithms in medicine. With Fully Homomorphic Encryption (FHE), a party without access to the secret key can perform calculations and advanced analytics on encrypted data without taking part of either the input data or the results. FHE can therefore work as an enabler for situations where computations are carried out by parties that are denied plain text access to sensitive data. It is a scenario often found with digital services that process personal health-related data or medical data originating from a healthcare provider, for example, when the service is delivered by a third-party service provider located in the cloud. There are practical challenges to be aware of when working with FHE. The current work aims to improve accessibility and reduce barriers to entry by providing code examples and recommendations to aid developers working with health data in developing FHE-based applications. HEIDA is available on the GitHub repository: https://github.com/rickardbrannvall/HEIDA.

We employ U-Pb calcite dating of structurally-controlled fracture fills within crystalline Caledonian basement in western Norway to reveal subtle large-scale tectonic events that affected this rifted continental margin. The ages (15 in total) fall into four distinct groups with ages mainly ranging from latest Cretaceous to Pleistocene. (1) The three oldest (Triassic-Jurassic) ages refine the complex faulting history of a reactivated fault strand originated from the Caledonian collapse and broadly correlate with known rifting events offshore. (2) Two ages of ca. 90-80 Ma relate to lithospheric stretching and normal fault reactivation of a major ENE-WSW trending late Caledonian shear zone. (3) We correlate five ages between ca. 70 and 60 Ma with far-field effects and dynamic uplift related to the proto-Iceland mantle plume, the effect and extent of which is highly debated. (4) The five youngest ages (< 50 Ma) from distinct NE-SW trending faults are interpreted to represent several episodes of post-breakup fracture dilation, indicating a long-lived Cenozoic deformation history. Our new U-Pb data combined with structural and isotopic data show that much larger tracts of the uplifted continental margin of western Norway have been affected by far-field tectonic stresses than previously anticipated, with deformation continuing into the late Cenozoic., (© 2023. The Author(s).)

Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Lung ischemia-reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate lungs before transplant but has failed to provide significant improvements after IRI. We hypothesized that liquid ventilation (LV) could be utilized for ex vivo lung reconditioning in a rat IRI model. We compared EVLP with LV in an isolated ex vivo rat lung with an aqueous ventilant using quantitative physiological and immunological parameters. We observed improved physiological parameters and mechanical clearance of alveolar macrophages and cytokines halting the propagation of the inflammatory response in IRI. While the wide applicability to large animal or human transplantation have yet to be explored, these findings represent a method for lung reconditioning in the setting of significant IRI that could widen the lung organ donation pool and limit morbidity and mortality associated with ischemia-induced primary graft dysfunction.

Objective: The relationship between fatigue and cognition has not been fully elucidated in children and adolescent survivors of brain tumours. The aim of the present study was to investigate the potential relationship between fatigue and cognitive impairments in these survivors, as this group is at risk for both types of deficits., Methods: Survivors of paediatric brain tumours (n = 45) underwent a neuropsychological testing on average 4 years after diagnosis. Mean age at follow-up was 13.41 years. Cognition was assessed with neuropsychological tests, and fatigue with the Pediatric Quality of Life (PedsQL™) Multidimensional Fatigue Scale. Regression analysis, adjusted for cranial radiotherapy and age at diagnosis, was used to investigate the associations between cognitive variables and fatigue subscales. Cognitive variables associated with fatigue were subsequently exploratively assessed., Results: Significant associations were found for cognitive fatigue and measures of cognitive processing speed; Coding: p = .003, r = .583, 95% CI [9.61; 22.83] and Symbol Search: p = .001, r = .585, 95% CI [10.54; 24.87]. Slower processing speed was associated with poorer results for cognitive fatigue. Survivors with the largest decrease in processing speed from baseline to follow-up also experienced the most cognitive fatigue. Survivors expressed more cognitive fatigue compared to other types of fatigue., Conclusions: The association between cognitive fatigue and cognitive processing speed in children and adolescents treated for brain tumours is in concordance with the results previously reported in adults. Some survivors experience fatigue without impairment in processing speed, indicating the need for comprehensive assessments. Moreover, the study supports that fatigue is a multidimensional concept which should be measured accordingly.

Background: Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide., Methods: The PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence., Results: 427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN-comparable to the risk among members of the general population with at least two first-degree relatives affected., Conclusions: Colonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken., Competing Interests: Competing interests: HL and TW are shareholders in, and have signed an intellectual property agreement with the company Concidera Health. The company develops clinical decision support tools for childhood cancer survivorship., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Survivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors., Methods: This largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated., Results: One hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs., Conclusions: We demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF., Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public., Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors., Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)