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Scientific Reports Jul 2024Ulcerative colitis (UC) is a chronic inflammatory bowel disease with intricate pathogenesis and varied presentation. Accurate diagnostic tools are imperative to detect...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with intricate pathogenesis and varied presentation. Accurate diagnostic tools are imperative to detect and manage UC. This study sought to construct a robust diagnostic model using gene expression profiles and to identify key genes that differentiate UC patients from healthy controls. Gene expression profiles from eight cohorts, encompassing a total of 335 UC patients and 129 healthy controls, were analyzed. A total of 7530 gene sets were computed using the GSEA method. Subsequent batch correction, PCA plots, and intersection analysis identified crucial pathways and genes. Machine learning, incorporating 101 algorithm combinations, was employed to develop diagnostic models. Verification was done using four external cohorts, adding depth to the sample repertoire. Evaluation of immune cell infiltration was undertaken through single-sample GSEA. All statistical analyses were conducted using R (Version: 4.2.2), with significance set at a P value below 0.05. Employing the GSEA method, 7530 gene sets were computed. From this, 19 intersecting pathways were discerned to be consistently upregulated across all cohorts, which pertained to cell adhesion, development, metabolism, immune response, and protein regulation. This corresponded to 83 unique genes. Machine learning insights culminated in the LASSO regression model, which outperformed others with an average AUC of 0.942. This model's efficacy was further ratified across four external cohorts, with AUC values ranging from 0.694 to 0.873 and significant Kappa statistics indicating its predictive accuracy. The LASSO logistic regression model highlighted 13 genes, with LCN2, ASS1, and IRAK3 emerging as pivotal. Notably, LCN2 showcased significantly heightened expression in active UC patients compared to both non-active patients and healthy controls (P < 0.05). Investigations into the correlation between these genes and immune cell infiltration in UC highlighted activated dendritic cells, with statistically significant positive correlations noted for LCN2 and IRAK3 across multiple datasets. Through comprehensive gene expression analysis and machine learning, a potent LASSO-based diagnostic model for UC was developed. Genes such as LCN2, ASS1, and IRAK3 hold potential as both diagnostic markers and therapeutic targets, offering a promising direction for future UC research and clinical application.
Topics: Humans; Machine Learning; Colitis, Ulcerative; Algorithms; Gene Expression Profiling; Transcriptome; Interleukin-1 Receptor-Associated Kinases; Male; Female; Lipocalin-2; Case-Control Studies; Biomarkers; Adult
PubMed: 38951638
DOI: 10.1038/s41598-024-65481-8 -
BMJ Open Jul 2024Persistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which...
INTRODUCTION
Persistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic disability after mTBI. This study will evaluate the efficacy of graded exposure therapy (GET) for reducing persistent symptoms following mTBI, with two primary aims: (1) To determine whether GET is more effective than usual care; (2) to identify for whom GET is the most effective treatment option, by evaluating whether baseline fear avoidance moderates differences between GET and an active comparator (prescribed aerobic exercise). Our findings will guide evidence-based care after mTBI and enable better matching of mTBI patients to treatments.
METHODS AND ANALYSIS
We will conduct a multisite randomised controlled trial with three arms. Participants (n=220) will be recruited from concussion clinics and emergency departments in three Canadian provinces and randomly assigned (1:2:2 ratio) to receive enhanced usual care, GET or prescribed aerobic exercise. The outcome assessment will occur remotely 14-18 weeks following baseline assessment, after completing the 12-week treatment phase. The primary outcome will be symptom severity (Rivermead Post-concussion Symptoms Questionnaire).
ETHICS AND DISSEMINATION
Informed consent will be obtained from all participants. All study procedures were approved by the local research ethics boards (University of British Columbia Clinical Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, University Health Network Research Ethics Board-Panel D). Operational approvals were obtained for Vancouver Coastal Health Research Institute and Provincial Health Services Authority. If GET proves effective, we will disseminate the GET treatment manual and present instructional workshops for clinicians.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov #NCT05365776.
Topics: Humans; Brain Concussion; Fear; Canada; Implosive Therapy; Avoidance Learning; Quality of Life; Randomized Controlled Trials as Topic; Post-Concussion Syndrome; Male; Multicenter Studies as Topic; Adult; Female
PubMed: 38950993
DOI: 10.1136/bmjopen-2024-086602 -
British Journal of Sports Medicine Jul 2024There is a lack of prospective data on mental health of elite Para athletes. The objective was to identify and follow elite Para athletes at risk of mental health...
OBJECTIVE
There is a lack of prospective data on mental health of elite Para athletes. The objective was to identify and follow elite Para athletes at risk of mental health problems.
METHODS
In a 124-week prospective cohort study, mental health of German elite Para athletes was monitored using the Patient Health Questionnaire-4 (PHQ-4). In case of positive screening (PHQ-4≥5) over 2 weeks, a follow-up contact was conducted by a sports psychiatrist, who asked the athletes about their mental condition and sources for their mental distress and offered support.
RESULTS
7543 PHQ-4 scores were obtained from 122 Para athletes with a mean weekly response rate of 84%. The PHQ-4 screening was considered positive for symptoms of depression or anxiety with a prevalence of 6.7%, affecting 48.4% (n=59) of all participants at some point during the study period. In 76.6% (n=49) of all follow-up contacts, athletes (n=34) reported at least one mental health problem, most frequently mental distress (n=31), followed by symptoms of depression (n=19) including acute suicidality (n=1). The most common mental stressors cited were related to education and problems with the team, coaches or federation. At follow-up, almost two-thirds of the athletes were either already in professional psychiatric or psychological care (25%) or were recommended to seek such care (32.8%).
CONCLUSION
Our screening and follow-up system revealed high rates of mental health problems in elite Para athletes. Programmes for early identification with mental health monitoring under the supervision of mental health professionals should be considered by sports federations for Para athletes.
PubMed: 38950918
DOI: 10.1136/bjsports-2023-107995 -
Seminars in Thrombosis and Hemostasis Jul 2024The optimal pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty is uncertain. We conducted a systematic review and network...
The optimal pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty is uncertain. We conducted a systematic review and network meta-analysis to compare the efficacy and safety of various medications. We searched multiple databases for randomized clinical trials (RCTs) comparing medications (including factor Xa inhibitors, factor IIa inhibitor, warfarin, unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], aspirin, pentasaccharide) for VTE prophylaxis post-arthroplasty. Outcomes included any postoperative VTE identified with screening, major bleeding, and death. We used LMWH as the main comparator for analysis and performed trial sequential analysis (TSA) for each pairwise comparison. Certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessments, Developments and Evaluations). We analyzed 70 RCTs (55,841 participants). Factor Xa inhibitors decreased postoperative VTE significantly compared with LMWH (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.44-0.68, high certainty). Pentasaccharides probably reduce VTE (OR: 0.61, 95% CI: 0.36-1.02, moderate certainty), while the factor IIa inhibitor dabigatran may reduce VTE (OR: 0.75, 95% CI: 0.40-1.42, low certainty). UFH probably increases VTE compared with LMWH (OR: 1.31, 95% CI: 0.91-1.89, moderate certainty), and other agents like warfarin, aspirin, placebo, and usual care without thromboprophylaxis increase VTE (high certainty). Factor Xa inhibitors may not significantly affect major bleeding compared with LMWH (OR: 1.06, 95% CI: 0.81-1.39, low certainty). No medications had a notable effect on mortality compared with LMWH (very low certainty). TSA suggests sufficient evidence for the benefit of factor Xa inhibitors over LMWH for VTE prevention. Compared with LMWH and aspirin, factor Xa inhibitors are associated with reduced VTE after hip or knee arthroplasty, without an increase in bleeding and likely no impact on mortality.
PubMed: 38950598
DOI: 10.1055/s-0044-1787996 -
The Journal of Clinical Investigation Jun 2024Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for...
Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Topics: Humans; Iron-Sulfur Proteins; Male; Female; Neuromuscular Diseases; Child; Cell Nucleus; Cytoplasm; Metallochaperones
PubMed: 38950322
DOI: 10.1172/JCI179559 -
PloS One 2024Acute compartment syndrome (ACS) is a syndrome in which local circulation is affected due to increased pressure within the compartment. We previously found in patients...
Acute compartment syndrome (ACS) is a syndrome in which local circulation is affected due to increased pressure within the compartment. We previously found in patients with calf fractures, the pressure of fascial compartment could be sharply reduced upon the appearance of tension blisters. Deep fascia, as the important structure for compartment, might play key role in this process. Therefore, the aim of the present study was to examine the differences in gene profile in deep fascia tissue in fracture patients of the calf with or without tension blisters, and to explore the role of fascia in pressure improvement in ACS. Patients with lower leg fracture were enrolled and divided into control group (CON group, n = 10) without tension blister, and tension blister group (TB group, n = 10). Deep fascia tissues were collected and LC-MS/MS label-free quantitative proteomics were performed. Genes involved in fascia structure and fibroblast function were further validated by Western blot. The differentially expressed proteins were found to be mainly enriched in pathways related to protein synthesis and processing, stress fiber assembly, cell-substrate adhesion, leukocyte mediated cytotoxicity, and cellular response to stress. Compared with the CON group, the expression of Peroxidasin homolog (PXDN), which promotes the function of fibroblasts, and Leukocyte differentiation antigen 74 (CD74), which enhances the proliferation of fibroblasts, were significantly upregulated (p all <0.05), while the expression of Matrix metalloproteinase-9 (MMP9), which is involved in collagen hydrolysis, and Neutrophil elastase (ELANE), which is involved in elastin hydrolysis, were significantly reduced in the TB group (p all <0.05), indicating fascia tissue underwent microenvironment reconstruction during ACS. In summary, the ACS accompanied by blisters is associated with the enhanced function and proliferation of fibroblasts and reduced hydrolysis of collagen and elastin. The adaptive alterations in the stiffness and elasticity of the deep fascia might be crucial for pressure release of ACS.
Topics: Humans; Proteomics; Compartment Syndromes; Male; Fascia; Middle Aged; Adult; Female; Acute Disease; Aged
PubMed: 38950026
DOI: 10.1371/journal.pone.0305275 -
EFORT Open Reviews Jul 2024The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new...
PURPOSE
The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new stabilized CT formulations are currently being introduced.
METHODS
A comprehensive and systemic literature search was conducted in PubMed/MEDLINE and Embase databases to identify articles with original data on CT treatment of preclinical OA and RA. Methodological quality was assessed using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool for animal intervention studies. To provide summary estimates of efficacy, a meta-analysis was conducted for outcomes reported in four or more studies, using a random-effects model. Subgroup analyses were employed to correct for study specifics.
RESULTS
Twenty-six studies were ultimately evaluated and data from 16 studies could be analyzed in the meta-analysis, which included the following outcomes: bone mineral density, bone volume, levels of cross-linked C-telopeptide of type I collagen, histopathological arthritis score, and mechanical allodynia. For all considered outcome parameters, CT-treated groups were significantly superior to control groups (P = 0.002; P = 0.01; P < 0.00001; P < 0.00001; P = 0.04). For most outcomes, effect sizes were significantly greater in OA than in RA (P ≤ 0.025). High in-between study heterogeneity was detected.
CONCLUSION
There is preclinical evidence for an antioxidant, anti-inflammatory, antinociceptive, cartilage- and bone-protective effect of CT in RA and OA. Given these effects, CT presents a promising agent for the treatment of both diseases, although the potential seems to be greater in OA.
PubMed: 38949173
DOI: 10.1530/EOR-23-0133 -
EFORT Open Reviews Jul 2024The association between fluoroquinolone intake and Achilles tendinopathy (AT) or Achilles tendon rupture (ATR) is widely documented. However, it is not clear whether...
PURPOSE
The association between fluoroquinolone intake and Achilles tendinopathy (AT) or Achilles tendon rupture (ATR) is widely documented. However, it is not clear whether different molecules have the same effect on these complications. The purpose of this study was to document Achilles tendon complications for the most prescribed fluoroquinolones molecules.
METHODS
A literature search was performed on Pubmed, Cochrane, Embase, and Web of Science databases up to April 2023. Inclusion criteria: studies of any level of evidence, written in English, documenting the prevalence of AT/ATR after fluoroquinolone consumption and stratifying the results for each type of molecule. The Downs and Black's 'Checklist for Measuring Quality' was used to evaluate the risk of bias.
RESULTS
Twelve studies investigating 439,299 patients were included (59.7% women, 40.3% men, mean age: 53.0 ± 15.6 years). The expected risk of AT/ATR was 0.17% (95% CI: 0.15-0.19, standard error (s.e.): 0.24) for levofloxacin, 0.17% (95% CI: 0.16-0.19, s.e.: 0.20) for ciprofloxacin, 1.40% (95% CI: 0.88-2.03, s.e.: 2.51) for ofloxacin, and 0.31% (95% CI: 0.23-0.40, s.e.: 0.77) for the other molecules. The comparison between groups documented a significantly higher AT/ATR rate in the ofloxacin group (P < 0.0001 for each comparison). Levofloxacin and ciprofloxacin showed the same risk (P = n.s.). The included studies showed an overall good quality.
CONCLUSION
Ofloxacin demonstrated a significantly higher rate of AT/ATR complications in the adult population, while levofloxacin and ciprofloxacin showed a safer profile compared to all the other molecules. More data are needed to identify other patient and treatment-related factors influencing the risk of musculoskeletal complications.
PubMed: 38949172
DOI: 10.1530/EOR-23-0181 -
EFORT Open Reviews Jul 2024To assess utility, benefits, and risks of 4th-generation alumina-zirconia ceramic pairings in elective total hip arthroplasty (THA).
PURPOSE
To assess utility, benefits, and risks of 4th-generation alumina-zirconia ceramic pairings in elective total hip arthroplasty (THA).
METHODS
A comprehensive mixed-methods best-evidence synthesis using data from systematic reviews, randomized controlled trials (RCTs), prospective and retrospective cohort studies, as well as joint replacement registries, was conducted to estimate overall revision and survival rates, periprosthetic infection, bearing fractures, and noise phenomena with 4th-generation alumina-zirconia ceramic versus other tribological couplings in elective THA. The systematic review part across multiple databases was registered with PROSPERO (CRD42023418076), and individual study data were extracted for statistical re-analysis.
RESULTS
Twenty overlapping systematic reviews, 7, 17, and 8 references from RCTs, cohort studies, and joint replacement registries form the basis of this work. According to current best evidence, it is (i) 15-33 times more likely that 4th-generation alumina-zirconia pairings avoid a revision for infection than causing a revision for audible noise, (ii) 38-85 times more likely that 4th-generation alumina-zirconia pairings avoid a revision for infection than causing a revision for ceramic head fractures, and (iii) three to six times more likely that 4th-generation alumina-zirconia pairings avoid a revision for infection than cause a revision for ceramic liner fractures.
CONCLUSION
Fourth-generation alumina-zirconia pairings in THA show a favorable benefit-risk ratio, with rare compound-specific adverse events and complications significantly outbalanced by long-term advantages, such as a markedly lower incidence of revision for infection.
PubMed: 38949170
DOI: 10.1530/EOR-23-0218 -
EFORT Open Reviews Jul 2024This systematic review aims to investigate the management and outcomes of pelvic ring fractures (PRFs) during pregnancy, emphasizing maternal and fetal mortality rates,...
PURPOSE
This systematic review aims to investigate the management and outcomes of pelvic ring fractures (PRFs) during pregnancy, emphasizing maternal and fetal mortality rates, mechanisms of injury, and treatment modalities.
METHODS
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive search of databases from 2000 to 2023, identifying 33 relevant studies. Data extraction included demographics, fracture types, treatment methods, and outcomes. Risk of bias was assessed using the JBI criteria.
RESULTS
Maternal mortality stood at 9.1%, with fetal mortality at 42.4%. Maternal factors impacting mortality included head trauma and hemodynamic instability. Fetal mortality correlated with mechanisms like motor vehicle accidents and maternal vital signs. Surgical and conservative treatments were applied, with a majority of pelvic surgeries performed before delivery. External fixators proved effective in fracture stabilization.
CONCLUSION
Pelvic ring fractures during pregnancy present significant risks to maternal and fetal health. Early stabilization and vigilant monitoring of maternal vital signs are crucial. Vaginal bleeding/discharge serves as a critical fetal risk indicator. The choice between surgical and conservative treatment minimally influenced outcomes. Multidisciplinary collaboration and tailored interventions are essential in managing these complex cases.
PubMed: 38949162
DOI: 10.1530/EOR-23-0164