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The protocol of a clinical effectiveness trial comparing standard step-up care, early combination DMARD therapy and early use of TNF inhibitors for the treatment of moderate to severe psoriatic arthritis: the 3-arm parallel group SPEED randomized controlled trial.
OBJECTIVES: The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic factors treated with standard step-up conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), combination csDMARDs or a course of early biologics. DESIGN: This multicentre UK trial was embedded within the MONITOR-PsA cohort, which uses a trial within cohort design. METHODS AND ANALYSIS: Patients with newly diagnosed PsA and at least one poor prognostic factor (polyarthritis, C-reactive protein >5 mg/dL, health assessment questionnaire >1, radiographic erosions) were randomized equally and open-label to either standard care with 'step-up' csDMARD therapy, initial therapy with combination csDMARDs (methotrexate with either sulfasalazine or leflunomide) or to early biologics induction therapy (adalimumab plus methotrexate). The primary outcome is the PsA disease activity score at week 24. ETHICS: Ethical approval for the study was granted by the South Central Research Ethics Committee (ref 18/SC/0107). DISCUSSION: Treatment recommendations for PsA suggest more intensive therapy for those with poor prognostic factors but there are no studies that have previously used prognostic factors to guide therapy. Applying initial intensive therapy has shown improved outcomes in other inflammatory arthritides but has never been tried in PsA. Combination csDMARDs have shown some superiority over single therapies but there are limited data and concerns about side effects. Early use of biologics has also been shown to be superior to methotrexate but these drugs are costly and not usually funded first line. However, if a short course of biologics can rapidly suppress inflammation allowing treatment to be withdrawn and response maintained on methotrexate, this may be a cost-effective model for early use. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03739853) and EudraCT (2017-004542-24).
Safety and efficacy of different transplant kidney biopsy techniques: comparison of two different coaxial techniques and needle types.
PURPOSE: Percutaneous ultrasound-guided renal biopsy is essential for diagnosing medical renal disorders in transplant kidneys. A variety of techniques have been advocated. The purpose of this study is to evaluate the safety and efficacy of two different coaxial techniques and biopsy devices. METHODS: This single-center dual-arm, observation study cohort included 1831 consecutive transplant kidney biopsies performed over a 68-month period. Two coaxial techniques were used, distinguished by whether the 17 gauge (G) coaxial needle was advanced into the renal cortex (intracapsular technique; IC) or to the edge of the cortex (extracapsular technique; EC). One of two needle types could be used with either technique: an 18G side-cutting (Bard Max-Core or Mission) or an 18G end-cutting (Biopince Ultra) needle. In all cases, the cortical tangential technique was used to reduce the risk of central artery transgression and unnecessary medullary sampling. Patients were monitored for 30 days post-procedurally and complications were evaluated using the SIR adverse event classification. RESULTS: Of the 1831 patients included in the study cohort, 13 suffered severe bleeding complications requiring operative intervention. Of these patients, 8 underwent biopsy with side-cutting needle and IC, 2 with side-cutting needle and approach not specified, 2 with end-cutting needle and IC, and 1 with end-cutting needle and EC. There was no statistically significant difference in the risk of bleeding complications between different coaxial techniques and needle types. However, there was a significantly increased chance of inadequate sampling when comparing the side-cutting needle (1.0%) to the end-cutting needle (0.1%). CONCLUSIONS: Transplant kidney biopsy performed with two different coaxial techniques and needle types did not show differences in bleeding complications. There is an increased risk of inadequate sampling when using side-cutting relative to end-cutting biopsy devices.
Gallic acid suppresses the progression of clear cell renal cell carcinoma through inducing autophagy via the PI3K/Akt/Atg16L1 signaling pathway.
Clear cell renal cell carcinoma (ccRCC), the most common type of renal cell carcinoma (RCC), is not sensitive to traditional radiotherapy and chemotherapy. The polyphenolic compound Gallic acid (GA) can be naturally found in a variety of fruits, vegetables and plants. Autophagy, an intracellular catabolic process, regulates the lysosomal degradation of organelles and portions in cytoplasm. It was reported that autophagy and GA could affect the development of several cancers. Therefore, the aim of the present study was to evaluate the effects of GA on ccRCC development and clarify the role of autophagy in this process. In the present study, the effects of GA on the proliferation, migration and invasion of ccRCC cells were investigated in vitro by Cell Counting Kit‑8, colony formation, flow cytometry, wound healing and Transwell migration assays, respectively. Additionally, the effects of GA on ccRCC growth and metastasis were evaluated using hematoxylin‑eosin and immunohistochemical staining in vivo. Moreover, it was sought to explore the underlying molecular mechanisms using transmission electron microscopy, western blotting and reverse transcription‑quantitative PCR analyses. In the present study, it was revealed that GA had a more potent viability inhibitory effect on ccRCC cells (786‑O and ACHN) than the effect on normal renal tubular epithelial cell (HK‑2), which demonstrated that GA selectively inhibits the viability of cancer cells. Furthermore, it was identified that GA dose‑dependently inhibited the proliferation, migration and invasion of ccRCC cells in vitro and in vivo. It was demonstrated that GA promoted the release of autophagy markers, which played a role in regulating the PI3K/Akt/Atg16L1 signaling pathway. All the aforementioned data provided evidence for the great potential of GA in the treatment of ccRCC.
Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response.
Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC.
Tea trolley teaching in critical care: Integrating evidence-based practice with library services.
Tea trolley teaching is a tried and tested method of providing bedside education to hospital staff. This project aimed to integrate the tea trolley teaching model, already established in our local critical care unit, with library services. The goal was to equip clinical staff with the necessary training to retrieve literature and support evidence-based practice. Our evaluation highlights the value of this combined intervention of teaching research skills to upskill staff working in our intensive care units. This paper describes a scalable model of critical care bedside education that integrates library-focused teaching to upskill nurses in some of the prerequisite skills needed for evidence-based practice (EBP).
A simulation study showed that linear regression and Mann-Whitney test can be used to analyse the Days Alive and at Home by day 30 (DAH30) outcome in a randomized controlled trial.
OBJECTIVE: The aims of the work were to consider the properties of the DAH30 from a statistical perspective, and to conduct a simulation study exploring the use of simple (unadjusted) linear regression and Mann-Whitney test as the method of analysis reflect realised analysis options. STUDY DESIGN AND SETTING: The days alive and at home by day 30 (DAH30) has been proposed a patient-centric outcome, and clinically relevant outcome suitable for clinical trials. It has unusual statistical properties, and suitability of standard statistical analysis methods is unclear. The properties of DAH30 were reviewed. Simulations based upon 1:1 allocation in a RCT based upon empirical data were conducted reflecting different additive and realised (reflecting the DAH30) treatment effects, sample sizes and distributions with varying and central locations and zero value level. A variety of metrics were used to assess performance (including bias, coverage, rejection rate). RESULTS: Linear regression provided a valid estimate of the unadjusted average treatment effect with an additive treatment. This was confirmed in terms of bias, estimation of variance, rejection rate in the absence of an effect, and coverage of the 95% confidence interval for the true realised effect. Mann-Whitney provided greater (power) than linear regression in some situations. CONCLUSION: Simple linear regression is a reasonable analytic option for the DAH30 for estimating the average treatment effect in the RCT cohort (i.e. an intention to treat, or "treatment policy" estimand) where zero-inflation is relatively low. Mann-Whitney test in some circumstances (small effects and smaller samples sizes) provides better ability (like for like) to detect a difference between the groups.
Liver damage and immune responses.
Chronic liver disease (CLD) has massive systemic repercussions including major impacts on the body's immune system. Abnormalities in phenotype, function and numbers of various immune cell subsets have been established by a large number of clinical and pre-clinical studies. The loss of essential immune functions renders CLD-patients exceptionally susceptible to bacterial and viral infections and also impairs the efficacy of vaccination. Consequently, infections represent a major clinical issue causing significant morbidity and mortality in these patients. Mechanistically, the immune dysfunction associated with CLD results from the increased translocation of bacteria and bacterial cues from the intestine. These trigger a signaling axis around the cytokines IFN I and IL-10 in hepatic myeloid cells, which aside from impairing the function of the myeloid cells themselves, also has notable negative impacts on the functionality of other immune cells. T cells in CLD-patients and -models are especially affected by this signaling axis and display a variety of quantitative and qualitative defects. Due to the high clinical relevance, understanding the mechanisms underlaying CED-associated immune dysfunction is of critical importance to discover and develop new therapeutic targets.
Precursors of exhausted T cells are preemptively formed in acute infection.
T cell exhaustion limits effector T cell function in chronic infection and tumors1,2. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections1,2. At that stage early developing TCF1+ precursor population shows an unexpected diversity, which includes precursors of normal memory T cells but also cells with a phenotype, gene-expression, and epigenetic profile that resembles precursors of exhausted T cells found in chronic infections. We demonstrate that high ligand affinity promotes, and PD-1 signaling restricts the development of these precursors. While these exhausted precursors are initially frequently found, they decline without being completely lost in infections the immune system resolves. We therefore concluded that precursor T cells with at least two distinct phenotypes are preemptively generated irrespectively of the outcome of the infection.
Prevalence of complications in older adults after hip fracture surgery: a systematic review and meta-analysis
Aims: Older adults with hip fractures are at high risk of experiencing complications after surgery, but estimates of the rate of specific complications vary by study design and follow-up period. The aim of this systematic review was to determine the prevalence of complications in older adults after hip fracture surgery. Methods: MEDLINE, Embase, CINAHL, and CENTRAL databases were searched from inception until 30 June 2023. Studies were included if they reported prevalence data of complications in an unselected, consecutive population of older adults (aged ≥ 60 years) undergoing hip fracture surgery. Results: A total of 95 studies representing 2,521,300 patients were included. For surgery-specific complications, the 30-day prevalence of reoperation was 2.31%, surgical site infection 1.69%, and deep surgical site infection 0.98%; the 365-day prevalence of prosthesis dislocation was 1.11%, fixation failure 1.77%, and periprosthetic or peri-implant fracture 2.23%. For general complications, the 30-day prevalence of acute kidney injury was 1.21%, blood transfusion 25.55%, cerebrovascular accident 0.79%, lower respiratory tract infection 4.08%, myocardial infarction 1.98%, urinary tract infection 7.01%, and venous thromboembolism 2.15%. Conclusion: Complications are prevalent in older adults who have had surgery for a hip fracture. Studies reporting complications after hip fracture surgery varied widely in terms of quality, and we advocate for the routine monitoring of complications in registries and clinical trials to improve the quality of evidence.
Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence.
Abnormal antioxidative capabilities were observed in the pathogenesis of steroid-induced osteoporosis (SIOP). Ferroptosis is a recently discovered type of cell death that is characterized by the overproduction of ROS in response to GPX4 and system Xc- downregulation, which is mediated by an Fe2+ fenton reaction. However, investigations focusing on the relationship between ferroptosis and steroid-induced bone disease remain limited. In the present study, high-dose dexamethasone was used to establish a mouse SIOP model, and extracellular vesicles extracted from bone marrow-derived endothelial progenitor cells (EPC-EVs) alleviated the pathological changes in SIOP via microtomography (micro-CT), with elevations in bone volume (BV), bone surface (BS), trabecular thickness (Tb.Th), and trabecular connectivity density (Conn-D) and decreases in trabecular separation (Tb.sp) and the structure model index (SMI). Histopathological analysis, such as haematoxylin and eosin (HE) and Masson staining, showed that EPC-EVs treatment increased the volume and density of the trabecular bone and bone marrow. RNA sequencing (RNA-seq) and bioinformatics analysis revealed subcellular biological alterations upon steroid and EPC-EVs treatment. Compared with the control, high-dose dexamethasone downregulated GPX4 and system XC-, and the Kyoto Encyclopedia of Genes and Genomes (KEGG)-based gene set enrichment analysis suggested that the ferroptotic pathway was activated. In contrast, combination treatment with EPC-EVs partly reversed the KEGG-mapped changes in the ferroptotic pathway at both the gene and mRNA expression levels. In addition, alterations in ferroptotic marker expression, such as SLC3A2, SLC7A11, and GPX4, were further confirmed by RNA-seq. EPC-EVs were able to reverse dexamethasone treatment-induced alterations in cysteine and several oxidative injury markers, such as malondialdehyde (MDA), glutathione (GSH), and glutathione disulphide (GSSG) (as detected by ELISA). In conclusion, EPC-EVs prevented mouse glucocorticoid-induced osteoporosis by suppressing the ferroptotic pathway in osteoblasts, which may provide a basis for novel therapies for SIOP in humans.
Resveratrol reduces store-operated Ca2+ entry and enhances the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1-STIM1 complex.
BACKGROUND: Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process. RESULTS: In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model. CONCLUSION: These results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1-STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.
Resveratrol alleviates inflammatory injury and enhances the apoptosis of fibroblast‑like synoviocytes via mitochondrial dysfunction and ER stress in rats with adjuvant arthritis.
Resveratrol, a bioactive compound predominantly found in grapes and red wine, provides a wide range of properties that are beneficial for health, including anticancer and anti‑inflammatory activities. Previously published studies have addressed the potential therapeutic effects of resveratrol on rheumatoid arthritis (RA); however, the subcellular mechanism remains to be fully elucidated. In the present study, the therapeutic effects of resveratrol on adjuvant arthritis (AA) in Sprague‑Dawley rats were investigated, and the mechanisms of resveratrol‑induced apoptosis in fibroblast‑like synoviocytes (FLSs) were further examined. Based on the findings, resveratrol treatment over a 12‑day period led to a reduction in paw swelling and arthritis scores at the macroscopic level, and an attenuation of inflammatory cell infiltration and synovial hyperplasia, upon a histopathological examination of the AA rats. Furthermore, the administration of resveratrol triggered decreases in the expression of interleukin (IL)‑1, IL‑6, IL‑8 and tumor necrosis factor‑α (TNF‑α) and an increase in the expression of IL‑10, alleviating inflammatory injury in AA rats in a dose‑dependent manner. In addition, resveratrol was revealed to induce the apoptosis of FLSs when administered with 5 µM H2O2 as determined by elevated levels of Bax, caspase‑3, caspase‑12 and C/EBP‑homologous protein, and the downregulation of B‑cell lymphoma 2 (Bcl‑2), suggesting that resveratrol is able to induce apoptosis in FLSs via the mitochondrial pathway and endoplasmic reticulum (ER) stress in a milieu containing 5 µM H2O2. Furthermore, JC‑1 was used as a fluorescent probe to detect the mitochondrial membrane potential (Δψm), and resveratrol was shown to reduce the Δψm in FLSs in the presence of 5 µM H2O2. However, resveratrol was not able to trigger intracellular calcium overload, although it did suppress ATP‑ and thapsigargin‑induced calcium release from the ER. In conclusion, the present study revealed that resveratrol was able to alleviate inflammatory injury in AA rats, triggering the apoptosis of FLSs via the mitochondrial pathway and ER stress. These results provide a theoretical basis for future treatments using resveratrol for RA.
Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro.
Depletion of the mitochondrial membrane potential (MMP, ΔΨm) is considered the earliest event in the apoptotic cascade. It even occurs ahead of nuclear apoptotic characteristics, including chromatin condensation and DNA breakage. Once the MMP collapses, cell apoptosis will initiate irreversibly. A series of lipophilic cationic dyes can pass through the cell membrane and aggregate inside the matrix of mitochondrion, and serve as fluorescence marker to evaluate MMP change. As one of the six members of the Cl- intracellular channel (CLIC) family, CLIC4 participates in the cell apoptotic process mainly through the mitochondrial pathway. Here we describe a detailed protocol to measure MMP via monitoring the fluorescence fluctuation of Rhodamine 123 (Rh123), through which we study apoptosis induced by CLIC4 knockdown. We discuss the advantages and limitations of the application of confocal laser scanning and normal fluorescence microscope in detail, and also compare it with other methods.
Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss.
The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.
Variability of Psoriatic Arthritis Impact of Disease questionnaire (PsAID12) thresholds in psoriatic arthritis: data from the ReFlaP study.
OBJECTIVES: To explore thresholds for the Psoriatic Arthritis (PsA) Impact of Disease questionnaire (PsAID12) score against disease activity measures in an observational setting, in patients with PsA. METHODS: The baseline data from the ReFlaP observational, prospective, multicentre and international study was used (NCT03119805). Cutoffs for PsAID12 were determined against disease activity scores, defining disease impact states (ie remission, low impact, moderate impact and high impact). Statistics used to assess the optimal cutoff point included the Youden's index and the 75th percentile method, with external anchors (i.e. DAPSA, VDLA/MDA and single questions for both patients and physicians) serving as gold standards. The diagnostic performance of these cutoffs was evaluated using Receiver Operating Characteristic (ROC) curve analyses. RESULTS: A total of 410 patients were analyzed. Mean (standard deviation, SD) PsAID12 score was 3.4 (SD 2.5). The prevalence of remission varied between 12.4% and 36.1%, while low disease activity ranged from 37.8% to 59.8%. PsAID12 performed well against external anchors, with high areas under the ROC curves ranging from 0.75-0.94. Using the DAPSA as external anchor, the proposed PsAID12 cutoffs were <1.7 for remission, ≥1.7 to ≤ 3.1 for low impact, >3.1 to
Psoriatic Arthritis Priority Setting Partnership: patient- and clinician-informed considerations for future UK health service delivery.
OBJECTIVES: Little is known about the ideal service delivery model and shortcomings in patient experiences in the NHS for patients with Psoriatic Arthritis (PsA). To identify unmet needs perceived within the current health service delivery model for PsA from the UK Psoriatic Arthritis Priority Setting Partnership (PsA PSP). METHODS: An online survey was conducted in 2020 and distributed to people with PsA, their carers and clinicians to identify research priorities in PsA. The participants were asked to submit three questions unanswered in PsA research. A proportion of submissions related to health service delivery were identified, which were deemed as out of scope for the main PsA-PSP but never-the-less important to report. Content analysis was used to analyse these submissions separately. RESULTS: We reviewed 138 submissions that were not related to the James Lind PSP and research priorities in PsA. Among these, 118 (86%) were focused on health service delivery and were classified into five main themes: rheumatology service, primary care navigation, education, holistic care, and ethnicity, diversity, and inclusion. Further analysis within the rheumatology service theme revealed additional sub-themes that emphasised integrating multidisciplinary services, improving access to advice lines and ensuring fair access to treatments. CONCLUSION: The five key themes provide valuable insights into the important areas of interest within health service delivery in the UK. By understanding these themes, policymakers, healthcare providers, and researchers can better prioritise their efforts and address the specific care needs of people with PsA, their care providers and clinicians.