Severe Form Of Disease Research Articles

Effectiveness of spinal cord stimulation in diabetic patients with chronic limb-threatening ischemia: small cohort study

BackgroundChronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease (PAD). Patients with diabetes mellitus (DM) have a faster progression of PAD and a fourfold increased risk of CLTI compared to patients without DM. Epidural spinal cord stimulation (SCS) has been used as a method to improve microcirculation, relieve ischemic pain and reduce the number of amputations in patients with PAD. This is a retrospective small cohort analysis of patients with diabetes and the long-term treatment effect of spinal cord stimulation.MethodsAs the main outcome of the study, we evaluated the survival and amputation of 13 diabetic patients with chronic lower-limb ischemia who were not eligible for surgical or interventional therapy. Secondary outcomes included ankle-brachial index (ABI), ischemic pain intensity, quality of life, use of analgesic medications and skin wound outcomes analyzed during long-term follow-up.ResultsBetween January 2010 and January 2017, 13 patients underwent SCS implantation in our vascular center. At 1-year follow-up, the limb salvage rate was 92.3% (12 of 13 patients), and limb ulcers healed in 75% of patients (6/8). No patient died during the one-year follow-up. A total of 4 of patients (31%) experienced major amputation during long-term follow-up, all of them were Fontaine stage IV. Pain intensity and quality of life improved significantly at 6-month follow-up (p < 0.05). ABI measurements were unaffected by SCS treatment. There were no complications related to the procedure or device.ConclusionsSCS is a promising treatment option for diabetic patients unsuitable for endovascular or surgical revascularization. The method improves limb survival in diabetic patients with critical limb ischemia, provides significant pain control, and improves patients' quality of life. However, more studies are needed to clarify the indications for SCS and clarify its effects on the vascular system.

Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia.

Silent cerebral infarcts (SCIs) are present in patients with sickle cell disease (SCD) and thalassemia, but the pathophysiology of SCIs is not fully understood. Previous studies mainly focused on cerebral hemodynamics and oxygen metabolism in patients with severe SCD (HbSS/HbSβ°) but not in milder forms of SCD (HbSC/HbSβ+) and thalassemia despite the high prevalence of SCIs in these patients. In this work, we studied the cerebral hemodynamics and oxygen metabolism, and SCI lesion load in 75 severe and 26 mild adult SCD patients, 18 thalassemia patients (as anemic comparison group), and 30 healthy controls before and after a vasodilatory challenge with acetazolamide. Cerebral blood flow was significantly higher in patients with severe SCD and thalassemia compared to patients with mild SCD and controls (p < 0.05). Conversely, oxygen extraction fraction and cerebral metabolic rate of oxygen (CMRO2) were significantly lower in patients with severe SCD and thalassemia compared to other groups (p < 0.01). In contrast, no difference in SCI volumes was found between mild and severe SCD and thalassemia patients. After acetazolamide administration, oxygen delivery increased less in severe SCD and thalassemia patients compared to other groups (p < 0.01) and CMRO2 decreased only in severe SCD patients (p < 0.01). Given the reduced CMRO2 values in severe SCD and thalassemia patients, we conclude that reduced cerebral oxygen consumption in these patient groups is mostly related to anemia. Our data suggest that the pathophysiology of SCIs in patients with milder forms of SCD might be more related to prior episodes of anemia or other sickle cell-related factors.

Eisenmenger Syndrome: Pathophysiology, Clinical Manifestations, and Contemporary Management Approaches in Advanced Cardiopulmonary Disease

Eisenmenger syndrome, a complex and severe form of congenital heart disease, results from prolonged left-to-right shunting due to underlying cardiac defects such as ventricular septal defects, atrial septal defects, or patent ductus arteriosus, ultimately leading to irreversible pulmonary arterial hypertension and a reversal of the initial shunt. This syndrome represents the most severe spectrum of pulmonary vascular disease associated with congenital heart defects and is characterized by hypoxemia, erythrocytosis, and systemic cyanosis. Despite advances in early diagnosis and intervention in congenital heart disease, Eisenmenger syndrome remains a significant concern due to the irreversible nature of pulmonary vascular changes and associated multisystem complications. This article provides a comprehensive review of the pathophysiology, clinical manifestations, and the role of pharmacologic and non-pharmacologic therapies, including advanced palliative care, to improve patient quality of life. Emerging therapies such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs show promise in symptom management, though surgical interventions, such as heart-lung transplantation, remain reserved for selected cases. Given the high mortality associated with Eisenmenger syndrome, a multidisciplinary approach is critical in managing complications, improving patient outcomes, and supporting functional status.

Alcohol-Associated Hepatitis: Short- and Long-Term Management.

Alcohol-associated hepatitis, considered a severe form of alcohol-associated liver disease, carries with it multiple negative health outcomes ranging not only to increased hospitalizations but also increased rates of mortality. While the inpatient management remains critical in optimizing clinical outcomes, a shift in focus to the outpatient management of alcohol-associated hepatitis is warranted as a long-term solution to this emerging health pandemic. Here, we review the clinical presentation, diagnosis, and current prognostication scoring systems for alcohol-associated hepatitis. We then offer a multimodal approach to the continued management of alcohol-associated hepatitis in the outpatient setting encompassing not only nutritional optimization, alcohol use disorder treatment, and the medical management of chronic liver disease, but also briefly review the current trend of the use of liver transplantation.

Costs associated with nonalcoholic steatohepatitis disease progression in Medicare patients: a retrospective cohort study.

Aim: Non-alcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a severe form of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MASLD), that may progress to advanced liver disease. Costs associated with progression are not well characterized. This study sought to quantify costs and healthcare resource utilization (HRU) associated with NASH progression. Methods: Patients were included if diagnosed with NASH (ICD-10: K75.81) in 100% Medicare claims data (2015-2021) who were ≥66years at index (diagnosis), continuously enrolled in Parts A, B and D for ≥12months prior to and 6months following index (unless death) and who had no evidence of other causes of liver disease. Patient-time was categorized into five severity states: non-cirrhotic NASH, compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver transplant (LT). Annualized HRU and costs were calculated during the study periods overall and stratified by occurrence and timing of progression. Results: In 14,806 unique patients (n=12,990 non-cirrhotic NASH; 1899 CC; 997 DCC; 209 HCC; 140 LT), mean age and follow-up were 72.2 and 2.8years, respectively. Average annualized costs increased from baseline following diagnosis, generally scaling with severity: $16,231 to $27,044; $25,122 to $57,705; $40,613 to $181,036; $36,549 to $165,121 and $35,626 to $108,918 in NASH; CC; DCC; HCC; and LT; respectively. Non-cirrhotic NASH and CC patients with progression had higher follow-up spending (1.6x for NASH; 1.7x for CC) than non-progressors (both p<0.001), 2.8 and 6.1-times higher odds of an inpatient stay and 2.6 and 3.6-times higher odds to be in the top 20% of spenders, respectively, relative to non-progressors (both p<0.001). Patients progressing within a year had costs 1.4, 1.6, 1.7 and 2.2-times more than year 2, 3, 4 and 5 progressors' costs, respectively, for non-cirrhotic NASH and 1.3, 1.8, 2.0 and 2.2-times more than year 2, 3, 4 and 5 progressors' costs, respectively, for CC. Conclusion: NASH progression is associated with high costs that increase in more severe disease states. Slower progression is associated with lower costs, suggesting a potential benefit of therapies that may delay or prevent progression.

Disease Caused by Filoviruses: An Update

The Marburg and Ebola viruses belong to the Filoviridae family and are known to cause emerging zoonotic diseases. These viruses have a high case fatality rate and are easily transmissible from person to person, which makes them capable of triggering outbreaks, including in non-endemic regions, and are also considered agents of bioterrorism. Fruit bats are the natural reservoirs of these filoviruses. Transmission to humans occurs through direct contact with bodily fluids or tissues from infected animals or humans. The most severe form of filovirus disease manifests as mucocutaneous hemorrhage, often accompanied by multiorgan failure, which is the main cause of death. Traditionally, these diseases are classified in the group of viral hemorrhagic fevers, although this term is being abandoned, as there are not always hemorrhagic manifestations or fever in the patient's clinical history. Currently, no specific antiviral treatment for filovirus disease exists, and the therapeutic approach consists of supportive measures. However, for the Zaire Ebola virus (EBOV), monoclonal antibodies have already been licensed for treatment and post-exposure prophylaxis, in addition to three vaccines available. Due to the public health importance and the possibility of cases outside Africa, this review aims to improve clinical knowledge and the approach to suspected cases of FD. Improved surveillance and preparedness for potential global outbreaks are essential measures to effectively respond to these public health threats and to ensure that healthcare professionals are well-informed and prepared to deal with these diseases.

Abstract 4129523: MicroRNA-1282 Rescues Diabetic Limb Ischemia Via a SERF2-Protein Aggregation Pathway

Introduction: Patients with diabetes are at higher risk of chronic limb-threatening ischemia (CLTI), a severe form of peripheral artery disease (PAD) causing restricted blood flow to the lower limbs due, in part, to impaired angiogenesis. However, the role of microRNAs (miRNAs) in diabetic CLTI remains poorly understood. By integrating plasma miRNA sequencing data from PAD patients with diabetes with a diabetic CLTI mouse model, we have recently identified the conserved miRNA miR-1282 that is in cis-antisense orientation to SERF2, a gene associated with amyloid aggregation. Therefore, we hypothesize that miR-1282 orchestrates endothelial angiogenesis and proteostasis during diabetic CLTI. Methods: Using miR-1282 overexpression or SERF2 knockdown studies, we characterized mouse orthologs of human miR-1282 and SERF2 for angiogenesis, apoptosis, protein aggregation, and oxidative stress in diabetic mouse skeletal muscle endothelial cells (ECs). In vivo, miR-1282 mimics were delivered intramuscularly to assess their impact on blood flow recovery, angiogenesis, and protein aggregation. Mechanistic insights in ECs were gained via RNA-seq, predictive algorithms, and proteomic analyses. Results: miR-1282 inhibited the expression of its cis-antisense target SERF2 by 98%. miR-1282 is a hypoxia-induced endothelial-enriched miRNA, and its expression was inversely correlated with SERF2 expression. miR-1282 levels were markedly reduced after femoral artery ligation (FAL) in diabetic db/db mice. Overexpression of miR-1282 or SERF2 knockdown enhanced angiogenesis and reduced protein aggregation, apoptosis, and oxidative stress in both normal and hypoxic conditions in vitro. Delivery of miR-1282 mimics in db/db mice improved blood flow recovery by 108% and angiogenesis by 98%, and reduced protein aggregation by 48% and tissue necrosis. Coupling RNA-seq profiling and prediction algorithms of ECs upon miR-1282 overexpression or SERF2 knockdown revealed EREG, BAG5, CASP3, ARG1, and HSP90AA1 as potential downstream regulators. Pathway enrichment analysis implicated inhibition of endothelial apoptosis, ER stress, and protein stability among the most dysregulated processes. Conclusion: A novel mouse ortholog of human miR-1282 augments endothelial functions and diminishes protein aggregation in diabetic CLTI via suppression of its cis-antisense target SERF2. These findings uncover new potential therapeutic targets in treating diabetic CLTI.

Abstract 4146306: Rural Urban Disparities in Inpatient Outcomes of Chronic Limb-Threatening Ischemia in the United States

Background: Chronic limb-threatening ischemia (CLTI) is a severe form of peripheral artery disease characterized by chronic ischemic rest pain, non-healing wounds, or gangrene in one or both legs. With prevalence rates of 1-2% in the United States (increasing with age, with over 20% of adults over 70 diagnosed with CLTI) and 1-year mortality rates approaching 20-25%, CLTI is a critical public health issue due to its significant impact on patient morbidity, mortality, and healthcare resources. Aims: To understand if disparities exist between rural and urban inpatient outcomes for patients with CTLI. Methods: A retrospective analysis of the National Inpatient Sample database from 2016 to 2021 was conducted to identify patients admitted with CLTI according to ICD-10 codes. Patients were stratified by rural and urban status, followed by propensity-matched analysis to compare inpatient outcomes between these groups. Results: A total of 2,667,279 patients with CLTI, with 445255 (16.7%) categorized as rural status and the remaining 83.3% categorized as urban status, were included in this study. Patients belonging to rural status had an increased odds of in-hospital mortality (aOR)=1.35; 95% CI 1.26-1.45; p&lt;0.001), in-patient sudden cardiac arrest (aOR=1.27; 95% CI=1.13-1.43; p&lt;0.001), cerebrovascular accidents (aOR=1.31; 95% CI=1.19-1.45; p&lt;0.001), venous thromboembolism (aOR=1.18; 95% CI=1.09-1.27; p&lt;0.001), surgical site infection (aOR=1.25; 95% CI=1.16-1.35; p&lt;0.001), requirement for vasopressors (aOR=2.02; 95% CI=1.76-2.32; p&lt;0.001), invasive (aOR=1.18; 95% CI=1.10-1.26; p&lt;0.001) and non-invasive (aOR=1.37; 95% CI=1.25-1.50; p&lt;0.001) mechanical ventilation, hemodialysis (aOR=1.11; 95% CI=1.06-1.15; p&lt;0.001), major amputation (aOR=1.38; 95% CI=1.32-1.43; p&lt;0.001), surgical revascularization (aOR=1.53; 95% CI=1.46-1.60; p&lt;0.001), endovascular revascularization (aOR=1.53; 95% CI=1.46-1.60; p&lt;0.001), and blood transfusion (aOR=0.92; 95% CI=0.88-0.97; p=0.001). No difference was observed in the odds of acute myocardial infarction (aOR=1.06; 95% CI=0.99-1.14; p=0.082) and risk of acute kidney injury (aOR=0.99; 95% CI=0.96-1.02; p=0.485). Conclusions: Disparities in CLTI outcomes are evident, with patients from rural areas experiencing worse outcomes than their urban counterparts. Future research should focus on understanding the underlying causes of these disparities and developing targeted interventions to bridge the gap between rural and urban health care outcomes.

R391 human dominant mutation does not affect TubB4b localization and sensory hair cells structure in zebrafish inner ear and lateral line

Heterozygous R391 TUBB4B pathogenic variations are responsible for an association of hearing loss and retinal dystrophy in human. With the goal of understanding the functions of TuBB4b and the pathogenic role of R391 variations, we characterized tubB4B in zebrafish and identified the gene regulatory elements necessary and sufficient for expression of TubB4b as in endogenous tissues. Using knock-out and transgenic approaches, we determined that R391 mutations impair neither localization of TubB4B within sensory hair cells (SHC) nor their structure, but induced to a small decrease in SHC number from anterior crista. Expression of R391 mutations in sensory hair cells has no effect on zebrafish audition, suggesting a different equilibrium between various tubulin isotypes in zebrafish possibly due to compensatory mechanisms. The careful expression analysis and transgenic tools generated in this study could help understand how recently described pathogenic variants lead to more severe clinical forms of TUBB4B-related diseases.

Optimized methods to image hepatic lipid droplets in zebrafish larvae.

The optical transparency of zebrafish larvae enables visualization of subcellular structures in intact organs, and these vertebrates are widely used to study lipid biology and liver disease. Lipid droplet (LD) presence is a prevalent feature of healthy cells, but, under conditions such as nutrient excess, toxicant exposure or metabolic imbalance, LD accumulation in hepatocytes can be a harbinger of more severe forms of liver disease. We undertook a comprehensive analysis of approaches useful to investigate LD distribution and dynamics in physiological and pathological conditions in the liver of zebrafish larvae. This comparative analysis of the lipid dyes Oil Red O, Nile Red, LipidTox and LipidSpot, as well as transgenic LD reporters that rely on EGFP fusions of the LD-decorating protein perilipin 2 (PLIN2), demonstrates the strengths and limitations of each approach. These protocols are amenable to detection methods ranging from low-resolution stereomicroscopy to confocal imaging, which enables measurements of hepatic LD size, number and dynamics at cellular resolution in live and fixed animals. This resource will benefit investigators studying LD biology in zebrafish disease models.

Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. qRT-PCR and western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet (HFD)-induced mouse models, and in hepatocytes induced by free fatty acids (FFA). Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and pro-inflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression.

RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function.

Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDMindependently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects(adjusted R2 = 0.6723) or exclusively in children with CDM (adjusted R2 = 0.5875). Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

POSSIBILITIES FOR MEDICAL REHABILITATION IN PATIENTS AFTER HIP ENDOPROSTHETICS

Hip replacement surgery is currently the only effective surgical treatment option for patients with severe forms of degenerative-dystrophic diseases of the hip joint, so the problem of medical rehabilitation of such patients remains very relevant. One of the problems that arise after hip replacement surgery is a violation of the biomechanics of the artificial joint. The leading role in this process is played by the functional state of muscle tissue, which determines the problem of adaptation of the endoprosthesis components and can subsequently cause complications. The solution to this problem lies in timely comprehensive medical rehabilitation, individually selected for each patient, taking into account the characteristics of the postoperative period. Traditional methods of medical rehabilitation, including various methods of therapeutic exercise, natural and preformed physical factors, are undoubtedly effective, as indicated by an extensive scientific evidence base, but despite the proven effectiveness, these methods are time-consuming and require the presence of specialists. Along with traditional methods of medical rehabilitation, new technologies are currently used, including telerehabilitation, digital products based on virtual reality and artificial intelligence, robotic mechanotherapy, the effectiveness of which has been proven by scientific works of domestic and foreign colleagues and is in no way inferior to classical methods of rehabilitation treatment.

A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of Tongmai Yangxin pill on ventricular remodeling in acute anterior STEMI patients after primary PCI

BackgroundAcute ST-segment elevation myocardial infarction (STEMI) is a severe form of coronary heart disease and a leading cause of mortality and morbidity. This can mainly be ascribed to adverse ventricular remodeling (VR). However, the efficacy of existing treatment strategies for STEMI is not entirely satisfactory. Tongmai Yangxin Pill (TMYX), a patented traditional Chinese medicine (TCM), has been approved for treating various cardiovascular diseases. PurposeThe purpose was to assess the effect of TMYX on VR in acute STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Study DesignA multicenter, randomized, double-blinded, and placebo-controlled trial conducted across 11 hospitals in China. MethodA total of 270 patients with acute anterior STEMI, undergoing PPCI within 10 days of symptom onset were enrolled and randomly assigned to receive either a placebo or TMYX, in addition to guideline-directed treatments for STEMI. The primary endpoint was a change in left ventricular end-diastolic volume index (LVEDVI) at 12 weeks. ResultAmong the 270 randomized patients, 218 (TMYX: 109 and placebo: 109) were included in the per-protocol analysis. At 4 and 12 weeks, TXMY significantly improved LVEDVI than the placebo group ([-2.17(-9.24, 8.28) vs. 3.76(-2.38, 11.48), p < 0.05] and [-1.17 (-12.19, 12.88) vs. 4.46 (-2.89, 11.99), p < 0.05]). Changes in left ventricular end-diastolic volume (LVEDV) at 4 weeks were superior in the TMYX group than the placebo group (-4.37 (-17, 13.99) vs. 7.41 (-4.56, 21.79), p < 0.05). Cardiac magnetic resonance imaging (CMRI) showed that left ventricular ejection fraction (LVEF) was significantly greater in the TMYX group than in the placebo group at 4 weeks. There were no statistically significant differences between groups for left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), 6 min walking distance (6MWD), and major adverse cardiac and cerebrovascular events (MACCEs) (p > 0.05). ConclusionTMYX, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly delayed VR in patients with acute anterior STEMI undergoing PPCI within 10 days of symptom onset.

Study of the relationships of polymorphisms of the folate cycle genes with the levels of homocysteine and folic acid as risk factors of cardiovascular disorders in the post-covid period

Enzymes of the folate cycle participate in the process of remethylation of homocysteine (HC) to methionine, where folates are coenzymes for methyl transfer. The aim of the work was to identify the interrelationships of gene polymorphisms of associations between folate cycle enzyme gene polymorphisms and cardiometabolic risk factors such as increased serum homocysteine levels and folic acid deficiency in patients in the post-covid period. In 51 patients who suffered from COVID-19, a general clinical and laboratory examination, and assessment of serum homocysteine and folic acid concentrations by immunoenzymatic method was carried out. Polymorphisms of the genes: methylenetetrahydrofolate reductase (677C&gt;T and 1298A&gt;C), methionine synthase-reductase (66A&gt;G) and methionine synthase (2756A&gt;G) were determined by real time polymerase chain reaction. For each of the named polymorphisms, the examined patients were divided into 3 groups according to the nucleotide alleles in the corresponding position: 1) homozygous dominant, 2) heterozygous and 3) homozygous recessive. For the methylenetetrahydro­folatereductase gene at position 677, serum levels of homocysteine and folate did not differ between the groups 1 and 2 with genotypes 677 C/C (n=26) and 677C/T (n=21), (p&gt;0.05); in group 3, the recessive genotype 677 T/T was found in only 4 people (8%), that did not allow comparison of indices. The distribution of patients into 3 groups according to the genotype of the same gene at position 1298 revealed that the recessive 1298 C/C mutation in group 3 (n=9) associated with an increased homocysteine level (19.56±1.89 μmol/l), versus 10.68±0.76 (p=0.012) and 11.63±1.25 μmol/l (p=0.013) in groups 1 and 2, with no difference in folate levels between groups. Group 3 differed by a higher degree of obesity, a higher frequency of hypertension disease and chronic heart failure (in 85% of patients in group 3, against 41 and 50% in groups 1 and 2), a higher number of platelets, a longer duration of hospitalization due to COVID-19, a higher level of D-dimer. The study of groups of patients, divided depending on the genotype of methioninesynthase reductase at position 66, showed that carriers of the recessive homozygous 66 G/G mutation (group 3, n=15) had increased serum homocysteine level (16.56±1.64 μmol/l) in comparison with individuals of group 1 (n=17) 66 A/A (10.28±1.17 μmol/l; p=0.004) and group 2 (n=19) 66 A/G (11.32±1.17 μmol/l, p=0.013). In group 3, a longer duration of hospitalization due to COVID-19 was noted (17.15±1.65 vs. 11.88±0.97 days, p=0.008), higher frequency of hypertension (67% vs. 35%) and heart failure (67% against 29%) compared to group 1. The use of a molecular genetic approach made it possible to establish that the presence of recessive mutations of the folate cycle genes is associated with a potential predisposition to hyperhomocysteinemia, thrombophilia, severe forms of cardiometabolic complications and coronavirus disease.

Molecular Scarring in Relapsing Psoriasis: Crosstalk of Keratinocytes and Immune Cells

Abstract Introduction/Objective Psoriasis is a chronic skin disorder with a tendency for relapse, characterized by immune- mediated mechanisms leading to papulosquamous lesions. Despite advances in treatment, many patients experience relapse, particularly in previously healed areas, referred to as “molecular scarring.” This scarring suggests a complex interaction between keratinocytes and immune cells, including tissue-resident memory T cells (TRMs), cytokines, and epigenetic modifications, contributing to the pattern-specific recurrence of psoriasis. Methods/Case Report After reviewing 31 articles on PubMed, we focused on the immunopathogenesis of psoriasis, examining the role of TRMs, the balance between regulatory T cells (Tregs) and Th17 cells, and the impact of various treatment modalities on disease recurrence. It evaluates the expression of TRM markers and the effectiveness of treatments such as anti-IL-17 agents and phototherapy in altering disease progression. The study also explores the genomic characteristics of psoriatic lesions post-treatment and the duration of clinical remission associated with different therapeutic approaches. Results (if a Case Study enter NA) The findings demonstrate a significant role of TRMs in psoriasis relapse, with environmental triggers reactivating these cells and leading to the production of inflammatory cytokines. Treatments targeting IL-17 showed a rapid decrease in TRM markers, particularly in the dermis, and were associated with different durations of disease remission based on the therapeutic approach. The study also found that the genomic profile of treated lesions does not fully normalize, with variations in gene expression linked to the type of treatment and possibly influencing the size of the molecular scar and relapse duration. Conclusion Psoriasis relapse is intricately linked to the presence of TRMs and the molecular scarring of previously healed lesions, influenced by various treatment modalities. The study underscores the importance of targeting TRMs and adjusting therapeutic strategies to extend the period of clinical remission and prevent the transition to more severe disease forms. Future research should focus on elucidating the detailed mechanisms of psoriasis relapse and developing targeted treatments to normalize the genomic profile of healed skin, ultimately improving patient outcomes and management of the disease.

Analysis of ICAM-1 rs3093030, VCAM-1 rs3783605, and E-Selectin rs1805193 Polymorphisms in African Women Living with HIV and Preeclampsia.

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms.

Predictive significance of hypertension in the incidence of complications in critically ill patients with COVID‑19: A retrospective cohort study.

The association between hypertension as a pre-existing comorbidity and the severe form of coronavirus disease 2019 (COVID-19) remains unclear due to the contradictory results of previously published studies. The present study evaluated the predictive significance of hypertension in the incidence of complications among critically ill patients with COVID-19. The present study included 372 critically ill adults with COVID-19 pneumonia, hospitalized between January 1 and December 31, 2021. The study cohort was divided into the hypertension group (HTA group), which included 245 patients with a history of hypertension, or a non-HTA group (control group), which included 127 patients without hypertension. The incidence of complications was retrospectively extracted from medical records and compared between groups. Multivariate regression analysis (adjusted for potential confounders) and receiver operating characteristic (ROC) curve analysis determined the predictive significance of hypertension on the incidence of complications. The patients in the HTA group were more likely to receive invasive mechanical ventilation [odds ratio (OR), 1.696; P<0.02], develop sepsis (OR, 1.807; P<0.01) and develop complications (OR, 3.101; P<0.001). Hypertension was an independent positive predictor for invasive mechanical ventilation [area under the curve (AUC), 0.67; positive predictive value (PPV), 71.7%; P<0.05], sepsis (AUC, 0.69; PPV, 77.5%; P<0.026) and total complications per patient (AUC, 0.71; PPV, 81.4%; P<0.001). On the whole, the data of the present study indicate that a history of hypertension should be considered as an independent clinical predictor of a higher incidence of complications in critically ill patients with COVID-19. Patients with pre-existing hypertension and a diagnosis of COVID-19 require timely identification, additional attention and treatment to avoid a critical course and help improve outcomes.

Prognostic significance of suppressor of tumorigenicity 2, endothelin-1, macrophage migration inhibitory factor, interleukin-6 and C-reactive protein in patients with acute myocardial infarction with ST-segment elevation and reduced glomerular filtration

Acute myocardial infarction with ST‑segment elevation (STEMI) is one of the most severe forms of cardiovascular disease, requiring immediate diagnosis and treatment. Prognostic biomarkers play a crucial role in risk stratification and guiding therapeutic strategies in STEMI patients, particularly those with reduced glomerular filtration rate (GFR). Objective — to evaluate the prognostic significance of suppressor of tumorigenicity 2 (ST2), endothelin­1 (ET­1), macrophage migration inhibitory factor (MIF), interleukin­6 (IL­6), and C­reactive protein (CRP) in STEMI patients with reduced GFR compared to those with normal GFR for improved risk stratification and management. Materials and methods. This study was conducted on a cohort of 762 patients diagnosed with STEMI. The mean age of the patients was (60.5±10.5) years, with 74.7% being male. The glomerular filtration rate was calculated using the CKD­EPI 2021 formula. Patients were categorized into two groups: 246 with GFR &lt;60 ml/min/1.73m2 and 516 with GFR ≥60 ml/min/1.73m2. Biomarker levels (ST2, ET­1, MIF, IL­6, CRP) were measured using enzyme­linked immunosorbent assay (ELISA) kits. Results. In patients with reduced GFR, ST2 and CRP levels were significantly higher than in patients with normal GFR (39.48 [26.49—80.71] and 33.78 [21.14—59.66] ng/ml, respectively, p=0.026 and 48 [36—96] and 24 [6—48] mg/l, p=0.015). The levels of MIF and IL‑6 were also increased in patients with reduced GFR, but the differences in these parameters were not statistically significant. No significant difference was recorded in ET‑1 levels between the groups. The analysis of ROC curves for ST2 revealed moderate prognostic accuracy in predicting survival in patients with reduced GFR (AUC=0.659; p=0.016). Conclusions. The results indicate the importance of ST2 as a prognostic marker in STEMI patients with reduced GFR. The use of these biomarkers in clinical practice can improve risk stratification and management in this patient group. Further research is warranted to develop individualized treatment approaches that consider the risks of cardiovascular events and renal dysfunction in STEMI patients.

PROVISIONAL STENTING IN LEFT MAIN STEM DISEASE: LONG-TERM OUTCOMES AND IMPACT ON SIDE BRANCH PERFUSION

Left main stem disease (LMSD) is a severe form of coronary artery disease (CAD) that involves a significant risk of mortality if not treated effectively. Traditionally, coronary artery bypass grafting (CABG) has been the primary method for revascularization in LMSD. However, percutaneous coronary intervention (PCI), especially provisional stenting using drug-eluting stents (DES), has gained popularity for its minimal invasiveness and comparable clinical outcomes. Provisional stenting allows treatment of the main vessel with additional side branch stenting only when needed, reducing complications and stent usage. Objective: The primary objective of this study is to evaluate the long-term outcomes of provisional stenting in patients with LMSD, focusing on its impact on side branch perfusion, in-stent restenosis (ISR), and major adverse cardiac events (MACE). Methods: This retrospective cohort study was conducted at a tertiary care hospital specializing in cardiology between January 2023 and December 2023. A total of 284 patients who underwent provisional stenting for LMSD were included. Fractional flow reserve (FFR) and quantitative coronary angiography (QCA) were used to assess side branch perfusion, with follow-up data including clinical outcomes such as ISR, MACE, and survival rates. Multivariate regression analysis was used to identify predictors of poor outcomes, and Kaplan-Meier survival curves were generated to compare outcomes based on side branch perfusion status. Results: The study found that 77.5% of patients achieved adequate side branch perfusion (FFR &gt; 0.80) after provisional stenting, while 22.5% had impaired perfusion (FFR ≤ 0.80). The incidence of MACE was 10.6%, and ISR was reported in 7.0% of patients during the one-year follow-up period. Kaplan-Meier analysis showed a significant survival benefit for patients with adequate side branch perfusion (Log-Rank p &lt; 0.001). Age and diabetes mellitus were significant predictors of MACE. Conclusion: Provisional stenting in LMSD provides favourable long-term outcomes, particularly in terms of side branch perfusion and reduced MACE. However, a subset of patients, particularly those with diabetes, may require additional interventions. Future studies should focus on improving outcomes in patients with impaired side branch perfusion and exploring the role of advanced imaging techniques in optimizing stenting strategies.