Paradoxical Changes: EMMPRIN Tissue and Plasma Levels in Marfan Syndrome-Related Thoracic Aortic Aneurysms.

Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.

The Overlooked Association Between Nutrition and the Development of Acute Myeloid Leukaemia: A Scoping Review.

PURPOSE OF REVIEW: Acute Myeloid Leukaemia (AML) constitutes a mere 1% of global cancer cases. This scoping review aims to investigate the association between nutrition and the development of AML, providing a foundation for future research in this field. RECENT FINDINGS: A systematic search was conducted across PubMed, EBSCO, Taylor and Francis, Science Direct and Cochrane Library using specific keywords. Inclusion criteria comprised observational studies and clinical trials examining the association between nutrition and the development of AML. Articles selected for analysis were restricted to those published in English between 1990-2023, and available as full text articles. Among the twenty-five articles that were screened, only six met the criteria for data extraction. Four studies did not reveal statistically significant correlations between nutrition and the development of AML, while two studies provided evidence for significant associations. The findings indicated increased AML risk associated with (a) heightened caloric intake, consumption of white potatoes, and red meat (pork and beef) and (b) diminished consumption of vegetables, seafood, nuts, and seeds. The scarcity of comprehensive studies exploring the connection between nutrition and AML, highlights the urgent need for additional research, encompassing pre-clinical studies. This imperative is critical for enhancing our understanding of the molecular mechanisms that underlie the connection between diet and the aetiology of AML. Such knowledge is paramount in advancing effective strategies for both prevention and management of this significant disease.

New Directions in Diagnostics for Aortic Aneurysms: Biomarkers and Machine Learning.

This review article presents an appraisal of pioneering technologies poised to revolutionize the diagnosis and management of aortic aneurysm disease, with a primary focus on the thoracic aorta while encompassing insights into abdominal manifestations. Our comprehensive analysis is rooted in an exhaustive survey of contemporary and historical research, delving into the realms of machine learning (ML) and computer-assisted diagnostics. This overview draws heavily upon relevant studies, including Siemens' published field report and many peer-reviewed publications. At the core of our survey lies an in-depth examination of ML-driven diagnostic advancements, dissecting an array of algorithmic suites to unveil the foundational concepts anchoring computer-assisted diagnostics and medical image processing. Our review extends to a discussion of circulating biomarkers, synthesizing insights gleaned from our prior research endeavors alongside contemporary studies gathered from the PubMed Central database. We elucidate the prevalent challenges and envisage the potential fusion of AI-guided aortic measurements and sophisticated ML frameworks with the computational analyses of pertinent biomarkers. By framing current scientific insights, we contemplate the transformative prospect of translating fundamental research into practical diagnostic tools. This narrative not only illuminates present strides, but also forecasts promising trajectories in the clinical evaluation and therapeutic management of aortic aneurysm disease.

Paraxylines A-G: Highly oxygenated preurianin-type limonoids with immunomodulatory TLR4 and cytotoxic activities from the stem bark of Dysoxylum parasiticum.

Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either as agonists or antagonists depending on the origin of the TLR4 receptor (human or mouse). The effect of these selected compounds on the expression of pro-inflammatory cytokines TNF-α, IL-1α, IL-1ß, and IL-6 of the NF-κB signaling pathway were examined in macrophage cell lines, revealing dose-dependent effects. Additionally, paraxylines A, C, D, and G also presented modest cytotoxic activity against MCF-7 and HeLa cell lines with IC50 values ranging from 23.1 to 43.5 µM.

Percutaneous Dilatational Tracheostomy in a Cardiac Surgical Intensive Care Unit: A Single-Center Experience.

Background: A significant proportion of cardiac surgery intensive care unit (CSICU) patients require long-term ventilation, necessitating tracheostomy placement. The goal of this study was to evaluate the long-term postoperative outcomes and complications associated with percutaneous dilatational tracheostomy (PDT) in CSICU patients. Methods: All patients undergoing PDT after cardiac, thoracic, or vascular operations in the CSICU between January 1, 2013 and January 1, 2021 were identified. They were evaluated for mortality, decannulation time, and complications including bleeding, infection, and need for surgical intervention. Multivariable regression models were used to identify predictors of early decannulation and the complication rate. Results: Ninety-three patients were identified for this study (70 [75.3%] male and 23 [24.7%] female). Furthermore, 18.3% of patients had chronic obstructive pulmonary disease (COPD), 21.5% had history of stroke, 7.5% had end-stage renal disease, 33.3% had diabetes, and 59.1% were current smokers. The mean time from PDT to decannulation was 39 days. Roughly one-fifth (20.4%) of patients were on dual antiplatelet therapy and 81.7% had anticoagulation restarted 8 hours post-tracheostomy. Eight complications were noted, including 5 instances of bleeding requiring packing and 1 case of mediastinitis. There were no significant predictors of decannulation prior to discharge. Only COPD was identified as a negative predictor of decannulation at any point in time (hazard ratio, 0.28; 95% confidence interval, 0.08-0.95; p=0.04). Conclusion: Percutaneous tracheostomy is a safe and viable alternative to surgical tracheostomy in cardiac surgery ICU patients. Patients who undergo PDT have a relatively short duration of tracheostomy and do not have major post-procedural complications.

Laparoscopic myomectomy complications: META analysis on RCTs and review of large cohort studies.

Complications of myomectomy are generally rare and highly dependent on the surgeons' skills and selection of patients. Haemorrhage, direct injury, post-operative pain and fever present as intra and peri-operative complications, while adhesions are considered late complications. 21 RCTs and 15 meta-analyses have been conducted to date, with the last comprehensive meta-analysis being published in 2009. The main disadvantage of the previous meta-analysis included incomplete selection of studies, inclusion of studies with small sample sizes, and major heterogeneity of methods used between studies. The aim of this meta-analysis comparing laparoscopic myomectomy (LMy) to open conservative myomectomy is to provide an updated review of the type, frequency and severity of complications. These results can direct teaching efforts and guidelines and give updated advice to gynaecologists. A literature search was conducted on PubMed and Google scholar for RCTs on this topic. 276 studies were identified and 19 RCTs ultimately met the criteria for inclusion in the meta-analysis and subsequent heterogeneity assessment. The results showed that laparoscopic myomectomy has a more favourable outcome with regards to several complications when compared with laparotomy. Laparoscopic myomectomy is significantly associated with lower Hg drop (WMD = -0.48, 95% CI [-0.89, -0.07], p = 0.02179); lower incidence of post-operative fever (RR = 0.43, 95% CI [0.29, 0.64], p < 0.001); lower levels of pain at 48Hrs post-op (WMD = -0.88, 95% CI [-1.63, -0.014], p = 0.02020) and decreased analgesia requests (RR = 0.49, 95% CI [0.37, 0.64], p < 0.0001). Prophylaxis use was associated with less adhesions (RR = 0.064, 95% CI [0.44, 0.92], p = 0.01), although not enough data was available to draw conclusions regarding specific prophylactic agents. No differences were found between LMy and laparotomy for blood loss (WMD = -13.6494, 95% CI [-44.48, 17.18], p = 0.38553) or pain at 24Hrs post-op (WMD = -0.19, 95% CI [-0.55, 0.18], p = 0.32136). These findings support previously published meta-analyses. Given the right indications of the surgery and training of the surgeon, LMy seems to be most preferable to laparotomy in achieving a better clinical result with fewer complications.

Paraneoplastic syndrome of arthropathies as presenting sign for non-small cell lung cancer.

The aim of this study is to showcase an example of paraneoplastic syndrome, so other healthcare providers can be aware of early NSCLC manifestations. This is also important so providers do not dismiss review of symptoms that may not seem pertinent.

The "not so good" thyroid cancer: a scoping review on risk factors associated with anxiety, depression and quality of life.

The incidence of thyroid cancer has increased in recent years, leading to a growing number of survivors facing lifelong consequences. This scoping review investigated anxiety, depression, and quality of life (QoL) in thyroid cancer survivors compared to the general population, those with benign pathology, and survivors of other types of cancers. Moreover, we aimed to identify the risk factors associated with anxiety, depression, and QoL in thyroid cancer patients. A total of 727 articles were identified through PubMed, ProQuest, Cochrane, and Google Scholar databases, and 68 articles that met the criteria were selected for data extraction. Thyroid cancer survivors have a poorer QoL compared to the general population, population with benign pathology, and survivors of other types of cancer associated with worse clinical outcomes. The main risk factors are grouped into socioeconomic factors, disease-specific factors, management factors, comorbidities, and patient perceptions. Effective communication between the patient and the medical team and behavioral interventions may reduce these risks. Despite the common perception of thyroid cancer as a "good cancer," the findings of this review demonstrate the need to address the risk factors associated with increased anxiety, depression, and lower QoL in survivors.

A standardized method for plasma extracellular vesicle isolation and size distribution analysis.

The following protocol describes our workflow for isolation and quantification of plasma extracellular vesicles (EVs). It requires limited sample volume so that the scientific value of specimens is maximized. These steps include isolation of vesicles by automated size exclusion chromatography and quantification by tunable resistive pulse sensing. This workflow optimizes reproducibility by minimizing variations in processing, handling, and storage of EVs. EVs have significant diagnostic and therapeutic potential, but clinical application is limited by disparate methods of data collection. This standardized protocol is scalable and ensures efficient recovery of physiologically intact EVs that may be used in a variety of downstream biochemical and functional analyses. Simultaneous measurement quantifies EV concentration and size distribution absolutely. Absolute quantification corrects for variations in EV number and size, offering a novel method of standardization in downstream applications.

Early surgical stabilization of rib fractures for flail chest is associated with improved patient outcomes: An ACS-TQIP review.

BACKGROUND: Rib fractures are a common in thoracic trauma. Increasingly, patients with flail chest are being treated with surgical stabilization of rib fractures (SSRF). We performed a retrospective review of the Trauma Quality Improvement Program database to determine if there was a difference in outcomes between patients undergoing early SSRF (≤3 days) versus late SSRF (>3 days). METHODS: Patients with flail chest in Trauma Quality Improvement Program were identified by CPT code, assessing those who underwent SSRF between 2017 and 2019. We excluded those younger than 18 years and Abbreviated Injury Scale head severity scores greater than 3. Patients were grouped based on SSRF before and after hospital Day 3. These patients were case matched based on age, Injury Severity Score, Abbreviated Injury Scale head and chest, body mass index, Glasgow Coma Scale, and five modified frailty index. All data were examined using χ2, one-way analysis of variance, and Fisher's exact test within SPSS version 28.0. RESULTS: For 3 years, 20,324 patients were noted to have flail chest, and 3,345 (16.46%) of these patients underwent SSRF. After case matching, 209 patients were found in each group. There were no significant differences between reported major comorbidities. Patients with early SSRF had fewer unplanned intubations (6.2% vs. 12.0%; p = 0.04), fewer median ventilator days (6 days Q1: 3 to Q3: 10.5 vs. 9 Q1: 4.25 to Q3: 14; p = 0.01), shorter intensive care unit length of stay (6 days Q1: 4 to Q3: 11 vs. 11 Q1: 6 to Q3: 17; p < 0.01), and hospital length of stay (15 days Q1: 11.75 to Q3: 22.25 vs. 20 Q1: 15.25 - Q3: 27, p < 0.01. Early plating was associated with lower rates of deep vein thrombosis and ventilator-acquired pneumonia. CONCLUSION: In trauma-accredited centers, patients with flail chest who underwent early SSRF (<3 days) had better outcomes, including fewer unplanned intubations, decreased ventilator days, shorter intensive care unit LOS and HLOS, and fewer DVTs, and ventilator-associated pneumonia. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Plasma microrna quantification protocol.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate translation and are involved in many pathological processes. They have emerged as promising biomarkers for diagnosis of conditions such as aortic aneurysm disease. Quantifying miRNAs in plasma is uniquely challenging because of the lack of standardized reproducible protocols. To facilitate the independent verification of conclusions, it is necessary to provide a thorough disclosure of all pertinent experimental details. In this technical note, we present a comprehensive protocol for quantifying plasma miRNAs using droplet digital PCR. We detail the entire workflow, including blood collection, plasma processing, cryo-storage, miRNA isolation, reverse transcription, droplet generation, PCR amplification, fluorescence reading, and data analysis. We offer comprehensive guidance regarding optimization, assay conditions, expected results, and insight into the troubleshooting of common issues. The stepwise normalization and detailed methodological guide enhance reproducibility. Moreover, multiple portions of this protocol may be automated. The data provided in this technical note is demonstrative of the values typically obtained when following its steps. To facilitate standardization in data reporting, we include a table of expected aortic aneurysm-related miRNA levels in healthy human plasma. This versatile protocol can be easily adapted to quantify most circulating miRNAs in plasma, making it a valuable resource for diagnostic development.

Development and Implementation of a Longitudinal Global Acute Care and Systems Strengthening Program.

BACKGROUND: Increasing access to safe, timely, and affordable acute care in low- and middle-income countries is a worldwide priority. Longitudinal curricula on systems of acute care have not been previously described. OBJECTIVES: The authors aimed to develop a novel four-year longitudinal curriculum for medical students addressing systems development across multiple acute care specialties. METHODS: The authors followed Kern's six-step framework for curriculum design. After review of literature, a group of medical students and school of medicine faculty conducted a targeted needs assessment. Foundational goals and objectives were adapted from the 39 interprofessional global health competencies by the Consortium of Universities for Global Health. Educational strategies include didactic sessions, workshops, journal clubs, preceptorships, and community outreach. Clinical years include specialty-specific emphases, guided junior-level discussions, and a capstone project. Yearly SWOT and Kirkpatrick model analyses served as program evaluation. FINDINGS: The Curriculum Council approved the program in July 2019. During the first cycle, the program matriculated 30 students from classes of 2023 (14) and 2022 (16). The first year produced 11 interactive sessions, 6 journal clubs, and 10 seminars led by 31 faculty and guest speakers; 29/30 students completed requirements; 87 evaluations reflected 4.57/5 content satisfaction and 4.73/5 instructor satisfaction. The 2023 cohort reported improved understanding of session objectives (3.13/5 vs. 3.82/5, p = 0.03). Free-text feedback led to implementation of pre-reading standardization and activity outlines. CONCLUSION: The Program was well-received and successfully implemented. It meets the needs of graduating medical students interested in leading global health work. This novel student-faculty collaborative model could be applied at other institutions seeking to provide students with a foundation in global acute care.

Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ.

Maladaptive repair after AKI may lead to progressive fibrosis and decline in kidney function. Sphingosine 1-phosphate has an important role in kidney injury and pleiotropic effects in fibrosis. We investigated the involvement of sphingosine kinase 1 and 2 (SphK1 and SphK2), which phosphorylate sphingosine to produce sphingosine 1-phosphate, in kidney fibrosis induced by folic acid (FA) or unilateral ischemia-reperfusion injury. Analysis of Masson trichrome staining and fibrotic marker protein and mRNA expression 14 days after AKI revealed that wild-type (WT) and Sphk1-/- mice exhibited more kidney fibrosis than Sphk2-/- mice. Furthermore, kidneys of FA-treated WT and Sphk1-/- mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated Sphk2-/- mice. In contrast, kidneys of Sphk2-/- mice exhibited greater expression of Ifng and IFN-γ-responsive genes (Cxcl9 and Cxcl10) than kidneys of WT or Sphk1-/- mice did at this time point. Splenic T cells from untreated Sphk2-/- mice were hyperproliferative and produced more IFN-γ than did those of WT or Sphk1-/- mice. IFN-γ blocking antibody administered to Sphk2-/- mice or deletion of Ifng (Sphk2-/-Ifng-/- mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of Sphk2-/- (but not Sphk2-/-Ifng-/- ) CD4 T cells into WT mice blocked FA-induced fibrosis. Finally, a selective SphK2 inhibitor blocked FA-induced kidney fibrosis in WT mice. These studies demonstrate that SphK2 inhibition may serve as a novel therapeutic approach for attenuating kidney fibrosis.

Levels of Matrix Metalloproteinases in Arthroplasty Patients and Their Correlation With Inflammatory and Thrombotic Activation Processes.

An imbalance of matrix metalloproteinases (MMPs) and their inhibitors is thought to play a major role in the pathophysiology of joint diseases. The aim of this study is to provide additional insights into the relevance of MMP levels in arthroplasty patients in relation to inflammation and thrombosis. Deidentified plasma samples from 100 patients undergoing total hip arthroplasty or total knee arthroplasty were collected preoperatively, on postoperative day 1, and on postoperative day 3. Tissue inhibitor of MMP 4, tumor necrosis factor α (TNF-α), pro-MMP1, MMP3, MMP9, MMP13, and d-dimer were measured using enzyme-linked immunosorbent assay kits. A biochip array was used to profile interleukin (IL) 2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, TNF-α, IL-1α, IL-1ß, monocyte chemoattractant protein 1, and endothelial growth factor (EGF) levels. The levels of MMP1, MMP9, MMP13, and TNF-α were elevated preoperatively in arthroplasty patients when compared to healthy individuals. The concentrations of MMP1 and MMP9 increased slightly in postsurgical samples. d-Dimer levels were elevated preoperatively, increased postoperatively, and started decreasing on postoperative day 3. Significant correlations between MMP9 with TNF-α, IL-6, IL-8, VEGF, and EGF were identified. Elevated preoperative MMP1, MMP9, and MMP13 concentrations suggest that they may play a role in the pathogenesis of arthritis. There is also evidence of increased coagulation activity and possible upregulation of several MMPs postsurgically. Correlation analysis indicates that MMP9 levels may potentially be related to inflammation and thrombosis in arthroplasty patients.