The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

Distinct fibroblast subsets drive inflammation and damage in arthritis.

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3-5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.

Nucleated red blood cells as a biomarker for mortality in infants and neonates requiring veno-arterial extracorporeal membrane oxygenation for cardiac disease.

INTRODUCTION: Nucleated red blood cells (NRBC) are rare in the peripheral circulation of healthy individuals and their presence have been associated with mortality in adults and very low birth weight newborns, however, its value as a biomarker for mortality in infants requiring veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) has yet to be studied. We sought to determine if NRBC can serve as a biomarker for ECMO mortality and inpatient mortality in infants requiring V-A ECMO. METHODS: A single-center retrospective chart review analyzing infants <1 year of age requiring VA ECMO due to myocardial dysfunction or post-cardiotomy between January 1, 2011 to June 30, 2020. RESULTS: One hundred two patients required VA ECMO. Sixty-five patients required ECMO post-cardiotomy, 19 for perioperative deterioration, and 18 for myocardial dysfunction. Fifty-one patients (50%) died (21 died on ECMO, 30 died post-ECMO decannulation). Multivariable analysis found Age <60 days (OR 13.0, 95% CI 1.9-89.6, p = 0.009), NRBC increase by >50% post-ECMO decannulation (OR 17.1, 95% CI 3.1-95.1, p = 0.001), Single Ventricle (OR 9.0, 95% CI 1.7-47.7, p = 0.01), and lactate at ECMO decannulation (OR 3.0, 95% CI 1.3-7.1, p = 0.011) to be independently associated with inpatient mortality. ROC curves evaluating NRBC pre-ECMO decannulation as a biomarker for mortality on ECMO (AUC 0.80, 95% CI 0.68-0.92, p ⩽ 0.001) and post-ECMO decannulation (AUC 0.75, 95% CI 0.65-0.84, p ⩽ 0.001) show NRBC to be an accurate biomarker for mortality. CONCLUSIONS: Greater than 50% increase in NRBC post-ECMO decannulation is associated with inpatient mortality. NRBC value pre-ECMO decannulation may be a useful biomarker for mortality while on ECMO and post-decannulation.

Poor sleep and multiple sclerosis: associations with symptoms of multiple sclerosis and quality of life.

BACKGROUND: Sleep difficulties are common in people with multiple sclerosis (MS), but whether associations between poor sleep quality and quality of life are independent of MS symptoms, obesity and other MS-related factors remains unclear. METHODS: Cross-sectional analyses of data from the Australian MS Longitudinal Study (n=1717). Sleep was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and International Restless Legs Syndrome Study Group Rating Scale; health-related quality of life using the Assessment of Quality-of-Life 8-D. RESULTS: Poor sleep quality was common (67%), and more common than in community samples. Sleep measures clustered independently within MS symptoms. The clusters 'fatigue and cognitive', 'feelings of anxiety and depression', 'pain and sensory', were independently associated with poor sleep quality. Quality-of-Life utility scores were a clinically meaningful 0.19 units lower in those with poor sleep. Sleep quality, daytime sleepiness and restless leg syndrome were associated with reduced quality of life, independent of MS-related symptoms and body mass index. CONCLUSION: Poor sleep quality is common in MS and was strongly associated with worse health-related quality of life, independent of other MS symptoms and did not cluster with other common MS symptoms. Improving sleep quality may substantially improve quality of life in people with MS.

Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

Nucleated red blood cells as a biomarker for mortality in neonates following cardiac surgery.

INTRODUCTION: Nucleated red blood cells (NRBCs) are immature red cells that under normal conditions are not present in the peripheral circulation. Several studies have suggested an association between elevated NRBC and poor outcome in critically ill adults and neonates. We sought to determine if elevations in NRBC value following cardiac surgery and following clinical events during the hospital stay can be used as a biomarker to monitor for mortality risk in neonates post-cardiac surgery. MATERIALS AND METHODS: We constructed a retrospective study of 264 neonates who underwent cardiac surgery at Children's Hospital, New Orleans between 2011 and 2020. Variables included mortality and NRBC value were recorded following cardiac surgery and following peri-operative clinical events. The study was approved by LSU Health IRB. Sensitivity, specificity, receiver operating characteristic (ROC) curves with area under the curve (AUC) and logistic regression analysis were performed. RESULTS: Thirty-six patients (13.6%) died, of which 32 had an NRBC value ≥10/100 white blood cell (WBC) during hospitalisation. Multi-variable analysis found extracorporeal membrane oxygenation use (OR 10, 95% CI 2.9-33, p=<0.001), NRBC ≥10/100 WBC (OR 16.1, CI 4.1-62.5, p ≤ 0.001) and peak NRBC in the 14-day period post-cardiac surgery (continuous variable, OR 1.05, 95% CI 1.0-1.09, p = 0.03), to be independently associated with mortality. Using a cut-off NRBC value of 10/100 WBC, there was an 88.9% sensitivity and a 90.8% specificity, with ROC curve showing an AUC of 0.9 and 0.914 for peak NRBC value in 14 days post-surgery and entire hospitalisation, respectively. CONCLUSIONS: NRBC ≥10/100 WBC post-cardiac surgery is strongly associated with mortality. Additionally, NRBC trend appears to show promise as an accurate biomarker for mortality.

Infodemiological Examination of Personal and Commercial Tweets About Cannabidiol: Term and Sentiment Analysis.

BACKGROUND: In the absence of official clinical trial information, data from social networks can be used by public health and medical researchers to assess public claims about loosely regulated substances such as cannabidiol (CBD). For example, this can be achieved by comparing the medical conditions targeted by those selling CBD against the medical conditions patients commonly treat with CBD. OBJECTIVE: The objective of this study was to provide a framework for public health and medical researchers to use for identifying and analyzing the consumption and marketing of unregulated substances. Specifically, we examined CBD, which is a substance that is often presented to the public as medication despite complete evidence of efficacy and safety. METHODS: We collected 567,850 tweets by searching Twitter with the Tweepy Python package using the terms "CBD" and "cannabidiol." We trained two binary text classifiers to create two corpora of 167,755 personal use and 143,322 commercial/sales tweets. Using medical, standard, and slang dictionaries, we identified and compared the most frequently occurring medical conditions, symptoms, side effects, body parts, and other substances referenced in both corpora. In addition, to assess popular claims about the efficacy of CBD as a medical treatment circulating on Twitter, we performed sentiment analysis via the VADER (Valence Aware Dictionary for Sentiment Reasoning) model on the personal CBD tweets. RESULTS: We found references to medically relevant terms that were unique to either personal or commercial CBD tweet classes, as well as medically relevant terms that were common to both classes. When we calculated the average sentiment scores for both personal and commercial CBD tweets referencing at least one of 17 medical conditions/symptoms terms, an overall positive sentiment was observed in both personal and commercial CBD tweets. We observed instances of negative sentiment conveyed in personal CBD tweets referencing autism, whereas CBD was also marketed multiple times as a treatment for autism within commercial tweets. CONCLUSIONS: Our proposed framework provides a tool for public health and medical researchers to analyze the consumption and marketing of unregulated substances on social networks. Our analysis showed that most users of CBD are satisfied with it in regard to the condition that it is being advertised for, with the exception of autism.

Fibroblasts and Osteoblasts in Inflammation and Bone Damage.

This review discusses the important role fibroblasts play in the process of inflammation and the evidence that these cells may drive the persistence of inflammation. Fibroblasts are key components of the stroma normally involved in maintenance of extracellular matrix and tissue function; however, the term 'fibroblast' is used to describe a heterogeneous population of cells that vary in phenotype both between and within anatomical sites. Fibroblasts possess Toll-like receptors allowing them to respond to pathogen and damage-related signals by producing proinflammatory mediators such as IL-6, PGE2, and GM-CSF and can produce a range of chemokines such as CXCL12, CXCL13, and CXCL8 which attract B and T lymphocytes, monocytes, and neutrophils to sites of inflammation. Interactions between leukocytes and fibroblasts can facilitate increased survival of the leukocytes and modulate phenotypes leading to differential gene expression in the presence of mediators involved in inflammation. Fibroblasts also contribute to collateral tissue damage during inflammation through the production of members of the metalloproteinase family and cathepsins and also through induction of osteoclastogenesis leading to increased bone resorption rates. In persistent diseases, fibroblasts obtain an imprinted, aggressive phenotype leading to the production of higher basal levels of proinflammatory cytokines and the ability to damage tissue in the absence of continual stimuli. This aggressive phenotype offers an attractive new target for therapeutics that could help alleviate the burden of persistent inflammation.

Complementary echo and CCTA findings with superior sinus venosus atrial septal defect.

A young female developed progressive dyspnea on minimal exertion. Echocardiography demonstrated a large right heart with severe pulmonary hypertension. Cardiac computed tomographic angiography then demonstrated a superior sinus venosus atrial septal defect with an anomalous right upper pulmonary venous drainage. Echo and CCTA were complementary in making a proper diagnosis.

Teaching EHRs security with simulation for non-technical healthcare professionals.

This paper intends to simplify challenging concepts through role-play demonstrations and serve as a foundation for understanding the basis of securing healthcare data. Disparity exists between the rising need for security of electronic healthcare information and the number of healthcare leaders who understand the concepts behind ensuring privacy and accuracy of such data. Healthcare managers with a basic understanding of data encryption and how it safeguards health information are vital to the success of Electronic Health Records. They often are responsible for proper oversight of such systems and should instill confidence in medical providers and patients that electronic medical data is safe and accurate. However, data security and privacy are complex concepts and remain foreign to many healthcare managers. This paper reviews the benefits of simulation learning and outlines a workshop and simulation game developed in response to difficulties teaching the technology of encryption. The simulation has been successfully tested with graduate health administration students, as well as members of the technical, academic, and teaching community.

The role of the synovial fibroblast in rheumatoid arthritis pathogenesis.

PURPOSE OF REVIEW: Synovial fibroblasts continue to grow in prominence both as the subjects of research into the pathogenesis of rheumatoid arthritis and as novel therapeutic targets. This timely review aims to integrate the most recent findings with existing paradigms of fibroblast-related mechanisms of disease. RECENT FINDINGS: Linking the role of synovial fibroblasts as innate sentinels expressing pattern recognition receptors such as toll-like receptors to their effector roles in joint damage and interactions with leukocyte subpopulations has continued to advance. Understanding of the mechanisms underlying increased fibroblast survival in the inflamed synovium has led to therapeutic strategies such as cyclin-dependent kinase inhibition. Major advances have taken place in understanding of the interactions between epigenetic and micro-RNA regulation of transcription in synovial fibroblasts, improving our understanding of the unique pathological phenotype of these cells. Finally, the impact of new markers for fibroblast subpopulations is beginning to become apparent, offering the potential for targeting of pathological cells as the roles of different populations become clearer. SUMMARY: Over the past 2 years, major advances have continued to emerge in understanding of the relationship between synovial fibroblasts and the regulation of inflammatory pathways in the rheumatoid arthritis synovium.

Backed into a corner: damage control surgery in the rural or austere setting.

Damage control surgery has evolved during the past 40 years. The initial cases and studies were performed at level 1 trauma centers but has now shifted to damage control at smaller hospitals. This buys time for definitive care at higher-level centers. There is a role for damage control surgery in both general surgery and trauma patients at community trauma centers. The successful implementation and completion of damage control surgery require thorough planning and a full understanding of resource limitation. Additional training or practice for infrequently performed procedures may be necessary. A systems-based approach with postoperative transfer to a higher level of care is acceptable and expected.

Detecting Tweets Containing Cannabidiol-Related COVID-19 Misinformation Using Transformer Language Models and Warning Letters From Food and Drug Administration: Content Analysis and Identification.

Background: COVID-19 has introduced yet another opportunity to web-based sellers of loosely regulated substances, such as cannabidiol (CBD), to promote sales under false pretenses of curing the disease. Therefore, it has become necessary to innovate ways to identify such instances of misinformation. Objective: We sought to identify COVID-19 misinformation as it relates to the sales or promotion of CBD and used transformer-based language models to identify tweets semantically similar to quotes taken from known instances of misinformation. In this case, the known misinformation was the publicly available Warning Letters from Food and Drug Administration (FDA). Methods: We collected tweets using CBD- and COVID-19-related terms. Using a previously trained model, we extracted the tweets indicating commercialization and sales of CBD and annotated those containing COVID-19 misinformation according to the FDA definitions. We encoded the collection of tweets and misinformation quotes into sentence vectors and then calculated the cosine similarity between each quote and each tweet. This allowed us to establish a threshold to identify tweets that were making false claims regarding CBD and COVID-19 while minimizing the instances of false positives. Results: We demonstrated that by using quotes taken from Warning Letters issued by FDA to perpetrators of similar misinformation, we can identify semantically similar tweets that also contain misinformation. This was accomplished by identifying a cosine distance threshold between the sentence vectors of the Warning Letters and tweets. Conclusions: This research shows that commercial CBD or COVID-19 misinformation can potentially be identified and curbed using transformer-based language models and known prior instances of misinformation. Our approach functions without the need for labeled data, potentially reducing the time at which misinformation can be identified. Our approach shows promise in that it is easily adapted to identify other forms of misinformation related to loosely regulated substances.

Off-the-shelf percutaneous deep vein arterialization for no-option chronic limb-threatening ischemia related to Buerger disease.

Percutaneous deep venous arterialization (pDVA) is an important technique in the pursuit of limb salvage for a certain high-risk subset of patients with chronic limb-threatening ischemia (CLTI) considered to have "no option" owing to the lack of tibial or pedal targets for revascularization. pDVA seeks to establish an arteriovenous connection at the level of the tibial vessels, in addition to tibial and/or pedal venoplasty, to provide a pathway for arterial perfusion via the tibial and/or plantar venous system. A commercial system for pDVA exists; however, it is not yet approved by the U.S. Food and Drug Administration. In the present report, we detail a method of pDVA that uses commercially available devices for a patient with no-option CLTI related to Buerger disease.

Disease-modifying therapies do not affect sleep quality or daytime sleepiness in a large Australian MS cohort.

BACKGROUND: Poor sleep is common in multiple sclerosis (MS) and may impact daily functioning. The extent to which disease-modifying therapies (DMTs) contribute to sleep outcomes is under-examined. OBJECTIVE: To compare the effects of DMTs on sleep outcomes in an Australian cohort of people with MS and investigate associations between DMT use and beliefs about sleep problems and daily functioning (social functioning and activity engagement). METHODS: Sleep outcomes were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. DMT use and functioning were self-reported. RESULTS: Of 1,715 participants, 64% used a DMT. No differences in sleep outcomes were detected between participants who did and did not use DMTs, the type of DMT used (lower vs higher efficacy, interferon-ß vs other DMTs), the timing of administration, or adherence to standard administration recommendations. Beliefs that DMT use worsened sleep were associated with poorer sleep quality and perceptions that sleep problems interfered with daily functioning. CONCLUSION: The use of a DMT does not appear to affect self-reported sleep outcomes in people with MS. However, beliefs that DMT use makes sleep worse were associated with poorer sleep quality and increased interference in daily functioning, suggesting a need for education to diminish negative perceptions of DMT use.

The Impact of Scarcity on Consumers' Impulse Buying Based on the S-O-R Theory.

Purpose: The global COVID-19 pandemic impacted the healthcare systems of every nation. The scarcity of medical protective equipment led to impulse buying at the early stages of the COVID-19 outbreak in China which resulted in stockpiling and the increase of prices by retailers and insufficiencies among frontline workers. This situation impacted epidemic control work and market order and is the context from which this paper identifies how the scarcity of medical protective equipment affected Chinese consumers' impulse buying based on the theories of S-O-R model and bandwagon effect. The research provides insight into the mechanism of mediation (fear of missing out) and moderation (bandwagon) in the relationship between scarcity and impulse buying. Design/Methodology/Approach: This study uses convenience sampling, surveying 488 Chinese consumers through an online questionnaire. Smart-PLS was used to test the hypotheses. Findings: The empirical findings demonstrate that scarcity makes consumers fear missing the chance of getting protective medical equipment, leading ultimately to impulse buying. Besides, the scarcity effect on consumers' impulse buying was found to depend on other consumers' follow up behaviour in such emergency situations. Research Limitations/Implications: The findings provide managerial and theoretical insight and a point of reference for businesses in the implementation of a scarcity strategy. The findings will also prove useful to the Chinese Risk Response Department as it continuously improves its responses to the risk of consumers' impulse buying during a pandemic. Originality/Value: This study consolidates and takes research forward in the areas of impulse buying and consumer behaviour, confirming the mediating effect of fear of missing out and the moderating effect of the bandwagon in the relationship between scarcity and impulse buying.

Assessing the Social Cohesion of a Translocated Pride of White Lions Integrated with Wild Tawny Lions in South Africa, Using Social Network Analysis.

In South Africa, lions are protected in national parks and smaller fenced reserves. Translocating lions between fenced reserves, whilst necessary to maintain genetic diversity, is disruptive and can impact survivorship and pride cohesion. Critical to translocation success is pride cohesion. White lions are a natural colour variant occurring in the Greater Kruger Park Region, where anthropogenic threats eliminated this population until reintroduction in 2006. Through social network analysis (SNA), the sociality of a released pride of captive-origin white and wild tawny lions was compared to two captive-origin and wild prides of tawny lions. Social interactions and pride dynamics were recorded for each pride. For all prides, cubs and subadults were central to the play network, while adults received the most social interactions. White and wild tawny adult males initiated more social interactions than captive-origin tawny males, whilst a keystone adult female was identified in each pride. For the constructed pride, social interactions were more evenly distributed, suggesting a high level of connectedness and cohesion. This is the first study to demonstrate that captive-origin white and wild tawny lions can form a socially functional pride, suggesting that white lions would survive in the wild in the absence of anthropogenic threats.

Optimal conduit choice for open lower extremity bypass in chronic limb-threatening ischemia.

Open bypass surgery remains a major tool for limb salvage in chronic limb-threatening ischemia (CLTI). Although rest pain and tissue loss both fall into the category of CLTI, goals of revascularization are markedly different for each context. Rest pain mandates long-term patency considerations. Tissue loss, however, requires consideration of infection risks and patency enough to heal the wound. Of the major conduit options, autologous saphenous vein graft continues to be the conduit of choice, given both superior patency and low risk of infection. When saphenous vein graft is not available or not available in appropriate length, arm vein, small saphenous vein, and spliced combinations of these have acceptable patency rates. Heparin-bonded polytetrafluoroethylene and Dacron grafts are prosthetic conduits with excellent patency rates when vein is not available. For infected wounds without other options, cryovein continues to provide acceptable patency for limb salvage. Creation of a bypass is only part of CLTI management. Appropriate postoperative surveillance with noninvasive studies, including ankle-brachial index and duplex ultrasound, can alert to impending graft failure, with a drop in ankle-brachial index of 0.15 and velocity ratios of 3 or more suggestive of significant stenoses. Anticoagulation has only been found in limited contexts (such as poor conduit or poor outflow) to offer some patency benefit, however, findings from the VOYAGER PAD (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) trial were a major breakthrough, showing a reduction in the composite outcome of major adverse limb, cardiac, and cerebrovascular events in revascularized patients taking low-dose rivaroxaban in conjunction with aspirin, without a substantial increase in bleeding risk.

Home Range and Movement Patterns of Reintroduced White Lions (Panthera leo melanochaita) in the Kruger to Canyons Biosphere Reserve, South Africa.

White lions are a colour variant of the African lion Panthera leo melanochaita and disappeared from the wild due to anthropogenic factors until their reintroduction to the Greater Kruger Park Region of South Africa in 2006. Natural home range behaviour is an index of reintroduction success. Therefore, the home range and movement of a pride of reintroduced white lions and a constructed pride consisting of reintroduced white lions and translocated wild tawny lionesses in small, fenced reserves was assessed. GPS data from collared adults were collected for the white lion pride between 2010-2011 and 2018-2020 for the constructed pride. Home ranges were estimated using kernel density estimation and minimum convex polygon, with minimum daily distance tested for differences between sex, season, and pride. Home ranges were small and average daily movements restricted for both prides (white lion pride: 5.41 km2 and 10.44 ± 4.82 km; constructed pride: 5.50 km2, 11.37 ± 4.72 km) due to the small reserve size of 7 km2. There was no difference between prides for annual and seasonal home range size, male and female home ranges, minimum daily distance travelled, or habitat selection. White lions from both prides established territories and displayed natural home ranging behaviour, suggesting that their reintroduction was successful, in the absence of anthropogenic threats.