Severe Disease Manifestations Research Articles

Qingxin Jieyu Granule alleviates myocardial infarction through inhibiting neutrophil extracellular traps via activating ANXA1/FPR2 axis

BackgroundMyocardial infarction (MI), representing the most severe manifestation of coronary artery disease (CAD), stands as a primary concern in the prevention and management of cardiovascular diseases. Clinical evidence demonstrates that Qingxin Jieyu Granule (QXJYG) is efficacious in treatment of MI patients. However, the mechanisms underlying its therapeutic effects remain to be elucidated. PurposeThis study aimed to evaluate the effects of QXJYG on MI and investigate its underlying mechanisms. Materials and methodsThe MI model in rats was developed through ligating the left anterior descending (LAD) artery. The effect of QXJYG on cardiac function impairment in MI rats was assessed by echocardiography, while the improvement of cardiomyocyte morphology and myocardial fibrosis after treatment with QXJYG was evaluated through hematoxylin-eosin (H&E) staining and Masson staining. The chemical constituents of QXJYG in blood were identified by using the UPLC-Q-TOF/MS technique. Furthermore, the molecular mechanism underlying the QXJYG therapeutic effect in MI was postulated based on the disease gene-drug target network analysis. Other technical methods such as ELISA, immunohistochemical staining, Western Blot analysis and application of pharmacological inhibitors were employed to verify the effectiveness of QXJYG in treating MI and explore its potential molecular targets. ResultsThe cardiac function in experimental rats post-MI was significantly impaired, as evidenced by an enlarged infarction area, disordered arrangement of cardiomyocytes, and aggravated myocardial fibrosis. QXJYG treatment significantly enhanced the cardiac function and reduced the pathological damage of the cardiac tissue in MI rats. Through the network pharmacology analysis, we identified that FPR2 might be a potential target of QXJYG in its cardiac protection role. QXJYG markedly downregulated the level of neutrophil extracellular traps (NETs) in MI rats, specifically manifested as a significant reduction in the Histone-DNA level and expression of myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) proteins. Furthermore, QXJYG upregulated the levels of ANXA1 and FPR2 proteins in MI rats. The level of FPR2 was markedly reduced in MI rats upon administration of WRW4, a specific inhibitor of FPR2, which was associated with exacerbated MI injury and an elevated level of NETs. When WRW4 was co-administered with QXJYG, the cardioprotective effects of QXJYG on MI were significantly diminished. However, the addition of DNase I did not result in significant changes of the outcomes in MI rats after QXJYG intervention. ConclusionQXJYG treatment alleviates cardiac tissue injury in MI rats by inhibiting NETs through activating the ANXA1/FPR2 axis. The findings extend our understanding of the therapeutic effectiveness of QXJYG and offer a scientific foundation for the clinical utilization of QXJYG.

SARS-CoV-2 induced vitamin D deficiency and psychological stress: a manifestation of autoimmune disease onset.

The global SARS-CoV-2 pandemic significantly altered lifestyles, access to healthcare, and social interactions, introducing unprecedented physical and psychological stress all over the world. This study explores the relationship between psychological stress, vitamin D (Vit-D) levels, and autoimmune connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis. The analysis was based on over one million patient data points derived from anti-nuclear antibody (ANA) testing conducted both before and during the COVID-19 pandemic 2017-2021. In a subset of patients, longitudinal data were collected bi-yearly to yearly over 5-8 years using the same three-month criteria. The dataset was analyzed using GraphPad Prism9 using paired t-tests or ordinary one-way ANOVA with a significance threshold of p < 0.05 to ensure robust correlations between the variables. Data indicated that Vit-D levels peaked between 2017 and 2019 before declining, while ANA data demonstrated a rise in autoimmune connective tissue disease cases during the pandemic, reaching a peak in 2021. A clear correlation was observed, with autoimmune disease incidence increasing as Vit-D levels decreased. In-depth case analysis revealed that declining Vit-D levels preceded higher ANA titers and increased autoimmune disease severity, whereas improvements in Vit-D levels were associated with reduced ANA titers and less severe disease manifestations. The findings suggest that maintaining mental health and ensuring adequate Vit-D supplementation could be essential strategies for mitigating autoimmune disease risks and maintaining immune stability, particularly in pandemic scenarios. Clinically, these results underscore the need for early interventions targeting both psychological well-being and Vit-D levels to reduce the burden of autoimmune diseases.

Special considerations for hidradenitis suppurativa in skin of colour: A review of literature

AbstractHidradenitis suppurativa, a chronic inflammatory skin condition, disproportionately affects individuals with skin of colour (SOC), particularly African Americans. Despite the increased prevalence in SOC, racial minorities are underrepresented in HS clinical trials, limiting our understanding of treatment efficacy. The purpose of this narrative review is to discuss the current literature regarding the clinical presentation, comorbidities, and management of HS in SOC individuals. A PubMed search was conducted using the terms Hidradenitis suppurativa, comorbidities, skin of colour, African–American, Hispanic, and quality of life with relevant studies written in English and pertaining to the demographics and clinical trials were included. African American patients with HS tend to experience more severe disease manifestations, higher rates of comorbidities like inflammatory bowel disease and anaemia, increased healthcare utilisation, and a greater likelihood of surgical interventions. While the current literature provides extensive information about African Americans regarding comorbidities and disease prevalence, there is a lack of research on Hispanic and other ethnic groups. For future research, it is important to broaden our focus to include various ethnic groups. Addressing these disparities requires focused interventions, inclusive clinical research initiatives, and healthcare policies tailored to the specific needs of patients with skin of colour.

Trans-acting genetic modifiers of clinical severity in heterozygous β-Thalassemia trait.

There is a group of beta (β)-thalassemia trait 'carriers' (with heterozygous mutations) who should be asymptomatic with minor abnormalities in their hematological parameters, but experience more severe disease manifestations than predicted based solely on their β-globin genotype. This review focuses on literature describing trans-acting genetic modifiers outside of the α- and β-globin gene clusters that could cause this phenomenon. These genetic modifiers are categorized into: mutations affecting the quantity of alpha-globin products, non-globin mutations affecting erythropoiesis, membranopathies, enzymopathies and erythrocyte-independent modifiers of complications relating to β-thalassemia. Although some genetic determinants seem to correlate more directly with β-thalassemia trait severity, such as mutations in SUPT5H, PIEZO1 and hereditary elliptocytosis, the difficulties of linking the contribution of other modulating factors are elucidated in this review. Targeted next generation sequencing of hemolytic anemias can be helpful but also raises another quandary in interpreting variants of uncertain significance. The accrual of knowledge, along with the increased availability of genetic testing for genetic modifiers has considerable potential for clinical applications such as genetic counselling, decision-making for clinical interventions and prognostication, and perhaps generating new therapeutic targets.

Investigation of the association between polymorphisms in DNA repair enzymes and STEMI

STEMI (ST-elevation myocardial infarction), a condition in which DNA damage likely contributes to its pathogenesis, is among the most severe manifestations of coronary artery disease. There are very few publications in this field in the literature. In our study, we examined the association between four polymorphisms in repair enzymes (LIG4 Thr9Ile, XRCC6 promoter C-57G, XPA -4A/G, OGG1 Ser326Cys) involved in three distinct DNA repair mechanisms [NHEJ (non-homologous end joining)], NER (nucleotide excision repair), and BER (base excision repair), and their impact on the risk of STEMI. This study involved 185 patients diagnosed with STEMI and included 155 healthy controls. The genotyping of SNPs was conducted through the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) method for the following variants: XRCC6 (rs2267437), XPA (rs1800975), LIG4 (rs1805388), and OGG1 (rs1052133). No significant differences were observed in the genotype distributions of the XRCC6 and OGG1 variations between the control and patient groups. On the other hand, our findings indicate that individuals carrying the mutant G allele for XPA polymorphism and the mutant T allele for LIG4 polymorphism are susceptible to STEMI. Our findings demonstrate the significance of NHEJ and NER DNA repair processes in the pathogenesis of STEMI, as evidenced by the observed relationship between LIG4 and XPA polymorphisms.

Satisfactory result of great saphenous vein endovenous laser ablation until below the knee on active venous leg ulcer: a case series

Background Active venous leg ulcer (VLU) is the most severe manifestation of chronic venous disease which not only affects patients’ health, but also decreases the quality of life, and delivers economic burdens. Treatment of superficial venous reflux with early endovenous laser ablation (EVLA) has been associated with reducing ulcer recurrence levels and promoting faster VLU healing. We reported three cases of patients with active VLU undergoing EVLA with different approaches. Case illustration Three patients came with complaint of leg ulcer, diagnosed with C6sEpAsdPr, with venous clinical severity scores (VCSS) of 15, 23, and 22 respectively. Severe great saphenous veins (GSV) reflux was found in all patients by duplex ultrasound examination. The second patient had undergone above-the-knee EVLA. All patients underwent EVLA using 1470-nano meter wavelength laser device and ELVeS radial fiber (Biolitec, Bonn, Germany). The laser energy protocol used was 6 W linear endovenous energy density (LEED) 50 J/cm for proximal until media ATK GSV ablation, 5 W LEED 40 J/cm for media ATK until proximal below-the-knee (BTK) GSV, and 2 W LEED 20 J/cm for proximal until distal BTK GSV. The third patient was also treated with EVLA for small saphenous vein severe reflux. Follow-up until 6 months post-EVLA showed significant healing of the ulcer with 14, 16, and 17 VCSS reduction consecutively without any complication. Conclusion We’ve reported three cases of patients with active VLU undergoing EVLA until BTK with significant results. The EVLA of GSV until BTK where there is still significant reflux is safe and provides satisfactory results in patients with VLU.

Lipidomic biomarkers in plasma correlate with disease severity in adrenoleukodystrophy

BackgroundX-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by pathogenic variants in ABCD1 resulting very long-chain fatty acids (VLCFA) accumulation in plasma and tissues. Males can present with various clinical manifestations, including adrenal insufficiency, spinal cord disease, and leukodystrophy. Female patients typically develop spinal cord disease and peripheral neuropathy. Predicting the clinical outcome of an individual patient remains impossible due to the lack of genotype-phenotype correlation and predictive biomarkers.MethodsThe availability of a large prospective cohort of well-characterized patients and associated biobank samples allowed us to investigate the relationship between lipidome and disease severity in ALD. We performed a lipidomic analysis of plasma samples from 24 healthy controls, 92 male and 65 female ALD patients.ResultsHere we show that VLCFA are incorporated into different lipid classes, including lysophosphatidylcholines, phosphatidylcholines, triglycerides, and sphingomyelins. Our results show a strong association between higher levels of VLCFA-containing lipids and the presence of leukodystrophy, adrenal insufficiency, and severe spinal cord disease in male ALD patients. In female ALD patients, VLCFA-lipid levels correlate with X-inactivation patterns in blood mononuclear cells, and higher levels are associated with more severe disease manifestations. Finally, hematopoietic stem cell transplantation significantly reduces, but does not normalize, plasma C26:0-lysophosphatidylcholine levels in male ALD patients. Our findings are supported by the concordance of C26:0-lysophosphatidylcholine and total VLCFA analysis with the lipidomics results.ConclusionsThis study reveals the profound impact of ALD on the lipidome and provides potential biomarkers for predicting clinical outcomes in ALD patients.

Movement of the A-strain maize streak virus in and out of Madagascar

The maize streak virus belongs in the genus Mastrevirus, in the family Geminiviridae. The A-strain of the virus (MSV-A) is recognised as the principal causative agent of the most severe manifestation of maize streak disease (MSD). This disease continues to be a persistent limitation on maize output across sub-Saharan Africa and the nearby Indian Ocean islands. Irrespective of the causes behind the spread of MSV-A, we can determine the paths and speeds with which MSV-A spreads by analysing MSV genome sequence data along with information on when and where samples were taken. This information is valuable for identifying the geographical origins of viral strains that cause sporadic MSD epidemics in specific places and the geographical regions where viruses remain in reservoirs and contribute to prolonged epidemics during outbreaks. Our aim is to utilise these analyses to estimate the timing and origin of the MSV-A that arrived on the island of Madagascar in the Indian Ocean. Specifically, we employ model-based phylogeographic analyses on 524 complete MSV-A genome sequences, which consist of 56 newly obtained genomes from infected maize plants collected in Madagascar. These studies allow us to reconstruct the most likely paths of MSV-A to Madagascar. We found strong evidence for the existence of at least four separate movements of MSV-A variants from East and southern Africa to Madagascar. These movements took place between roughly 1979 (with a 95% highest probability density interval [HPD] ranging from 1976 to 1982) and 2003 (with a 95% HPD ranging from 2002 to 2003). While we inferred that MSV-A variants are spreading at an average rate of 38.9 km/year (with a 95% highest posterior density interval of 34.0–44.4) across their geographical range. Since their arrival in Madagascar, MSV-A variants have been migrating at an average rate of 47.6 km/year (with a 95% highest posterior density interval of 36.05–61.70). Human influences are likely significant contributors to both sporadic long-range movements of MSV-A between mainland Africa and Madagascar, as well as shorter to medium range movements within the island.

The predictive value of serum fibrinogen and platelet distribution width for long-term cardiac death in acute myocardial infarction patients.

Acute myocardial infarction (AMI) is the most severe manifestation of coronary heart disease (CHD), and timely and effective opening of the culprit vessels has been effective in reducing its mortality, but long-term death still threatens the life of patients. Therefore, finding biomarkers to predict death post-myocardial infarction (MI) is crucial. The aim of our study is to find biomarkers that predicted long-term death in Chinese AMI patients. This retrospective analysis included patients with AMI from 1 January 2017 to 30 September 2019. All patients were followed up at least 4 years. Propensity score matching was used to mitigate the influence of nonrandom selection in MI-survival and MI-death groups. Cox analysis was applied for analyzing the risk factors of death post-MI. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of biomarkers. Of the 1,059 AMI patients analyzed, 130 died during follow-up. After propensity matching, there were 116 patients in each of the two groups. In addition to the traditional risk factors for long-term death post-MI, two important risk factors platelet distribution width (PDW) [hazard ratio (HR) =1.210, 95% confidence interval (CI): 1.080-1.356, P=0.001] and fibrinogen (HR =1.218, 95% CI: 1.027-1.444, P=0.02) were found. The area under the curve (AUC) of PDW and fibrinogen was 0.604 (P=0.007) and 0.684 (P<0.001) respectively. The optimal thresholds were 13.05% and 3.562 g/L respectively. PDW and fibrinogen seem to be useful as biomarkers for long-term death prediction post-MI. The current research provides new insight into the prevention and treatment of death in Chinese patients post-MI.

Mild/moderate phenotypes in AADC deficiency: Focus on the aromatic amino acid decarboxylase protein.

AADC deficiency is a severe neurometabolic inherited rare disorder due to the absence or decrease of dopamine and serotonin levels, causing deep motor and neurodevelopmental impairments. The disease is often fatal in the first decade of life, and pharmacological treatments (dopamine agonists, pyridoxine, and monoamine oxidase inhibitors as the first-line choices) can only alleviate the symptoms. Gene therapy surgery is now available for severe patients in the European Union and the United Kingdom, and follow-up data witness encouraging improvements. In the past few years, mostly due to the increased awareness and knowledge of AADC deficiency, together with newborn screening programs and advancements in methods for genetic diagnosis, the number of mild/moderate phenotypes of AADC deficiency patients has increased to 12% of the total. A review of the genotypes (homozygous/compound heterozygous) of AADC deficiency mild/moderate patients is presented here. The pathogenicity classification of each genetic variant is discussed. Then, we focused on the type of AADC protein possessed by patients and on the predictable structural score of the homodimeric/heterodimeric species of each protein variant. Since the terminology used for genetic and protein variants is the same, we highlighted how it could be misleading. We analyzed the loss-of-function as a fold-change decrease of activity of the recombinant purified AADC enzyme(s) theoretically synthesized by mild/moderate patients. A minimal residual kcat of 8% and/or kcat/Km of 1% seems necessary to avoid a severe disease manifestation. Overall, this cluster of mild/moderate patients needs consideration for a more appropriate and aimed therapeutic approach.

Direct antiglobulin (Coombs) test in HIV-positive Talaromycosis marneffei patients.

Talaromycosis marneffei (T.M) is the primary opportunistic infection of AIDS patients, and its morbidity and mortality are extremely high. To further clarify the disease characteristics of patients and provide a solid basis for in-depth exploration of their pathogenic mechanisms, we retrospectively summarized and analyzed their clinical data. We included all T.M patients tested for direct antiglobulin test (DAT) in the study. Interestingly, we found that AIDS-T.M patients had an extremely high rate of DAT positivity (92/127, 72.44%). In univariate analysis, a positive DAT was associated with blood culture of TM (P=.021), hypoproteinemia (P=.001), anemia (P=.001), thrombocytopenia (P=.003), sepsis (P=.007), and Sequential Organ Failure Assessment (SOFA) (P=.001). Hypoproteinemia, anemia, SOFA, APTT>32.6 s, and AST > 40U/l were studied by logistic regression. Logistic regression revealed that SOFA (OR=1.311, P=.043), hypoproteinemia (OR=0.308, P=.021), and anemia (OR=0.19, P=.044) were associated with positive DAT. Positive DAT was associated with severe disease manifestations such as sepsis, and the DAT test is crucial in patients with fungemia.

Abstract We076: Humoral profile of individuals with Chagas Cardiomyopathy

Chronic Chagas cardiomyopathy (CCC) is the most severe manifestation of Chagas disease and one of the main causes of cardiomyopathy in Latin America. The number of individuals infected with Trypanosoma cruzi (T. cruzi), the causative parasite of Chagas disease, exceeds 6 million, with an increasing presence in non-endemic regions such as Europe, Japan, Canada, and the USA. While approximately 70% of infected individuals remain asymptomatic and are categorized as indeterminate (IND), the remaining 30% develop cardiac manifestations several decades after the initial infection. Despite extensive efforts to elucidate the triggers and predictors underlying the progression from IND to CCC, the exact causative factors remain elusive. Hypotheses have been proposed that focus on the specific humoral response, including the production of antibodies that effectively neutralize the parasite or demonstrate cross-reactivity between parasite and cardiac proteins. Here, using PhIP-seq technology we comprehensively characterized the IgG profile of 897 T. cruzi seropositive individuals. We identified 628 epitopes with increased IgG reactivity in chronic T. cruzi seropositive individuals. Mucin TcMUCII, trans-sialidase, and MASP emerged as the primary classes of proteins showing elevated IgG response. Remarkably, the serum of CCC individuals showed robustly elevated reactivity against 84 epitopes compared to IND individuals, while IgG response against 23 epitopes was increased in the serum of IND individuals. Trans-sialidase and mucin-like glycoproteins were the main classes of proteins distinguishing these two groups. Among all epitopes with increased reactivity in the serum of CCC individuals compared to IND, 36 epitopes showed linear sequence similarity to 210 human proteins highly expressed in human heart. These included sarcomere structural proteins, suggesting potential cross-reactions between the antibodies targeting T. cruzi epitopes and proteins with key roles in cardiac function. Overall, our study describes the humoral landscape of Chagas disease, expanding the pool of potential candidates for future vaccine development or as targets for infection/trials efficiency monitoring. Additionally, we identified potential sources of antibody cross-reaction that may contribute to CCC progression, including epitopes sharing sequence similarities with key proteins involved in cardiac structure.

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Diffuse Alveolar Hemorrhage With Avacopan.

Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

Peripheral Blood Mononuclear Cells and Serum Cytokines in Patients with Lupus Nephritis after COVID-19.

Systemic lupus erythematosus (SLE) patients have an increased risk of infections and infection-related mortality. Therefore, during the global SARS-CoV-2 pandemic, SLE patients were particularly vulnerable to SARS-CoV-2 infections. Also, compared to other patients, SLE patients seem to develop more severe manifestations of coronavirus disease 2019 (COVID-19), with higher rates of hospitalization, invasive ventilation requirements, or death. This study evaluated the immune parameters after SARS-CoV-2 infection in SLE patients. We analyzed subpopulations of peripheral blood cells collected from patients with renal manifestation of SLE (lupus nephritis, LN). LN patients were divided into two subgroups: those unexposed to SARS-CoV-2 (LN CoV-2(-)) and those who had confirmed COVID-19 (LN-CoV-2(+)) six months earlier. We analyzed basic subpopulations of T cells, B cells, monocytes, dendritic cells (DCs), and serum cytokines using flow cytometry. All collected data were compared to a healthy control group without SARS-CoV-2 infection in medical history. LN patients were characterized by a decreased percentage of helper T (Th) cells and an increased percentage of cytotoxic T (Tc) cells regardless of SARS-CoV-2 infection. LN CoV-2(+) patients had a higher percentage of regulatory T cells (Tregs) and plasmablasts (PBs) and a lower percentage of non-switched memory (NSM) B cells compared to LN CoV-2(-) patients or healthy controls (HC CoV-2(-)). LN patients had a higher percentage of total monocytes compared with HC CoV-2(-). LN CoV-2(+) patients had a higher percentage of classical and intermediate monocytes than LN CoV-2(-) patients and HC CoV-2(-). LN CoV-2(+) patients had higher serum IL-6 levels than HC CoV-2(-), while LN CoV-2(-) patients had higher levels of serum IL-10. LN patients are characterized by disturbances in the blood's basic immunological parameters. However, SARS-CoV-2 infection influences B-cell and monocyte compartments.

Malnutrition Severity Predicts Clinical Outcomes in Alcoholic Hepatitis: Evidence from National Data

Objective Alcoholic hepatitis (AH) represents a severe manifestation of alcoholic liver disease (ALD) associated with a wide severity spectrum. ALD is linked to nutritional deficiencies, with the gravity of malnutrition escalating as alcohol abuse and ALD progress. This study aims to delve into the impact of malnutrition on the clinical trajectory of AH. Methods We identified adult patients admitted with AH using the National Readmission Database (NRD) 2016–2020. We further classified AH patients based on the severity of malnutrition. We compared the outcomes of AH hospitalizations using a multivariate regression model. Results We included 82,367 AH patients, of whom 15,693 (19.00%) had malnutrition. 4,243 (5.15%) patients exhibited mild to moderate malnutrition, 5,862 (7.07%) patients had severe malnutrition, and 5,588 (6.78%) patients had unspecified severity of malnutrition. We found that adjusted in-hospital mortality due to AH was higher in patients with malnutrition, corresponding to the severity of malnutrition (adjusted odds ratio [aOR] 1.62 and 3.14 in mild-moderate malnutrition and severe malnutrition, respectively; p < .01). Additionally, patients with malnutrition had progressively elevated odds of septic shock, vasopressor requirement, mechanical ventilation, and intensive care unit (ICU) admission with escalating intensity of malnutrition. Liver-related complications, such as spontaneous bacterial peritonitis, coagulopathy, hepatorenal syndrome, and hepatic encephalopathy, were also found to have an increased likelihood in the presence of malnutrition. Furthermore, resource utilization showed a progressive increase with increasing severity of malnutrition. Conclusion Our findings indicate that malnutrition is a common comorbidity in AH patients, with varying degrees of severity, which correlates with higher mortality rates, emphasizing the critical role of nutritional status in the prognosis of AH. These findings underscore the importance of addressing and managing malnutrition in patients with AH, not only for its potential contribution to mortality but also because of its association with a spectrum of complications and increased healthcare resource utilization.

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia

BackgroundCritical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties.Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.MethodsBalb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.ResultsAT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.ConclusionsThe combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).

Prognostic Value of Systemic Arterial Lactate Levels in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Abstract Background Acute myocardial infarction is the most severe manifestation of coronary artery disease, which causes more than 2.4 million deaths in the USA, more than 4 million deaths in Europe and northern Asia, and more than a third of deaths in developed nations annually. Objective To assess the prognostic value of systemic arterial lactate levels in patients with ST segment elevation myocardial infarction undergoing primary PCI and correlate with the results of primary PCI and 30 days MACE follow up. Patients and Methods This study included 300 patients who presented with documented STEMI and underwent reperfusion by successful primary PCI in Ain Shams University hospitals. Results There was statistically significant positive correlation found between serum lactate and (WBCs) count, (HbA1C) level and cardiac enzymes (CKtotal - CKmb – troponin) and negative correlation found between serum lactate and ejection fraction in echocardiography. Also, we found that other parameters were associated with MACE follow up in 30 days such as Killip class at admission, ST segment elevation resolution, heart block in ECG, lower ejection fraction, dyslipidemia, post-procedure TIMI flow, peri-procedural time intervals and occurrence of complications. Conclusion The value of an early lactate measurement in patients with STEMI is to be a part of the risk stratification of these patients and intensified medical care should be considered to patients with strongly elevated lactate levels. Also, increasing arterial lactate levels were associated with occurrence of MACE in 30 days, worse hemodynamics, lower ejection fraction in echocardiography, higher HbA1C level, large infarct area (cardiac biomarkers peak level), poor post-procedure TIMI flow and thrombus grade.

Severe hypocalcemia in the emergency department: a retrospective cohort study of prevalence, etiology, treatment and outcome.

The aim of this study was to evaluate the prevalence of severe hypocalcemia in patients attending the emergency department. Symptoms, causes, treatment, and outcome of severe hypocalcemia as well as course of calcium concentrations were assessed. This retrospective case series included all adult patients with measurements of serum calcium concentrations presenting to the emergency department of the Bürgerspital Solothurn between January 01 in 2017 and December 31 in 2020. Medical record reviews were performed of all patients with severe hypocalcemia, defined by a serum calcium concentration < 1.9mmol/L, to assess clinical presentation and management. 1265 (3.95%) patients had a serum calcium concentration of < 2.1mmol/L of which 139 (11%) had severe hypocalcemia of < 1.9mmol/L. 113 patients had at least one measurement of albumin. Of these, 43 (3.4%) had an albumin-corrected serum calcium < 1.9mmol/L defining true, severe hypocalcemia. Hypocalcemia was identified and documented in 35% of all cases. The mean serum calcium concentration was 1.74 ± 0.14mmol/L. Calcium concentrations in malignancy-related hypocalcemia were similar to non-malignancy-related hypocalcemia. The main symptoms attributed to hypocalcemia were cardiac and neurologic. 12% of patients with severe hypocalcemia received intravenous and 23% oral calcium replacement. Active malignancy was the main cause of severe hypocalcemia in 28%, while in most cases, the main cause remained unclear. 41.9% of severely hypocalcemic patients reattended the emergency department for another episode of hypocalcemia within 1 year. Hypocalcemia is common in patients attending the emergency department, however, appears to be neglected frequently. The disorder is often a manifestation of severe disease, triggered by multiple causes. Calcium replacement was administered in less than half of the patients with severe hypocalcemia in this study. Due to frequent readmissions to the emergency department and a high mortality, increased awareness of the disorder and careful follow-up are desirable.

Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunction in vitro, and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.

Using Administrative Data to Better Treat Chronic Limb Threatening Ischemia

Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral arterial disease and represents a particularly high-risk subgroup of patients. As such, efforts to better understand this complex patient population through well-designed clinical research studies are critical to improving CLTI care. Prospective randomized clinical trials (RCTs) remain the gold standard in clinical research, but these trials are resource-intensive and have highly selective patient populations, which limit their feasibility and generalizability. Alternatively, retrospective studies are less expensive than RCTs, have a larger sample size, and are more generalizable owing to a broader patient population. Health care administrative data provide rich sources of information that may be used for research purposes and are increasingly being used for the study of vascular surgery conditions, including CLTI. Although administrative data are collected for billing purposes, they may be leveraged to study a broad range of topics in vascular surgery including those related to health care delivery, epidemiology, health disparities, and outcomes. This review provides an overview of administrative data available for CLTI research, the strengths and limitations of these data sources, current areas of investigation, and future opportunities for further study with the goal of improving outcomes in this high-risk population.