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Liver transplantation is the most effective treatment for end-stage liver disease. Despite improvements in surgical techniques, transplant rejection remains a significant concern. The liver is considered an immune-privileged organ due to its unique microenvironment and complex interactions among various cell types. Alloimmune responses mediated by T cells and antigen-presenting cells (APCs) play crucial roles in transplant rejection. The liver’s dual blood supply and unique composition of its sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs) contribute to its immune privilege. Alloantigen recognition by T cells occurs through direct, indirect, and semidirect pathways, leading to acute cellular rejection (ACR) and chronic rejection. ACR is a T cell-mediated process that typically occurs within the first few weeks to months after transplantation. Chronic rejection, on the other hand, is a gradual process characterized by progressive fibrosis and graft dysfunction, often leading to graft loss. Acute antibody-mediated rejection (AMR) is less common following surgery compared to other solid organ transplants due to the liver’s unique anatomy and immune privilege. However, when it does occur, AMR can be aggressive and lead to rapid graft dysfunction. Despite improvements in immunosuppression, rejection remains a challenge, particularly chronic rejection. Understanding the mechanisms of rejection and immune tolerance, including the roles of regulatory T cells (Tregs) and hepatic dendritic cells (DCs), is crucial for improving transplant outcomes. Strategies to induce immune tolerance, such as modulating DC function or promoting Treg activity, hold promise for reducing rejection and improving long-term graft survival. This review focuses on the liver’s unique predisposition to rejection and tolerance, highlighting the roles of individual cell types in these processes. Continued research into the mechanisms of alloimmune responses and immune tolerance in liver transplantation is essential for developing more effective therapies and improving long-term outcomes for patients with end-stage liver disease.

Abstract Wildlife crossing structures and road calming measures are frequently implemented to improve habitat connectivity and mitigate the risks of wildlife–vehicle collisions on roads. Although Southeast Asia is a known biodiversity hotspot, majority of studies assessing effectiveness of such structures were conducted outside the region. Existing studies also tended to be non‐comparative and focused on crossing structures in silo. We addressed this gap by simultaneously surveying and comparing the usage frequency of mammals across three crossing types—culverts, roads and rope bridges—along a road surrounded by forests in Singapore. This allowed us to evaluate the preferences of mammals, assess usage patterns and investigate factors influencing the use of different crossing types. Using camera traps and closed‐circuit televisions, we documented 1133 independent crossing events across a 9‐month study period from March to November 2021. Fourteen mammal species were detected across all crossing types, with wild boar (Sus scrofa) being the most prevalent species (68.2%). Locally critically endangered species such as the Malayan porcupine (Hystrix brachyura), Sunda pangolin (Manis javanica), and Raffles' banded langur (Presbytis femoralis femoralis) were also recorded to use culverts, roads, and rope bridges for crossings, respectively. Although many species used multiple crossing types, most species had a preferred crossing method. Between culverts and roads, factors that influenced crossing preferences included group size for wild boars and time of day and presence of fences for other mammals. Even though such culverts were intended for drainage, they were still widely used by mammals. Overall, all three crossing methods were crucial in facilitating the movement of animals between habitats. Thus, a variety of infrastructure and measures to accommodate the diversity of wildlife moving across forest patches in a fragmented landscape is recommended.

Background Bariatric surgery is the most effective treatment for severe obesity. There can be variation in the degree of weight reduction following bariatric surgery. It is unknown whether single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor locus (GRL) affect postoperative weight loss and metabolic outcomes.Materials/methods We studied the association between selected candidate SNPs and postoperative weight loss and metabolic outcomes in patients with severe obesity undergoing bariatric surgery. The polymorphisms rs41423247 (Bcl1), rs56149945 (N363S) and rs6189/rs6190 (ER22/23EK) were analysed.Results The 139 participants included 95 women (68.3%) and had a median (interquartile range) age of 53.0 (46.0–60.0) years and mean (SD) weight of 140.8 (28.8) kg and body mass index of 50.3 (8.6) kg/m2. At baseline, 59 patients had type 2 diabetes (T2D), 60 had hypertension and 35 had obstructive sleep apnoea syndrome treated with continuous positive airway pressure (CPAP). 84 patients (60.4%) underwent gastric bypass and 55 (39.6%) underwent sleeve gastrectomy. There were no significant differences in weight loss, glycated haemoglobin (HbA1c) or lipid profile categorized by genotype status, sex or median age. There was significant weight reduction after bariatric surgery with a postoperative BMI of 34.1 (6.8) kg/m2 at 24 months (p

Abstract Licuala ferruginea Becc., a tropical forest understorey palm, is observed to have fruits that appear red in colour when unripe, turning pink, then white, purple and finally black in colour as they ripen. We monitored 13 fruiting palms in rainforest fragments and recorded the consumption of fruits by animals via camera traps. We also documented the fruiting phenology of two palms in the nursery. In the rainforest fragments, a Cream‐vented Bulbul (Pycnonotus simplex) was observed plucking a mature purple fruit from a L. ferruginea palm, before flying away with the fruit in its beak. This was the only bird that was observed feeding on the mature fruit. A range of mammals, dominated by edge species such as the Long‐tailed Macaque and Wild Boar, were observed to consume L. ferruginea fruits indiscriminately across all five colour stages, thereby limiting the dispersal of the fruits. Forest bulbul gape sizes also matched the fruit size, suggesting that forest bulbuls are the likely dispersers of the palm in the original forest where edge species are not in high densities. We further posit that the initial phase of red fruits, with high contrasting red reflectance against a green foliage background, might be a form of early advertisement to birds. The fruit then turns pink and white, which have high green reflectance and is less contrasting, thereby reducing the conspicuity of the fruit. This allows the fruit to ripen with high fructose and glucose content, and turn purple and black, which are known visual cues for birds. This study provides indicative support for the dispersal syndrome hypothesis and highlights the potential effects of forest fragmentation on plant–frugivore interactions.

Objectives As part of a wider study, our aim was to elicit perspectives of people with congenital heart disease (CHD) and/or their parents/carers about their experiences of healthcare and what is important to them when receiving care.Design and setting A qualitative study involving a series of closed, asynchronous, online discussion forums underpinned by an interpretivist framework and set up and moderated by three patient charities via their Facebook pages.Participants People with CHD and parents/carers of people with CHD from the UK.Results Five forums were run for 12–24 weeks across the three charities, and 343 participants signed up to the forums. Four linked themes related to processes of care were identified following thematic analysis of the transcripts: relationships and communication; access and coordination; experience of discrete episodes of care and psychological support. These impacted how care was experienced and, for some patients, outcomes of CHD and its treatment as well as broader health outcomes. In addition, context relating to stages of the patient journey was described, together with patient-related factors such as patients’ knowledge and expertise in their own condition.Conclusions People with CHD and their parents/carers want individualised, person-centred care delivered within an appropriately resourced, multidisciplinary service. Although examples of excellent care were provided it is evident that, from the perspective of patients and parents/carers, some National Health Service Standards for people with CHD were not being met.

ObjectivesThe majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses.DesignDefinitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis.SettingPrimary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States.ParticipantsOver 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021.Main outcome measuresRelative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases.ResultsINTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from −10.9% [95% confidence interval (CI): −33.1 to +11.3%] in Norway to −79.9% (95% CI: −86.4% to −73.4%) in China for acute infectious respiratory disease visits and − 2.1% (95% CI: −12.1 to +7.8%) in Peru to −59.9% (95% CI: −68.6% to −51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic.ConclusionThe COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

Abstract Background The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. Methods Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student’s unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason’s correlation coefficient was used to examine relationships between variables. Results During cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (−0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (−0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = −0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. Conclusions The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

Abstract Heart valve disease is a major cause of mortality and morbidity worldwide with no effective medical therapy and no ideal valve substitute emulating the extremely sophisticated functions of a living heart valve. These functions influence survival and quality of life. This has stimulated extensive attempts at tissue engineering “living” heart valves. These attempts utilised combinations of allogeneic/ autologous cells and biological scaffolds with practical, regulatory, and ethical issues. In situ regeneration depends on scaffolds that attract, house and instruct cells and promote connective tissue formation. We describe a surgical, tissue-engineered, anatomically precise, novel off-the-shelf, acellular, synthetic scaffold inducing a rapid process of morphogenesis involving relevant cell types, extracellular matrix, regulatory elements including nerves and humoral components. This process relies on specific material characteristics, design and “morphodynamism”.

Abstract Air‐entraining whitecaps provide an important source of bubbles over the global oceans, yet the rate at which the associated air is entrained is not well known. This lack of understanding limits the ability to accurately parameterize bubble‐mediated gas exchange and sea spray aerosol flux. In this paper I present a model to predict the total volume of air entrained by individual whitecaps and extend it to estimate the rate at which air is entrained per unit sea surface area. The model agrees well with existing models and measurements and can be forced by the rate at which energy is dissipated by the wavefield which can be routinely provided by spectral wave models. I then use the model to present the first distributions of the estimated total volume of air entrained by individual whitecaps, as well as their rate of air entrainment and air degassing.

Abstract Mycelia were cultivated from a Thai wild mushroom identified as Ganoderma australe based on polymerase chain reaction (PCR) and morphological analyses. The mycelial extracts were examined for their active ingredients using a liquid chromatography-tandem mass spectrometry (LC‒MS/MS) method. This revealed the presence of lovastatin and tentative compounds including p-coumaric, nicotinamide, gamma-aminobutyric acid, choline, nucleosides, amino acids, and saccharides. The extracts had an inhibitory effect on the activity of HMG-CoA reductase in a concentration-dependent manner. At 2.5 mg/mL, the G. australe extracts did not interfere with the viability of HepG2 spheroids, but their biochemical composition was altered as determined by Fourier-transform infrared (FTIR) spectroscopy. The lipid profile of the spheroids treated with the mycelial extract was distinct from that of the control and the 5 µM lovastatin treatment, corresponding with the production of cholesterol by the spheroids. The mycelia of G. australe increased the percentage of high-density lipoprotein (HDL) production to 71.35 ± 2.74%, compared to the control and lovastatin-treated spheroids (33.26 ± 3.15% and 32.13 ± 3.24%, respectively). This study revealed the superior effect of natural compound mixtures to pure lovastatin, and the potential use of Thailand’s wild G. australe as a functional food to prevent or alleviate hypercholesterolemia.

Primary hypothyroidism affects about 3% of the general population in Europe. Early treatments in the late 19th Century involved subcutaneous as well as oral administration of thyroid extract. Until the early 1970s, the majority of people across the world with hypothyroidism were treated with natural desiccated thyroid (NDT) (derived from pig thyroid glands) in various formulations, with the majority of people since then being treated with levothyroxine (L-thyroxine). There is emerging evidence that may account for the efficacy of liothyronine (NDT contains a mixture of levothyroxine and liothyronine) in people who are symptomatically unresponsive to levothyroxine. While this is a highly selected group of people, the severity and chronicity of their symptoms and the fact that many patients have found their symptoms to be alleviated, can be viewed as valid evidence for the potential benefit of NDT when given after careful consideration of other differential diagnoses and other treatment options.

Abstract Background: Clinical research trials rely on informed consent forms (ICFs) to explain all aspects of the study to potential participants. Despite efforts to ensure the readability of ICFs, concerns about their complexity and participant understanding persist. There is a noted gap between Institutional Review Board (IRB) standards and the actual readability levels of ICFs, which often exceed the recommended 8th-grade reading level. This study evaluates the readability of over five thousand ICFs from ClinicalTrials.gov in the USA to assess their literacy levels. Methods: We analyzed 5,239 US-based ICFs from ClinicalTrials.gov using readability metrics such as the Flesch Reading Ease, Flesch-Kincaid Grade Level, Gunning Fog Index, and the percentage of difficult words. We examined trends in readability levels across studies initiated from 2005 to 2024. Results: Most ICFs exceeded the recommended 8th-grade reading level, with an average Flesch-Kincaid Grade Level of 10.99. While 91% of the ICFs were written above the 8th-grade level, there was an observable improvement in readability, with fewer studies exceeding a 10th-grade reading level in recent years. Conclusions: The study reveals a discrepancy between the recommended readability levels and actual ICFs, highlighting a need for simplification. Despite a trend toward improvement in more recent years, ongoing efforts are necessary to ensure ICFs are comprehensible to participants of varied educational backgrounds, reinforcing the ethical integrity of the consent process.

Fibrotic diseases account for 45% of all deaths in the developed world, and progressive scarring conditions, such as dystrophic epidermolysis bullosa (EB), result in a significant reduction in quality of life. There is thus a need for novel approaches in fibrosis prevention. Herein, it is shown that iota carrageenan, a low‐cost, regulatory approved polysaccharide, is effective at preventing scarring by inhibiting collagen fibrillogenesis, abrogating the transforming growth factor beta 1 (TGFβ1) pathway, and lubricating the epithelium. It is demonstrated that iota carrageenan, and other anionic polysaccharides, can prevent collagen fibril formation, a key step in scar formation. It also binds TGFβ1 to prevent myofibroblast transdifferentiation, evidenced by a significant reduction in both transcription and translation of collagen 1 and alpha smooth muscle actin. Iota carrageenan may be formulated as a microparticle suspension, to allow spraying for even coverage on hard‐to‐reach anatomical sites, like the oral mucosa. This formulation provides good lubrication, to reduce the shear forces that initiate the progressive oral scarring in EB. This study not only provides a novel therapy for fibrosis prevention, but also demonstrates the potential of self‐delivering immunomodulatory polysaccharides as a safe, cost‐effective, and stable platform, which can be more easily translated for clinical benefit.

Sedentary behavior among hospitalized older adults is a well-described challenge that can increase the risk of loss of function and mortality. Therefore, it is important to encourage physical activity (PA) during hospitalization. Exertion Games (exergames) have repeatedly been suggested as a tool to encourage and sustain motivation in rehabilitation programs. This article presents early findings from a convergent parallel mixed methods study that explored whether social presence and PA could be combined through the novel use of immersive virtual reality technology in a feasible group exercise constellation. Inpatients (n=10, 50% female, 80.3±8.2 years) were invited to participate in a bi-weekly VR group session. Most participants (62%) responded that it was a good experience to a large/great extent, which they would like to use repeatedly (76%). The technology was easy for untrained healthcare professionals and had minimal adverse events for the participants. However, a major finding illustrates that the enclosing immersiveness of the headset hindered conversation during exercise sessions. The exclusion of sight likely had a negative effect on forming relations between the participants, which conversely caused the participants to experience a lack of cohesion and relatedness with the other participants. VR-mediated group therapy may be a promising solution to existing physiotherapy practices since it may incorporate basic psychological needs. However, to optimize for social interaction, future systems will need to afford a higher degree of social presence, e.g., through avatar embodiment in a shared virtual environment, to support older adults' autonomous motivation for PA through social interaction and novel technologies.

Climate change and plastic pollution are two of the most pressing environmental challenges caused by human activity, and they are directly and indirectly linked. We focus on the relationship between marine plastic litter and the air-sea flux of greenhouse gases (GHGs). Marine plastic litter has the potential to both enhance and reduce oceanic GHG fluxes, but this depends on many factors that are not well understood. Different kinds of plastic behave quite differently in the sea, affecting air-sea gas exchange in different, largely unknown, ways. The mechanisms of air-sea exchange of GHGs have been extensively studied and if air-sea gas transfer coefficients and concentrations of the gas in water and air are known, calculating the resulting GHG fluxes is reasonably straightforward. However, relatively little is known about the consequences of marine plastic litter for gas transfer coefficients, concentrations, and fluxes. Here we evaluate the most important aspects controlling the exchange of GHGs between the sea and the atmosphere and how marine plastic litter could change these. The aim is to move towards improving air-sea GHG flux calculations in the presence of plastic litter and we have largely limited ourselves to identifying processes, rather than estimating relative importance.

Background An elevated ventilatory efficiency slope during exercise (minute ventilation/volume of expired CO2; VE/VCO2 slope) is a strong prognostic indicator in heart failure. It is elevated in people with heart failure with preserved ejection, many of whom have hypertension. However, whether the VE/VCO2 slope is also elevated in people with primary hypertension versus normotensive individuals is unknown. We hypothesize that there is a spectrum of ventilatory inefficiency in cardiovascular disease, reflecting an increasingly abnormal physiological response to exercise. The aim of this study was to evaluate the VE/VCO2 slope in patients with hypertension compared with age‐, peak oxygen consumption–, and sex‐matched healthy subjects. Methods and Results Ramped cardiovascular pulmonary exercise tests to peak oxygen consumption were completed on a bike ergometer in 55 patients with primary hypertension and 24 normotensive controls. The VE/VCO2 slope was assessed from the onset of exercise to peak oxygen consumption. Data were compared using unpaired Student t test. Age (mean±SD, 66±6 versus 64±6 years; P=0.18), body mass index (25.4±3.5 versus 24±2.4 kg/m2; P=0.13), and peak oxygen consumption (23.2±6.6 versus 24±7.3 mL/min per kg; P=0.64) were similar between groups. The VE/VCO2 slope was elevated in the hypertensive group versus controls (31.8±4.5 versus 28.4±3.4; P=0.002). Only 27% of the hypertensive group were classified as having a normal VE/VCO2 slope (20–30) versus 71% in the control group. Conclusions Ventilatory efficiency is impaired people with hypertension without a diagnosis of heart failure versus normotensive individuals. Future research needs to establish whether those patients with hypertension with elevated VE/VCO2 slopes are at risk of developing future heart failure.

Testosterone (T), the principal androgen secreted by the testes, plays an essential role in male health. Male hypogonadism is diagnosed based on a combination of associated clinical signs and symptoms and laboratory confirmation of low circulating T levels. In this review, we have highlighted factors, both biological and analytical, that introduce variation into the measurement of serum T concentrations in men; these need to be considered when requesting T levels and interpreting results. There is an ongoing need for analytical standardisation of T assays and harmonisation of pre- and post-analytical laboratory practices, particularly in relation to the laboratory reference intervals provided to clinicians. Further, there is a need to share with service users the most up-to-date and evidence-based action thresholds for serum T as recommended in the literature. Estimation of free testosterone may be helpful. Causes of secondary hypogonadism should be considered. A comprehensive approach is required in the management of male hypogonadism, including lifestyle modification as well as medication where appropriate. The goal of treatment is the resolution of symptoms as well as the optimisation of metabolic, cardiovascular, and bone health. The advice of an endocrinologist should be sought when there is doubt about the cause and appropriate management of the hypogonadism.

Objectives Given the challenge of limiting the transmission of coronavirus disease 2019 while simultaneously continuing to provide medical care for other chronic and degenerative diseases and monitor therapy, a remote medical advice and guidance program was created to help individuals receive health services at their homes. Methods A descriptive, cross-sectional, and observational study was performed from April 13, 2020 to April 19, 2021 among Petroleos Mexicanos (PEMEX) health services beneficiaries. Mobile text messages were used to assign patients throughout Mexico to a doctor, who coordinated a video call with the nursing service for advice and remote care. Results In total, 17,472 calls were registered, with an average duration of 10.28 minutes. Almost half (49.4%) of the people who requested attention through the remote program were workers, 31.5% were workers’ relatives, and 19.1% were retired workers. The average age of the program users was 50.66 ± 18.02 years. A total of 144 doctors from 28 different specialties participated. In this program, 7,163 calls were made because of respiratory symptoms, 1,514 for therapeutic monitoring (prescriptions), and 8,183 because of other diseases, including mental health. Conclusions Remote healthcare programs have shown the potential to support the health system. This program is the first to deploy real-time video calls with a health team utilizing institutional electronic clinical records in Mexico. The implementation of this pandemic management program impacted the number of consultations given remotely, resulting in effective triage.

Abstract The feral pigeon (Columba livia) is a globally commensal bird that can cause dis‐amenities such as soiling and is a potential vector of various diseases. Aside to limiting food as a management strategy, reducing the availability of roosting and nesting sites can help regulate feral pigeon populations. Despite their prevalence, current knowledge of their roosting and nesting preferences is lacking. Feral pigeons commonly use railway viaduct expansion gaps in Singapore for roosting and nesting. These gaps provided an ideal experimental platform to examine feral pigeon roost and nest site selection while controlling for differing cavity sizes which can significantly affect their reproductive success and site selection decisions. We also conducted an in‐situ experiment to test the efficacy of nest removal as a management option. Our nationwide surveys of 80.3 km of railway viaducts and 6048 gaps revealed that feral pigeon day roosting and nesting preferences are influenced by structural height and more importantly, their proximity to human food sources. There was a significantly higher probability of feral pigeon roosting in a gap if it had more pigeon feeding incidences in its vicinity and was higher. The probability of feral pigeon nesting in gap was higher if it was closer to a railway station, lower and further from water bodies. In our field experiment, we did not find any significant differences in the proportions of the abundances of feral pigeon to other urban commensal bird species at the gaps before and after nests were removed. Overall, our results suggest that a concerted effort to reduce anthropogenic food availability to feral pigeons is central in limiting their reproductive success and controlling their population.

Abstract Re‐establishing extirpated wildlife—or “rewilding”—is touted as a way to restore biodiversity and ecosystem processes, but we lack real‐world examples of this process, particularly in Southeast Asia. Here, we use a decade of aggregated camera trap data, N‐mixture occupancy models, and input from local wildlife experts to describe the unassisted recolonization of two native large herbivores in Singapore. Sambar deer (Rusa unicolor) escaped from captivity (in private or public zoos) in the 1970s and contemporary camera trap data show they have only colonized nearby forest fragments and their abundance remains low. Wild pigs (Sus scrofa), in contrast, naturally recolonized by swimming from Malaysia in the 1990s and have rapidly expanded their range and abundance across Singapore. While wild pigs have not recolonized all viable green spaces yet, their trajectory indicates they soon will. We also note that a third ungulate, the muntjac deer (Muntiacus muntjak), was captured in camera trapping in 2014 and 2015 but was never recorded afterward despite increased sampling effort, and thus we do not focus on their presumably unsuccessful recolonization. The divergent rewilding trajectories between sambar deer and wild pigs suggest different conservation outcomes and management requirements. Sambar deer may restore lost plant–animal interactions such as herbivory and seed dispersal without requiring significant management. Wild pigs, in contrast, have reached high numbers rapidly and may require active management to avoid hyperabundance and negative ecological impacts in regions, such as Singapore that lack both hunting and large predators.

Abstract The Circumsporozoite Protein (CSP) of Plasmodium falciparum contains an N-terminal region, a conserved Region I (RI), a junctional region, 25–42 copies of major (NPNA) and minor repeats followed by a C-terminal domain. The recently approved malaria vaccine, RTS,S/AS01 contains NPNAx19 and the C-terminal region of CSP. The efficacy of RTS,S against natural infection is low and short-lived, and mapping epitopes of inhibitory monoclonal antibodies may allow for rational improvement of CSP vaccines. Tobacco Mosaic Virus (TMV) was used here to display the junctional epitope (mAb CIS43), Region I (mAb 5D5), NPNAx5, and NPNAx20 epitope of CSP (mAbs 317 and 580). Protection studies in mice revealed that Region I did not elicit protective antibodies, and polyclonal antibodies against the junctional epitope showed equivalent protection to NPNAx5. Combining the junctional and NPNAx5 epitopes reduced immunogenicity and efficacy, and increasing the repeat valency to NPNAx20 did not improve upon NPNAx5. TMV was confirmed as a versatile vaccine platform for displaying small epitopes defined by neutralizing mAbs. We show that polyclonal antibodies against engineered VLPs can recapitulate the binding specificity of the mAbs and immune-focusing by reducing the structural complexity of an epitope may be superior to immune-broadening as a vaccine design approach. Most importantly the junctional and restricted valency NPNA epitopes can be the basis for developing highly effective second-generation malaria vaccine candidates.

In this manuscript, we offer a brief understanding of the educational experiences of gang-impacted students in K-12 and postsecondary education. Using evidence-based and interconnected support systems that account for the multifaceted needs of gang-impacted students, such as basic needs, mental health, workforce development, technology, and other resources, we then focus on the necessary institutional and programmatic practices to design and support them to thrive and graduate from an urban community college.

Abstract Plasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA)n repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA)n epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA)n. In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.

Internships are widely viewed as “door openers” to opportunity, yet students without ample financial, social, and institutional supports are often excluded from these experiences. This exclusion is especially problematic for Latinx students attending Hispanic-Serving Institutions, for whom an internship could be transformative. In this article, we elaborate upon Núñez’s (2014) multilevel model of intersectionality to highlight how agents’ perceptions, social categories, embodied practices, and broader contextual forces interrelate to shape Latinx students’ access to internship opportunities at a university in the border region of Texas. Using inductive thematic, correlational, and social-network analysis techniques to analyze survey (n = 192) and focus group (n = 12) data, we find that gender, academic major, socioeconomic status, and race intersect with organizational (e.g., insufficient information) and contextual (e.g., labor markets) factors to shape students’ access and perceptions. We provide recommendations for disrupting systemic inequalities in internship access and culturally appropriate programming and ideas for future research.

BackgroundPublic health scientists have used spatial tools such as web-based Geographical Information System (GIS) applications to monitor and forecast the progression of the COVID-19 pandemic and track the impact of their interventions. The ability to track SARS-CoV-2 variants and incorporate the social determinants of health with street-level granularity can facilitate the identification of local outbreaks, highlight variant-specific geospatial epidemiology, and inform effective interventions. We developed a novel dashboard, the University of Massachusetts’ Graphical user interface for Geographic Information (MAGGI) variant tracking system that combines GIS, health-associated sociodemographic data, and viral genomic data to visualize the spatiotemporal incidence of SARS-CoV-2 variants with street-level resolution while safeguarding protected health information. The specificity and richness of the dashboard enhance the local understanding of variant introductions and transmissions so that appropriate public health strategies can be devised and evaluated. ObjectiveWe developed a web-based dashboard that simultaneously visualizes the geographic distribution of SARS-CoV-2 variants in Central Massachusetts, the social determinants of health, and vaccination data to support public health efforts to locally mitigate the impact of the COVID-19 pandemic. MethodsMAGGI uses a server-client model–based system, enabling users to access data and visualizations via an encrypted web browser, thus securing patient health information. We integrated data from electronic medical records, SARS-CoV-2 genomic analysis, and public health resources. We developed the following functionalities into MAGGI: spatial and temporal selection capability by zip codes of interest, the detection of variant clusters, and a tool to display variant distribution by the social determinants of health. MAGGI was built on the Environmental Systems Research Institute ecosystem and is readily adaptable to monitor other infectious diseases and their variants in real-time. ResultsWe created a geo-referenced database and added sociodemographic and viral genomic data to the ArcGIS dashboard that interactively displays Central Massachusetts’ spatiotemporal variants distribution. Genomic epidemiologists and public health officials use MAGGI to show the occurrence of SARS-CoV-2 genomic variants at high geographic resolution and refine the display by selecting a combination of data features such as variant subtype, subject zip codes, or date of COVID-19–positive sample collection. Furthermore, they use it to scale time and space to visualize association patterns between socioeconomics, social vulnerability based on the Centers for Disease Control and Prevention’s social vulnerability index, and vaccination rates. We launched the system at the University of Massachusetts Chan Medical School to support internal research projects starting in March 2021. ConclusionsWe developed a COVID-19 variant surveillance dashboard to advance our geospatial technologies to study SARS-CoV-2 variants transmission dynamics. This real-time, GIS-based tool exemplifies how spatial informatics can support public health officials, genomics epidemiologists, infectious disease specialists, and other researchers to track and study the spread patterns of SARS-CoV-2 variants in our communities.

Abstract Background Mindfulness has emerged as an important correlate of well-being in various clinical populations. The present study evaluated the psychometric properties of the 20-item short form of the Five Facet Mindfulness Questionnaire (FFMQ-SF) in the Chinese context. Methods The study sample was 127 Chinese colorectal cancer patients who completed the FFMQ-SF and validated physical and mental health measures. Factorial validity of the FFMQ-SF was assessed using Bayesian structural equation modeling (BSEM) via informative priors on cross-loadings and residual covariances. Linear regression analysis examined its convergent validity with the health measures on imputed datasets. Results The five-factor BSEM model with approximate zero cross-loadings and one residual covariance provided an adequate model fit (PPP = 0.07, RMSEA = 0.06, CFI = 0.95). Satisfactory reliability (ω = 0.77–0.85) was found in four of the five facets (except nonjudging). Acting with awareness predicted lower levels of perceived stress, negative affect, anxiety, depression, and illness symptoms (β = − 0.37 to − 0.42) and better quality of life (β = 0.29–0.32). Observing, nonjudging, and nonreacting did not show any significant associations (p > .05) with health measures. Acting with awareness was not significantly correlated (r

Abstract Background Bipolar disorder is the fourth most common mental health condition, affecting ~ 1% of UK adults. Lithium is an effective treatment for prevention of relapse and hospital admission, and is widely recommended as a first-line treatment. We previously showed in other areas that laboratory testing patterns are variable with sub-optimal conformity to guidance. We therefore examined lithium results and requesting patterns relative to monitoring recommendations. Methods Data on serum lithium levels and intervals between requests were extracted from Clinical Biochemistry laboratory information systems at the University Hospitals of North Midlands, Salford Royal Foundation Trust and Pennine Acute Hospitals from 2012 to 2018 (46,555 requests; 3371 individuals). Data were examined with respect to region/source of request, age and sex. Results Across all sites, lithium levels on many requests were outside the recommended UK therapeutic range (0.4–0.99 mmol/L); 19.2% below the range and 6.1% above the range (median [Li]: 0.60 mmol/L). A small percentage were found at the extremes (3.2% at

Collapsing glomerulopathy is an aggressive form of focal segmental glomerulosclerosis with diverse causes. The presence of the apolipoprotein L1 (APOL1) high-risk genotype is a major risk factor for collapsing glomerulopathy in African Americans. Coronavirus disease 2019 (COVID-19) is an emerging pandemic with predominant respiratory manifestations. However, kidney involvement is being frequently noted and is associated with higher mortality. Currently, kidney pathology data for COVID-19 are scant and mostly come from postmortem findings. We report 2 African American patients who developed acute kidney injury and proteinuria in temporal association with COVID-19 infection. Kidney biopsy specimens showed collapsing glomerulopathy, endothelial tubuloreticular inclusions, and acute tubular injury, without evidence by electron microscopy or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in situ hybridization of viral infection of kidney cells. Both patients had the APOL1 high-risk genotype. We propose that collapsing glomerulopathy represents a novel manifestation of COVID-19 infection, especially in people of African descent with APOL1 risk alleles.

Cardiac valves exhibit highly complex structures and specialized functions that include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied. In this work we analyzed the differential methylation profiles of 12 non-diseased aortic and mitral valve tissue samples (in matched pairs). Analysis of methylation data [reduced representation bisulfite sequencing (RRBS)] of 16,101 promoters genome-wide revealed 584 differentially methylated (DM) promoters, of which 13 were reported in endothelial mesenchymal trans-differentiation (EMT), 37 in aortic and mitral valve disease and 7 in ECM remodeling. Both functional classification as well as network analysis showed that the genes associated with the DM promoters were enriched for WNT-, Cadherin-, Endothelin-, PDGF-, HIF-1 and VEGF- signaling implicated in valvular physiology and pathophysiology. Additional enrichment was detected for TGFB-, NOTCH- and Integrin- signaling involved in EMT as well as ECM remodeling. This data provides the first insight into differential regulation of human aortic and mitral valve tissue and identifies candidate genes linked to DM promoters. Our work will improve the understanding of valve biology, valve tissue engineering approaches and contributes to the identification of relevant drug targets.

Coronavirus disease 2019 (COVID-19) has negatively affected the delivery of respiratory diagnostic services across the world due to the potential risk of disease transmission during lung function testing. Community prevalence, reoccurrence of COVID-19 surges and the emergence of different variants of SARS-CoV-2 have impeded attempts to restore services. Finding consensus on how to deliver safe lung function services for both patients attending and for staff performing the tests are of paramount importance. This international statement presents the consensus opinion of 23 experts in the field of lung function and respiratory physiology balanced with evidence from the reviewed literature. It describes a robust roadmap for restoration and continuity of lung function testing services during the COVID-19 pandemic and beyond. Important strategies presented in this consensus statement relate to the patient journey when attending for lung function tests. We discuss appointment preparation, operational and environmental issues, testing room requirements including mitigation strategies for transmission risk, requirement for improved ventilation, maintaining physical distance and use of personal protection equipment. We also provide consensus opinion on precautions relating to specific tests, filters, management of special patient groups and alternative options to testing in hospitals. The pandemic has highlighted how vulnerable lung function services are and forces us to re-think how long-term mitigation strategies can protect our services during this and any possible future pandemic. This statement aspires to address the safety concerns that exist and provide strategies to make lung function tests and the testing environment safer when tests are required.

ObjectiveWe have previously reported that human calcified aortic cusps have abundant expression of smooth muscle (SM) markers and co-activators. We hypothesised that cells in bicuspid aortic valve (BAV) cusps and those affected by rheumatic heart valve (RHV) disease may follow a similar phenotypic transition into smooth muscle cells, a process that could be regulated by transforming growth factors (TGFs).AimsCusps from eight patients with BAV and seven patients with RHV were analysed for early and late SM markers and regulators of SM gene expression by immunocytochemistry and compared to healthy aortic valves from 12 unused heart valve donors. The ability of TGFs to induce these markers in valve endothelial cells (VECs) on two substrates was assessed.ResultsIn total, 7 out of 8 BAVs and all the RHVs showed an increased and atypical expression of early and late SM markers α-SMA, calponin, SM22 and SM-myosin. The SM marker co-activators were aberrantly expressed in six of the BAV and six of the RHV, in a similar regional pattern to the expression of SM markers. Additionally, regions of VECs, and endothelial cells lining the vessels within the cusps were found to be positive for SM markers and co-activators in three BAV and six RHV. Both BAVs and RHVs were significantly thickened and HIF1α expression was prominent in four BAVs and one RHV. The ability of TGFβs to induce the expression of SM markers and myocardin was greater in VECs cultured on fibronectin than on gelatin. Fibronectin was shown to be upregulated in BAVs and RHVs, within the cusps as well as in the basement membrane.ConclusionBicuspid aortic valves and RHVs expressed increased numbers of SM marker-positive VICs and VECs. Concomittantly, these cells expressed MRTF-A and myocardin, key regulators of SM gene expression. TGFβ1 was able to preferentially upregulate SM markers and myocardin in VECs on fibronectin, and fibronectin was found to be upregulated in BAVs and RHVs. These findings suggest a role of VEC as a source of cells that express SM cell markers in BAVs and RHVs. The similarity between SM marker expression in BAVs and RHVs with our previous study with cusps from patients with aortic stenosis suggests the existance of a common pathological pathway between these different pathologies.

Abstract Background Finger prick blood glucose (BG) monitoring remains a mainstay of management in people with type 2 diabetes (T2DM) who take sulphonylurea (SU) drugs or insulin. We recently examined patient experience of BG monitoring in people with type 1 diabetes (T1DM). There has not been any recent comprehensive assessment of the performance of BG monitoring strips or the patient experience of BG strips in people with T2DM in the UK. Methods An online self‐reported questionnaire containing 44 questions, prepared following consultation with clinicians and patients, was circulated to people with T2DM. 186 responders provided completed responses (25.5% return rate). Fixed responses were coded numerically (eg not confident = 0 fairly confident = 1). Results Of responders, 84% were treated with insulin in addition to other agents. 75% reported having had an HbA1c check in the previous 6 months. For those with reported HbA1c ≥ 65 mmol/mol, a majority of people (70%) were concerned or really concerned about the shorter term consequences of running a high HbA1c This contrasted with those who did not know their recent HbA1c, of whom only 33% were concerned/really concerned and those with HbA1c

This article addresses the problem of balancing an inverted spherical pendulum on a quadrotor. The full dynamic model is obtained via the Euler-Lagrange formalism, where the dynamics of the pendulum is coupled to the dynamics of the quadrotor, taking as control inputs the torques associated with the yaw, roll, and pitch dynamics, and a control input for the vertical displacement in height. A trajectory tracking control scheme is proposed by means of an active disturbance rejection control based on a discontinuous extended state observer (ADRC-DESO) that allows controlling the system in the translational dynamics of the quadrotor including the rotational dynamics and the inverted pendulum dynamics. To address this problem, the dynamic model is linearized around an equilibrium point, taking into consideration that the system operates in close vicinity of the equilibrium points, thus considerably simplifying the dynamic model. Proving that the linear model is controllable and therefore differentiable flat, flat outputs are proposed around the displacements associated with the three cartesian axes of the Euclidean space, including a dynamic associated with the yaw dynamics of the quadrotor allowing to parameterize the full linear system. Simulation results as well as a convergence analysis validate the performance of the strategy.

A hybrid approach based on laser texturing and surface coating for the combined modification of surface topography and chemistry has been proposed to provide a versatile approach for the development of functional surfaces. The experimental procedure comprised nanosecond pulsed laser texturing of AISI 304 stainless steel substrates followed by the deposition of thin (a) in the range 0.2–6.4 µm. Coatings were then deposited on laser-textured substrates to quantify the deposition effectiveness and the influence of the coating type and parameters on the resulting surface topography and chemistry. Sol–gel deposition was found to be more effective with a polymeric interlayer, improving adhesion between the coating and the textured surface; however, this also led to an increase in Sa of approximately 0.5 µm. Conversely, PE-CVD was effective in modifying the surface chemistry while inducing no measurable differences in surface morphology, effectively decoupling the texturing and coating processes. Analysis of the surface chemistry showed a higher concentration of silicon for PE-CVD than sol–gel deposition and therefore a more pronounced effect on the surface chemical composition.

Background Lithium is viewed as the first-line long-term treatment for prevention of relapse in people with bipolar disorder. Aims This study examined factors associated with the likelihood of maintaining serum lithium levels within the recommended range and explored whether the monitoring interval could be extended in some cases. Method We included 46 555 lithium rest requests in 3371 individuals over 7 years from three UK centres. Using lithium results in four categories (

Aims. We previously showed that the glycated haemoglobin (HbA1c) testing frequency links to diabetes control. Here, we examine the effect of variability in test interval, adjusted for the frequency, on change in HbA1c (ΔHbA1c). Materials & Methods. HbA1c results were collected on 83,872 people with HbA1c results at baseline and 5 years (±3 months) later and ≥6 tests during this period. We calculated the standard deviation (SD) of test interval for each individual and examined the link between deciles of SD of the test interval and ΔHbA1c level, stratified by baseline HbA1c. Results. In general, less variability in testing frequency (more consistent monitoring) was associated with better diabetes control. This was most evident with moderately raised baseline HbA1c levels (7.0–9.0% (54–75 mmol/mol)). For example, in those with a starting HbA1c of 7.0–7.5% (54–58 mmol/mol), the lowest SD decile was associated with little change in HbA1c over 5 years, while for those with the highest decile, HbA1c rose by 0.4–0.6% (4–6 mmol/mol; p

The emergence of novel potentially pandemic pathogens necessitates the rapid manufacture and deployment of effective, stable, and locally manufacturable vaccines on a global scale. In this study, the ability of the Escherichia coli expression system to produce the receptor binding domain (RBD) of the SARS-CoV-2 spike protein was evaluated. The RBD of the original Wuhan-Hu1 variant and of the Alpha and Beta variants of concern (VoC) were expressed in E. coli, and their biochemical and immunological profiles were compared to RBD produced in mammalian cells. The E. coli-produced RBD variants recapitulated the structural character of mammalian-expressed RBD and bound to human angiotensin converting enzyme (ACE2) receptor and a panel of neutralizing SARS-CoV-2 monoclonal antibodies. A pilot vaccination in mice with bacterial RBDs formulated with a novel liposomal adjuvant, Army Liposomal Formulation containing QS21 (ALFQ), induced polyclonal antibodies that inhibited RBD association to ACE2 in vitro and potently neutralized homologous and heterologous SARS-CoV-2 pseudoviruses. Although all vaccines induced neutralization of the non-vaccine Delta variant, only the Beta RBD vaccine produced in E. coli and mammalian cells effectively neutralized the Omicron BA.1 pseudovirus. These outcomes warrant further exploration of E. coli as an expression platform for non-glycosylated, soluble immunogens for future rapid response to emerging pandemic pathogens.

A significant amount of knowledge has been gained with the use of cell-based assays to elucidate the mechanisms that mediate heart valve calcification. However, cells used in these studies lack their association with the extra-cellular matrix or the influence of other cellular components of valve leaflets. We have developed a model of calcification using intact porcine valve leaflets, that relies upon a biological stimulus to drive the formation of calcified nodules within the valve leaflets. Alizarin Red positive regions were formed in response to lipopolysaccharide and inorganic phosphate, which could be quantified when viewed under polarized light. Point analysis and elemental mapping analysis of electron microscope images confirmed the presence of nodules containing calcium and phosphorus. Immunohistochemical staining showed that the development of these calcified regions corresponded with the expression of RUNX2, osteocalcin, NF-kB and the apoptosis marker caspase 3. The formation of calcified nodules and the expression of bone markers were both inhibited by adenosine in a concentration-dependent manner, illustrating that the model is amenable to pharmacological manipulation. This organ culture model offers an increased level of tissue complexity in which to study the mechanisms that are involved in heart valve calcification.

Objectives Globally, healthcare systems have been stretched to the limit by the COVID-19 pandemic. Significant changes have had to be made to the way in which non-COVID-19-related care has been delivered. Our objective was to understand, from the perspective of patients with a chronic, life-long condition (congenital heart disease, CHD) and their parents/carers, the impact of COVID-19 on the delivery of care, how changes were communicated and whether healthcare providers should do anything differently in a subsequent wave of COVID-19 infections.Design and setting Qualitative study involving a series of asynchronous discussion forums set up and moderated by three patient charities via their Facebook pages.Participants Patients with CHD and parents/carers of patients with CHD.Main outcome measures Qualitative responses to questions posted on the discussion forums.Results The forums ran over a 6-week period and involved 109 participants. Following thematic analysis, we identified three themes and 10 subthemes related to individual condition-related factors, patient-related factors and health professional/centre factors that may have influenced how patients and parents/carers experienced changes to service delivery as a result of COVID-19. Specifically, respondents reported high levels of disruption to the delivery of care, inconsistent advice and messaging and variable communication from health professionals, with examples of both excellent and very poor experiences of care reported. Uncertainty about follow-up and factors related to the complexity and stability of their condition contributed to anxiety and stress.Conclusions The importance of clear, consistent communication cannot be over-estimated. Our findings, while collected in relation to patients with CHD, are not necessarily specific to this population and we believe that they reflect the experiences of many thousands of people with life-long conditions in the UK. Recommendations related to communication, service delivery and support during the pandemic may improve patients’ experience of care and, potentially, their outcomes.

Aims: We investigated whether a lifestyle intervention could influence expression and DNA methylation of diabetes-related genes in patients with impaired glucose regulation (IGR), the results were compared to bariatric surgery, considering it an intensive change. Methods: Twenty participants with IGR had adipose tissue biopsy and blood collected pre- and post-lifestyle (6 months) intervention; 12 obese patients had subcutaneous fat taken before and after bariatric surgery. RNA/DNA was extracted from all samples and underwent qPCR. DNA was bisulphite converted and 12 CpG sites of Caveolin-1 (CAV1) promoter were pyrosequenced. Results: lifestyle intervention resulted in opposite direction changes in fat tissue and blood for CAV1 expression and DNA methylation and these changes were correlated between tissues, while no significative differences were found in CAV1 expression after bariatric surgery. Conclusions: Our findings suggest a role for CAV1 in modulating adipocyte function as a consequence of lifestyle changes, as exercises and diet. These results may provide insights into new therapeutic targets for diabetes prevention.

We analysed if levels of four miRNAs would change after a lifestyle intervention involving dietary and exercises in prediabetes. MiRNAs previously shown to be associated with diabetes (Let-7a, Let-7e, miR-144 and miR-92a) were extracted from serum pre- and post-intervention. mRNA was extracted from fat-tissue for gene expression analyses. The intervention resulted in increased Let-7a and miR-92a. We found correlations between miRNAs and clinical variables (triglycerides, cholesterol, insulin, weight and BMI). We also found correlations between miRNAs and target genes, revealing a link between miR-92a and IGF system. A lifestyle intervention resulted in marked changes in miRNAs. The association of miRNAs with insulin and the IGF system (both receptors and binding proteins) may represent a mechanism of regulating IGFs metabolic actions.

6,6,12-graphyne is an intriguing synthetic allotrope of carbon that is predicted to have unique electronic properties but has not been successfully synthesized. Here, the authors prepare a series of radiaannulene oligomers that can be regarded as large segments of this elusive graphyne allotrope.

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1–/– mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1–/–mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.