Search results
Found 30036 matches for
Systemic inflammation impairs myelopoiesis and interferon type I responses in humans.
Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.
Three-dimensional, in-vitro approaches for modelling soft-tissue joint diseases
Diseases affecting the soft tissues of the joint represent a considerable global health burden, causing pain and disability and increasing the likelihood of developing metabolic comorbidities. Current approaches to investigating the cellular basis of joint diseases, including osteoarthritis, rheumatoid arthritis, tendinopathy, and arthrofibrosis, involve well phenotyped human tissues, animal disease models, and in-vitro tissue culture models. Inherent challenges in preclinical drug discovery have driven the development of state-of-the-art, in-vitro human tissue models to rapidly advance therapeutic target discovery. The clinical potential of such models has been substantiated through successful recapitulation of the pathobiology of cancers, generating accurate predictions of patient responses to therapeutics and providing a basis for equivalent musculoskeletal models. In this Review, we discuss the requirement to develop physiologically relevant three-dimensional (3D) culture systems that could advance understanding of the cellular and molecular basis of diseases that affect the soft tissues of the joint. We discuss the practicalities and challenges associated with modelling the complex extracellular matrix of joint tissues—including cartilage, synovium, tendon, and ligament—highlighting the importance of considering the joint as a whole organ to encompass crosstalk across tissues and between diverse cell types. The design of bespoke in-vitro models for soft-tissue joint diseases has the potential to inform functional studies of the cellular and molecular mechanisms underlying disease onset, progression, and resolution. Use of these models could inform precision therapeutic targeting and advance the field towards personalised medicine for patients with common musculoskeletal diseases.
The World Hip Trauma Evaluation (WHiTE) platform trial: a framework for randomized comparisons of interventions for fragility hip fracture.
AIMS: Hip fracture is one of the biggest challenges facing patients and healthcare systems. Worldwide, there are currently 1.3 million hip fractures per year, projected to rise to more than six million by 2050. This protocol describes a platform trial framework, designed to efficiently deliver multiple randomized comparisons of interventions for patients with a fragility hip fracture. METHODS: All patients aged 60 years and over with a hip fracture presenting to the World Hip Trauma Evaluation (WHiTE) recruitment centres will be considered for eligibility for each of the randomized comparisons appended to the platform at the time of recruitment. They will be offered the opportunity to take part in any or all of the randomized comparisons for which they are eligible. Comparisons may be contemporaneous or distributed throughout the treatment pathway. This master protocol describes the trial procedures, core dataset, and documentation. It describes those components of the research process which will be consistent between randomized comparisons. Where additional procedures are planned, specific to a randomized comparison, these will be described in a separate appendix protocol for that randomized comparison. CONCLUSION: The WHiTE platform trial will provide randomized evidence regarding the clinical and cost-effectiveness of interventions to improve outcomes for patients with fragility hip fracture. Findings will inform national and international policy and practice guidelines for the management of patients with a hip fracture.
A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Development of a nanoparticle-based tendon-targeting drug delivery system to pharmacologically modulate tendon healing.
Satisfactory healing following acute tendon injury is marred by fibrosis. Despite the high frequency of tendon injuries and poor outcomes, there are no pharmacological therapies in use to enhance the healing process. Moreover, systemic treatments demonstrate poor tendon homing, limiting the beneficial effects of potential tendon therapeutics. To address this unmet need, we leveraged our existing tendon healing spatial transcriptomics dataset and identified an area enriched for expression of Acp5 (TRAP) and subsequently demonstrated robust TRAP activity in the healing tendon. This unexpected finding allowed us to refine and apply our existing TRAP binding peptide (TBP) functionalized nanoparticle (NP) drug delivery system (DDS) to facilitate improved delivery of systemic treatments to the healing tendon. To demonstrate the translational potential of this DDS, we delivered niclosamide (NEN), an S100a4 inhibitor. While systemic delivery of free NEN did not alter healing, TBP-NPNEN enhanced both functional and mechanical recovery, demonstrating the translational potential of this approach to enhance the tendon healing process.
The origin and speciation of orchids.
Orchids constitute one of the most spectacular radiations of flowering plants. However, their origin, spread across the globe, and hotspots of speciation remain uncertain due to the lack of an up-to-date phylogeographic analysis. We present a new Orchidaceae phylogeny based on combined high-throughput and Sanger sequencing data, covering all five subfamilies, 17/22 tribes, 40/49 subtribes, 285/736 genera, and c. 7% (1921) of the 29 524 accepted species, and use it to infer geographic range evolution, diversity, and speciation patterns by adding curated geographical distributions from the World Checklist of Vascular Plants. The orchids' most recent common ancestor is inferred to have lived in Late Cretaceous Laurasia. The modern range of Apostasioideae, which comprises two genera with 16 species from India to northern Australia, is interpreted as relictual, similar to that of numerous other groups that went extinct at higher latitudes following the global climate cooling during the Oligocene. Despite their ancient origin, modern orchid species diversity mainly originated over the last 5 Ma, with the highest speciation rates in Panama and Costa Rica. These results alter our understanding of the geographic origin of orchids, previously proposed as Australian, and pinpoint Central America as a region of recent, explosive speciation.
Identification of Periostin as a critical niche for myofibroblast dynamics and fibrosis during tendon healing.
Tendon injuries are a major clinical problem, with poor patient outcomes caused by abundant scar tissue deposition during healing. Myofibroblasts play a critical role in the initial restoration of structural integrity after injury. However, persistent myofibroblast activity drives the transition to fibrotic scar tissue formation. As such, disrupting myofibroblast persistence is a key therapeutic target. While myofibroblasts are typically defined by the presence of αSMA+ stress fibers, αSMA is expressed in other cell types including the vasculature. As such, modulation of myofibroblast dynamics via disruption of αSMA expression is not a translationally tenable approach. Recent work has demonstrated that Periostin-lineage (PostnLin) cells are a precursor for cardiac fibrosis-associated myofibroblasts. In contrast to this, here we show that PostnLin cells contribute to a transient αSMA+ myofibroblast population that is required for functional tendon healing, and that Periostin forms a supportive matrix niche that facilitates myofibroblast differentiation and persistence. Collectively, these data identify the Periostin matrix niche as a critical regulator of myofibroblast fate and persistence that could be targeted for therapeutic manipulation to facilitate regenerative tendon healing.
No sign of quitting: incidental exposure to “no smoking” signs ironically boosts cigarette‐approach tendencies in smokers
AbstractThe unconscious mind tends to disregard negations in its processing of semantic meaning. Therefore, messages containing negated concepts can ironically prime mental representations and evaluations that are opposite to those intended. We hypothesized that the subtle presentation of a negated concept (e.g., “no smoking”) would activate ironic motivational orientations as well. We tested this hypothesis in a public health context. Smokers viewed photographs in which “no smoking” signs were either inconspicuously embedded (prime condition) or edited out (control condition). Primed smokers showed amplified automatic approach tendencies toward smoking‐related stimuli, but not toward smoking‐unrelated stimuli: an ironic motivational response to exposure to the signs. Since passive priming effects generally serve to facilitate forms of action, not inhibit them, antismoking and other public health campaigns may ironically increase the very behaviors they seek to reduce.
A preliminary study of medial temporal lobe function in youths with a history of caregiver deprivation and emotional neglect.
Previous research findings have linked caregiver deprivation and emotional neglect with sensitivity to threatening cues. The present preliminary study investigated whether dysfunctions of the medial temporal lobe could underlie these associations. Using fMRI, we measured medial temporal lobe responses to emotional faces (angry, fearful, happy, neutral) among 30 youths. Eleven of the youths had a history of caregiver deprivation and emotional neglect. Attention states (i.e., attention to anger, fear, or physical attributes, or passive viewing) were systematically manipulated. Relative to comparison youths, youths with a history of caregiver deprivation and emotional neglect showed significantly greater left amygdala and left anterior hippocampus activation during the processing of threatening information. To our knowledge, these findings are the first to demonstrate altered medial temporal lobe function during the processing of threat cues in youths with a history of caregiver deprivation and emotional neglect.
The Role of Social Prescribers in Engaging Older Adults in Strength and Balance Training After Being Discharged From Physiotherapy Rehabilitation: A Qualitative Investigation
Background: Older adults are advised to undertake strength and balance training (SBT) to prevent falls. This can be provided by physiotherapy services for a limited time, but long‐term engagement is required to maintain the benefits. Finding ways to support long‐term engagement is needed.Aim: To understand if it is feasible to develop a referral pathway from physiotherapy services to social prescribers for engaging older adults in long‐term SBT within their daily lives.Methods: We purposefully recruited and interviewed social prescribers via Microsoft Teams. We undertook a framework analysis based on the Capability‐Opportunity‐Motivation behaviour change framework.Results: We interviewed eight social prescribers including one manager and two whose role was related specifically to physical activity and exercise. All participants demonstrated motivation to engage older adults in SBT. However, there was variation in their perceived capability and opportunity to do this. Some felt their roles were well suited to encourage SBT as their role was linked to exercise provision, but others felt less confident and identified barriers. All participants identified that the social prescribers were becoming overwhelmed by their workload. They identified motivation as the most potent barrier to older adults engaging in SBT along with opportunity and capability barriers. Participants felt that improving motivation would be the biggest driver of behaviour change but not all felt equipped to do this.Conclusion: It may be feasible to trial setting up a referral pathway from physiotherapy services to social prescribing to support older adults to engage in SBT. However, services may lack capacity, and there was variability in how services work and social prescribers identified barriers to engaging older adults in SBT. A better option may be to explore the development of a pathway from outpatient physiotherapy services directly to community physical activity services.
Feasibility assessment of radiolabeled FAPI-04 for diagnostic and therapeutic use in rheumatoid arthritis.
OBJECTIVE: Fibroblast activation protein alpha (FAPα) plays a key role in cartilage degradation, inflammation, and bone erosion, particularly in rheumatoid arthritis (RA) where fibroblast-like synoviocytes in synovial tissue show elevated FAPα expression. This study explored radiolabeled FAP inhibitors for arthritis diagnosis and therapy. DESIGN: We used the radiotracer 68Ga-FAPI-04 for PET/CT imaging to predict collagen-induced arthritis (CIA) onset. Weekly scans quantified tracer uptake via SUV values, correlating results with disease scores and incidence. For therapeutic evaluation, 177Lu-FAPI-04 targeted FAPα-expressing cells, and arthritis scores of treated CIA mice were compared with untreated controls using one-way ANOVA. RESULTS: CIA mice with elevated SUV one week post-booster immunization had a 94.6 % arthritis incidence. SUV correlated with arthritis severity, reflecting increased FAPα expression. Treatment with 177Lu-FAPI-04 reduced arthritis scores by 64 % compared to controls (p
Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): a randomized controlled trial.
BACKGROUND AND AIMS: Barrett's esophagus (BE) is a precursor lesion for esophageal adenocarcinoma (EA). Surveillance endoscopy aims to detect early malignant progression: though widely practised it has not previously been tested in a randomized trial. METHODS: BOSS was a randomized controlled trial at 109 centres in the UK. Patients with BE were randomized to two-yearly surveillance endoscopy or 'at need' endoscopy, offered only for symptoms. Follow up was a minimum of 10 years. The primary outcome was overall survival in the intention-to-treat population. Secondary outcomes included cancer-specific survival; time to diagnosis of EA; stage of EA at diagnosis; frequency of endoscopy and serious adverse events related to interventions. RESULTS: 3453 patients were recruited. 1733 patients were randomized to surveillance and 1719 to 'at need' endoscopy. Median follow up time was 12·8 years for the primary outcome. There was no evidence of a difference in overall survival between surveillance (333 deaths in 1733 patients) versus 'at need' arms (356 deaths in 1719 patients), hazard ratio 0·95 (95% CI 0·82-1·10), stratified log-rank p=0·503). There was no evidence of a difference for surveillance versus 'at need' endoscopy in cancer-specific survival (108 vs. 106 deaths from any cancer, HR 1·01 (95% CI 0·77-1·33), p=0·926), time to diagnosis of EA (40 vs. 31 patients had a diagnosis of EA, HR 1·32 (95% CI 0·82-2·11), p=0·254), or cancer stage at diagnosis. 8 (0·46%) surveillance patients and 7 (0·41%) 'at need' patients reported serious adverse events. CONCLUSION: Surveillance did not improve overall survival or cancer-specific survival. 'At need' endoscopy may be a safe alternative for low-risk patients.