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Background Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone.Methods and analysis E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials.Ethics and dissemination The East Midlands—Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings.Trial registration number EudraCT number 2022-002659-20; ISRCTN 10615985.

Abstract Recent advancements in diagnostic CT detector technology have made it possible to resolve anatomical features smaller than 20 LP/cm, referred to as ultra-high-resolution (UHR) CT. Subtle biological motions that did not affect standard-resolution (SR) CT may not be neglected in UHR. This study aimed to quantify the cardiac-induced motion of the pancreas and simulate its impact on the image quality of UHR-CT. We measured the displacement of the head of the pancreas in three healthy volunteers using Displacement Encoding with Stimulated Echoes (DENSE) MRI. The results were used to simulate SR- and UHR-CT acquisitions affected by pancreatic motion. We found pancreatic displacement in the 0.24–1.59 mm range during one cardiac cycle across the subjects. The greatest displacement was observed in the anterior–posterior direction. The time to peak displacement varied across subjects. Both SR and UHR images showed reduced image quality, as measured by radial modulation transfer function, due to cardiac-induced motion, but the motion artifacts caused more severe degradation in UHR acquisitions. Our investigation of cardiac-induced pancreatic displacement reveals its potential to degrade both standard and UHR-CT scans. To fully utilize the improvement in spatial resolution offered by UHR-CT, the effects of cardiac-induced motion in the abdomen need to be understood and corrected. Relevance statement Advancements in CT detector technology have enhanced CT scanner spatial resolution to approximately 100 µm. Consequently, previously ignored biological motions such as the cardiac-induced motion of the pancreas now demand attention to fully utilize this improved resolution. Graphical Abstract

Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb‐girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0–50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age‐ and sex–matched healthy control cohort (n=50). Cardiovascular magnetic resonance markers, including 3‐dimensional strain and fibrosis, were assessed for their respective association with major adverse cardiac events. Our results showed that markers of contractile performance were reduced across all muscular dystrophy groups. In particular, the dystrophinopathies cohort experienced reduced left ventricular (LV) ejection fraction and high burden of replacement fibrosis. Patients with type 1 myotonic dystrophy showed a 26.8% relative reduction in LV mass with corresponding reduction in chamber volumes. Eighty‐two major adverse cardiac events occurred over a median follow‐up of 5.2 years. Although LV ejection fraction was significantly associated with major adverse cardiac events (adjusted hazard ratio [aHR], 3.0 [95% CI, 1.4–6.4]) after adjusting for covariates, peak 3‐dimensional strain amplitude demonstrated greater predictive value (minimum principal amplitude: aHR, 5.5 [95% CI, 2.5–11.9]; maximum principal amplitude: aHR, 3.3 [95% CI, 1.6–6.8]; circumferential amplitude: aHR, 3.4 [95% CI, 1.6–7.2]; longitudinal amplitude: aHR, 3.4 [95% CI, 1.7–6.9]; and radial strain amplitude: aHR, 3.0 [95% CI, 1.4–6.1]). Minimum principal strain yielded incremental prognostic value beyond LV ejection fraction for association with major adverse cardiac events (change in χ2=13.8; P

Background Myocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non‐invasively in human explanted hearts. Methods and Results Biventricular tissue iron levels were measured in both failing (n=138) and non‐failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1–150.3] versus 137.4 [109.2–165.9] μg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 μg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF‐MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF‐MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron‐deficient hearts. Mechanistically, iron uptake pathways were impeded in HF‐MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts. Conclusions MID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non‐invasively monitor MID.

Pre conditioning injury or environmental enrichment have been shown to promote axon regeneration. Here the authors show that environmental enrichment, combined with preconditioning injury promotes regeneration via a redox signalling dependent mechanism.

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of

Early neurological improvement as assessed with the NIH stroke scale (NIHSS) at 24 h has been associated with improved long-term functional outcomes following acute ischemic stroke (AIS). Cardiac dysfunction is often present in AIS, but its association with outcomes is incompletely defined. We performed a pilot study to evaluate the association between non-invasively measured cardiac parameters and 24-h neurological improvement in prospectively enrolled patients with suspected AIS who presented within 12 h of symptom-onset and had an initial systolic blood pressure>140 mm Hg. Patients receiving thrombolytic therapy or mechanical thrombectomy were excluded. Non-invasive pulse contour analysis was used to measure mean arterial blood pressure (MAP), cardiac stroke volume index (cSVI), cardiac output (CO) and cardiac index (CI). Transcranial Doppler recorded mean middle cerebral artery flow velocity (MFV). We defined a decrease of 4 NIHSS points or NIHSS ≤ 1 at 24-h as neurological improvement. Of 75 suspected, 38 had confirmed AIS and did not receive reperfusion therapy. Of these, 7/38 (18.4%) had neurological improvement over 24 h. MAP was greater in those without improvement (108, IQR 96–123 mm Hg) vs. those with (89, IQR 73–104 mm Hg). cSVI, CO, and MFV were similar between those without and with improvement: 37.4 (IQR 30.9–47.7) vs. 44.7 (IQR 42.3–55.3) ml/m2; 5.2 (IQR 4.2–6.6) vs. 5.3 (IQR 4.7–6.7) mL/min; and 39.9 (IQR 32.1–45.7) vs. 34.4 (IQR 27.1–49.2) cm/s, respectively. Multivariate analysis found MAP and cSVI as predictors for improvement (OR 0.93, 95%CI 0.85–0.98 and 1.14, 95%CI 1.03–1.31). In this pilot study, cSVI and MAP were associated with 24-h neurological improvement in AIS.

Abstract The French government has supported as part of its “Investments for the Future” program a 9‐year research project, PeaMUST, devoted to pea and to a lesser extent, faba bean improvement. Focusing on the main causes of yield irregularity that limit pea and faba bean cultivation, an integrated approach, including molecular exploitation of the pea genome sequence, was applied to identify and incorporate favorable alleles and allele combinations in prebreeding material.

Abstract Background Wolfram syndrome is a rare genetic, progressive, neurodegenerative disorder characterised by childhood-onset diabetes mellitus, diabetes insipidus, optic atrophy and deafness. To date, the economic burden of Wolfram syndrome has not been well-studied or reported. The aim of this study was to evaluate the cost of illness (COI) of all people with Wolfram syndrome in the UK and to identify major determinants of cost from a service provider perspective (National Health Service, NHS). Methods A prevalence-based approach was used to model the UK Wolfram syndrome specialist service. Model inputs were informed by a pragmatic literature review and UK reference costs, in conjunction with patient interviews and expert opinion. A deterministic sensitivity analysis (DSA) was run at 10% to identify major cost drivers. Results The total COI of all people with Wolfram syndrome to the NHS was £1,055,899 per year, with an average annual cost per person with Wolfram syndrome of £16,498. Costs associated with diabetes mellitus care, late-stage diabetes mellitus complications and hearing impairment contributed most to the COI (18.9, 21.4 and 15.8% of the COI, respectively). The DSA identified costs associated with hearing impairment, diabetes mellitus care and end-stage renal disease (a diabetes mellitus complication) as major model drivers. Conclusions The annual cost of Wolfram syndrome to the NHS was found to be substantial, with areas of potential cost savings identified, such as diabetes mellitus management. This model provides crucial information to facilitate economic evaluation of prospective therapies for this disease.

Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P=0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P=0.018), of retransplantation on rejection risk (hazard ratio 6.3, P=0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P=0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.

Background Rectal biopsy for the diagnosis for Hirschsprung's disease (HD) can be performed in several ways. Suction rectal biopsy (SRB) is the most widely used method for neonates and younger infants while open strip biopsy (OSB) is reserved for older children. Current notions suggest that SRB should not be used in older infants due to perceived thicker fibrous tissue in their rectal walls leading to higher rates of inconclusive results. This study aims to compare the inconclusive rates of both methods in children of different age groups.Methods A retrospective study were carried out with patients aged 13 years who underwent SRB or OSB during a 4-year period in a single center. Rectal biopsies were performed on patients with HD with previous endorectal pull-through surgeries excluded. Primary outcomes were rates of inconclusive results for SRB and OSB overall and when divided into different age groups.Results 79 biopsies (57 SRB and 22 OSB) were included in the study. 12 biopsies (9 SRB and 3 OSB) were deemed inconclusive. There was no significant difference in the rate of inconclusive results between patients underwent SRB and OSB overall (15.8% vs 13.6%, p=1.000). The same results were obtained when patients were divided into under one year and over one year groups or other different age groups (30.0% vs 33.3%, p=1.000).Conclusions Despite low biopsy numbers, our study suggests that SRB provides comparable rates of inconclusive results with OSB in children of all age groups.

Abstract Background Congenital hyperinsulinism (CHI) is a rare, genetic disease which causes persistent hypoglycaemia, typically in new-borns. Patients with the diffuse disease variant often require near-total surgical removal of the pancreas, causing insulin-dependent diabetes mellitus (IDDM). The CHI economic burden is currently unknown. This study aimed to estimate the annual cost of illness (COI) of CHI patients in the UK from a service provider perspective (National Health Service, NHS and Personal Social Services), and to explore cost distribution within the patient population. Methods The model was based on standard practice of two CHI centres of excellence. Model inputs were informed by a pragmatic literature review, NHS Reference Costs (2015–2016) and the British National Formulary (2017). Only direct costs to the NHS and Personal Social Services were considered. A prevalence-based approach was used and annual costs incurred at all ages were calculated. A deterministic sensitivity analysis (DSA; run at 10%) identified major cost drivers. Results The COI of CHI patients to the NHS was £3,408,398.59 annually and average cost per patient was £2124.95. Cost distribution was skewed among CHI patients, with 5.9% of patients (95 patients in their first year of life) contributing to 61.8% (£2,105,491.07) of total costs. DSA results identified lack of response to first-line therapy and IDDM development post surgery (and associated healthcare costs) as major cost drivers. Conclusions Despite its rare disease status, estimated annual costs of CHI to the NHS were substantial. Development and management of post-surgical IDDM as a major cost driver highlights the need for effective treatments to mitigate such consequences and costs.

Abstract Background Allele-specific transcriptional regulation, including of imprinted genes, is essential for normal mammalian development. While the regulatory regions controlling imprinted genes are associated with DNA methylation (DNAme) and specific histone modifications, the interplay between transcription and these epigenetic marks at allelic resolution is typically not investigated genome-wide due to a lack of bioinformatic packages that can process and integrate multiple epigenomic datasets with allelic resolution. In addition, existing ad-hoc software only consider SNVs for allele-specific read discovery. This limitation omits potentially informative INDELs, which constitute about one fifth of the number of SNVs in mice, and introduces a systematic reference bias in allele-specific analyses. Results Here, we describe MEA, an INDEL-aware Methylomic and Epigenomic Allele-specific analysis pipeline which enables user-friendly data exploration, visualization and interpretation of allelic imbalance. Applying MEA to mouse embryonic datasets yields robust allele-specific DNAme maps and low reference bias. We validate allele-specific DNAme at known differentially methylated regions and show that automated integration of such methylation data with RNA- and ChIP-seq datasets yields an intuitive, multidimensional view of allelic gene regulation. MEA uncovers numerous novel dynamically methylated loci, highlighting the sensitivity of our pipeline. Furthermore, processing and visualization of epigenomic datasets from human brain reveals the expected allele-specific enrichment of H3K27ac and DNAme at imprinted as well as novel monoallelically expressed genes, highlighting MEA’s utility for integrating human datasets of distinct provenance for genome-wide analysis of allelic phenomena. Conclusions Our novel pipeline for standardized allele-specific processing and visualization of disparate epigenomic and methylomic datasets enables rapid analysis and navigation with allelic resolution. MEA is freely available as a Docker container at https://github.com/julienrichardalbert/MEA.

Traumatic brain injury (TBI) can be defined as a disorder in the function of the brain after a bump, blow, or jolt to the head, or penetrating head injury. Mild traumatic brain injury (mTBI) can cause devastating effects, such as the initiation of long-term neurodegeneration in brain tissue. In the current study, the effects of mTBI were investigated on rat brain regions; cortex (Co) and corpus callosum (CC) after 24 h (subacute trauma) by Fourier transform infrared (FTIR) imaging and immunohistochemistry (IHC). IHC studies showed the formation of amyloid-β (Aβ) plaques in the cortex brain region of mTBI rats. Moreover, staining of myelin basic protein presented the shearing of axons in CC region in the same group of animals. According to FTIR imaging results, total protein and lipid content significantly decreased in both Co and CC regions in mTBI group compared to the control. Due to this significant decrease in both lipid and protein content, remarkable consistency in lipid/protein band ratio in mTBI and control group, was observed. Significant decrease in methyl content and a significant increase in olefinic content were observed in Co and CC regions of mTBI rat brain tissues. Classification amongst distinguishable groups was performed using principal component analysis (PCA) and hierarchical clustering (HCA). This study established the prospective of FTIR imaging for assessing biochemical changes due to mTBI with high sensitivity, precision and high-resolution.

Abstract Parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease in those eligible for cardiovascular magnetic resonance (CMR). Parametric mapping with CMR now permits the routine spatial visualization and quantification of changes in myocardial composition based on changes in T1, T2, and T2*(star) relaxation times and extracellular volume (ECV). These changes include specific disease pathways related to mainly intracellular disturbances of the cardiomyocyte (e.g., iron overload, or glycosphingolipid accumulation in Anderson-Fabry disease); extracellular disturbances in the myocardial interstitium (e.g., myocardial fibrosis or cardiac amyloidosis from accumulation of collagen or amyloid proteins, respectively); or both (myocardial edema with increased intracellular and/or extracellular water). Parametric mapping promises improvements in patient care through advances in quantitative diagnostics, inter- and intra-patient comparability, and relatedly improvements in treatment. There is a multitude of technical approaches and potential applications. This document provides a summary of the existing evidence for the clinical value of parametric mapping in the heart as of mid 2017, and gives recommendations for practical use in different clinical scenarios for scientists, clinicians, and CMR manufacturers.

This article presents the psychosocial risk factors identified in the cases of 20 children less than four years of age who were victims of fatal or near-fatal physical abuse during a 12 month period in the Commonwealth of Kentucky. These data are related to the article “History, injury, and psychosocial risk factor commonalities among cases of fatal and near-fatal physical child abuse” (Pierce et al., 2017) [1].

Microplastic litter is a pervasive pollutant present in marine systems across the globe. The legacy of microplastics pollution in the marine environment today may remain for years to come due to the persistence of these materials. Microplastics are emerging contaminants of potential concern and as yet there are few recognised approaches for monitoring. In 2008, the EU Marine Strategy Framework Directive (MSFD, 2008/56/EC) included microplastics as an aspect to be measured. Here we outline the approach as discussed by the European Union expert group on marine litter, the technical Subgroup on Marine litter (TSG-ML), with a focus on the implementation of monitoring microplastics in seawater in European seas. It is concluded that harmonization and coherence is needed to achieve reliable monitoring.

Diastolic filling of the left ventricle (LV) occurs in two phases, early and late filling. Early filling, manifest as the “E-wave”, is thought to be substantially due to diastolic suction (DS), a phenomenon where the LV aspirates blood and fills itself, independent of atrial activity. Late filling, resulting in the mitral flow “A-wave” is a result of left atrial contraction. Adequate filling of the LV is necessary to maintain normal heart function at rest and under stress. DS is thought to be an important mechanism in the efficiency of filling. To study DS, we have invasively measured pressure and used cardiac MRI to evaluate cavitary volume and flow in an animal model to quantify different measures of DS under varied experimental conditions. The amount of filling due to DS (VDS), determined by the change in volume between mitral valve opening and LV pressure minimum of the pressure-volume loop (Katz 1930), is related to the measured end systolic volume (ESV). As ESV decreases the VDS increases. The smaller the ESV, the larger the recoil energy of the LV as it relaxes towards resting volume. This contributes increased energy for the suction of blood into the ventricle in early filling. Wave intensity analysis (the separation of forward and backwards waves and wave type) and intraventricular pressure gradients will also be considered in order to determine which best describes DS and whether they can be used together to better understand changes in filling dynamics under varied loading conditions.

Cracking sounds emitted from human synovial joints have been attributed historically to the sudden collapse of a cavitation bubble formed as articular surfaces are separated. Unfortunately, bubble collapse as the source of joint cracking is inconsistent with many physical phenomena that define the joint cracking phenomenon. Here we present direct evidence from real-time magnetic resonance imaging that the mechanism of joint cracking is related to cavity formation rather than bubble collapse. In this study, ten metacarpophalangeal joints were studied by inserting the finger of interest into a flexible tube tightened around a length of cable used to provide long-axis traction. Before and after traction, static 3D T1-weighted magnetic resonance images were acquired. During traction, rapid cine magnetic resonance images were obtained from the joint midline at a rate of 3.2 frames per second until the cracking event occurred. As traction forces increased, real-time cine magnetic resonance imaging demonstrated rapid cavity inception at the time of joint separation and sound production after which the resulting cavity remained visible. Our results offer direct experimental evidence that joint cracking is associated with cavity inception rather than collapse of a pre-existing bubble. These observations are consistent with tribonucleation, a known process where opposing surfaces resist separation until a critical point where they then separate rapidly creating sustained gas cavities. Observed previously in vitro, this is the first in-vivo macroscopic demonstration of tribonucleation and as such, provides a new theoretical framework to investigate health outcomes associated with joint cracking.

The additions of artificial structures to the landscape are usually translated into habitat loss and fragmentation, since they provide homogeneous habitats less diverse in types and number of microhabitats. Moreover, the smooth surface of artificial structures increases the degree of environmental stress (e.g. desiccation) experienced by intertidal organisms. Local biodiversity can be increased with microhabitats availability by attracting or supporting species of macrofauna and seaweeds. E.g., distribution and survival of the mollusc Patella candei, a limpet exploited in intertidal coasts of Açores, has been showed to be strongly influenced by availability of microhabitats. We experimentally analyzed the influence of microhabitat aggregation and dispersion on the distribution of several species of gastropods on midshores of artificial substrates. Data were compared with distributions within unmanipulated plots. Effects were found among treatments and control plots in densities of Tectarius striatus and at the different life-history stages of limpets (recruits, immature and adult individuals) inhabiting artificial substrata with manipulated aggregation levels. In case of Melaraphe neritoides, only in site 2 numbers of were greater in manipulated than in control plots. Configurations with different dispersion levels also showed greater densities than controls. Both aggregation and dispersion effects were more evident at site 2; however, due to the high variability among examined plots, no clear significant responses were found among the different treatments.

The pursuit of authenticity in fashion has taken more than a few interesting turns in the modern world. Consider its role in the political project of President Mobutu Sese Seko [...]