Disease Progression Outcomes Research Articles

Preoperative systemic inflammation response index enhances the prognostic value of tumor multifocalityin upper tract urothelial carcinoma.

In cancer, tumor-related inflammation affects disease progression and survival outcomes. However, the role of systemic inflammation in tumor multifocality in upper tract urothelial carcinoma (UTUC) is not well understood. The aim of the present study was to evaluate the impact of the systemic inflammation response index (SIRI) on tumor multifocality for predicting oncological outcomes in patients with UTUC after radical nephroureterectomy (RNU). For this purpose, data from 645 patients with non-metastatic UTUC who underwent RNU between 2008 and 2020 were retrospectively analyzed. Survival outcomes such as overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) RATES were assessed using the Kaplan-Meier method, and independent prognostic factors were identified through a multivariable Cox proportional hazards regression model. Of the 645 patients with UTUC included in the present study, 163 (25%) had multifocal UTUC. Kaplan-Meier analysis indicated that multifocal UTUC synchronous with a high-level SIRI was significantly associated with poorer outcomes after RNU. Furthermore, the results of the multivariate Cox proportional hazards model analysis demonstrated that multifocal tumor coupled with a high-level SIRI was an independent factor for predicting a shorter survival and disease progression. In conclusion, the results of the present study indicated that an elevated SIRI significantly influenced the survival rate of patients with multifocal UTUC. Specifically, integrating multifocal UTUC with a high-level SIRI emerged as an independent risk factor for poorer OS, CSS and RFS. These findings highlighted the potential role of SIRI in the risk stratification and management of patients with multifocal UTUC.

TP53 mutations in myeloid neoplasms: implications for accurate laboratory detection, diagnosis, and treatment.

Genetic alterations that affect the function of p53 tumor suppressor have been extensively investigated in myeloid neoplasms, revealing their significant impact on disease progression, treatment response, and patient outcomes. The identification and characterization of TP53 mutations play pivotal roles in subclassifying myeloid neoplasms and guiding treatment decisions. Starting with the presentation of a typical case, this review highlights the complicated nature of genetic alterations involving TP53 and provides a comprehensive analysis of TP53 mutations and other alterations in myeloid neoplasms. Currently available methods used in clinical laboratories to identify TP53 mutations are discussed, focusing on the importance of establishing a robust testing protocol within clinical laboratories to ensure the delivery of accurate and reliable results. The treatment implications of TP53 mutations in myeloid neoplasms and clinical trial options are reviewed. Ultimately, we hope that this review provides valuable insights into the patterns of TP53 alterations in myeloid neoplasms and offers guidance to establish practical laboratory testing protocols to support the best practices of precision oncology.

Noninvasive Tests to Assess Fibrosis and Disease Severity in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Risk of disease progression and clinical outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with fibrosis stage and presence of "at-risk metabolic dysfunction-associated steatohepatitis (MASH)." Although liver biopsy is considered the gold standard to diagnose MASH and stage of fibrosis, biopsy is infrequently performed in clinical practice and has associated sampling error, lack of interrater reliability, and risk for procedural complications. Noninvasive tests (NITs) are routinely used in clinical practice for risk stratification of patients with MASLD. Several NITs are being developed for detecting "at-risk MASH" and cirrhosis. Clinical care guidelines apply NITs to identify patients needing subspecialty referral. With recently approved Food and Drug Administration treatment for MASH and additional emerging pharmacotherapy, NITs will identify patients who will most benefit from treatment, monitor treatment response, and assess risk for long-term clinical outcomes. In this review, we examine the performance of NITs to detect "at-risk MASH," fibrosis stage, response to treatment, and risk of clinical outcomes in MASLD and MASH.

Overcoming Chemoresistance in Cancer: The Promise of Crizotinib.

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).

Navigating Disease Management: A Comprehensive Review of the De Ritis Ratio in Clinical Medicine.

The De Ritis ratio, defined as the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, is a widely recognized biochemical marker with significant applications in diagnosing and managing various diseases, particularly liver disorders. This comprehensive review synthesizes current knowledge surrounding the clinical relevance of the De Ritis ratio, examining its historical development, diagnostic utility, and prognostic significance across various medical conditions, including liver diseases, cardiovascular disorders, and muscular pathologies. Through an in-depth analysis of literature spanning several decades, this review highlights the role of the De Ritis ratio not only in differential diagnosis but also as a prognostic indicator for disease progression and patient outcomes. The ratio's ability to distinguish between different types of liver pathology, aid in early disease detection, and its potential use in monitoring treatment response are discussed. Additionally, the review addresses the methodological considerations, such as confounding factors and interpretation challenges, that impact the clinical utility of the De Ritis ratio. Given the evolving landscape of clinical diagnostics and the push toward more personalized medicine, the review concludes with recommendations for further research. These include longitudinal studies to explore the ratio's changes over time, comparative research across diverse populations, and technological integration to enhance diagnostic accuracy and patient care. This review aims to reaffirm the importance of the De Ritis ratio in modern clinical practice and encourages continued exploration into its potential applications and benefits in healthcare.

Prevalence and Association of Risk Factors According to Liver Steatosis and Fibrosis Stages among Nonalcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus in India: A Cross-sectional Study.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are linked to the global diabetes epidemic, leading to increased disease progression and adverse health outcomes. The renaming of NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD) at the 2023 European Association for the Study of the Liver Congress highlights the complex relationship between metabolic disorders and liver health. Taking this into consideration, we aimed this study to identify prevalence and risk factors associated with the stages of NAFLD in individuals with T2DM in the Indian population. This observational, cross-sectional study was conducted on 1,521 T2DM patients at Dr Panikar's Speciality Care Centre, Mumbai, between September 1, 2022 and October 31, 2022. Demographic parameters such as age, gender, height, weight, and anthropometric parameters such as body mass index (BMI) and waist circumference were measured. Liver fibrosis and steatosis stages were identified by vibration-controlled transient elastography (VCTE) using FibroScan®. The prevalence of liver steatosis was 75.1% among the 1,521 diabetes cases [S0 (24.9%), S1 (15.1%), S2 (24%), and S3 (36%)], whereas the prevalence of liver fibrosis was 28.0% [F0 (72%), F1 (19%), F2 (5%), F3 (1.5%), and F4 (3.4%)]. The S1 (p = 0.012), S3 (p = 0.001), F1 (p = 0.001), and F2 (p = 0.001) grades showed significant gender-related changes, demonstrating a positive connection. Furthermore, waist circumference was associated with disease severity in both liver steatosis and fibrosis stages (p = 0.001), but BMI was solely associated with the degree of steatosis (p = 0.001). The mean age differences between these categories, however, did not reach statistical significance (p-values of 0.149 and 0.078, respectively, for the steatosis and fibrosis grades). The study reveals a high prevalence of NAFLD (steatosis and fibrosis) in T2DM patients, increasing the risk of advanced fibrosis. In T2DM patients with risk factors including waist circumference and BMI, appropriate screening and intervention are required.

Dynamic Assessment of Hematological Parameters as Predictive Biomarkers for Disease Severity and Prognosis in COVID-19 Patients: A Longitudinal Study.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to substantial morbidity and mortality worldwide. Hematological abnormalities are common in COVID-19 patients and play a significant role in disease pathogenesis and prognosis. This study aimed to longitudinally monitor hematological parameters in COVID-19 patients and investigate their predictive value for disease severity and prognosis. A prospective longitudinal design was employed to enroll 121 adult patients diagnosed with COVID-19 based on positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test results. Baseline demographic and clinical data were collected, and hematological parameters, including complete blood count (CBC) indices, inflammatory markers, and coagulation profiles, were measured at predefined time points during hospitalization or outpatient visits. Follow-up assessments were conducted longitudinally to monitor the disease progression and clinical outcomes. This study revealed dynamic changes in hematological parameters over the course of COVID-19. Hemoglobin levels showed a decrease from baseline (mean ± SD: 12.5 ± 1.8 g/dL) to the peak of illness (10.2 ± 2.0 g/dL), indicating the development of anemia during the acute phase of infection. White blood cell counts demonstrated an initial increase (8.9 ± 3.2 × 10^9/L) followed by a decline (5.4 ± 1.9 × 10^9/L) as the disease progressed, suggesting an early inflammatory response followed by immune suppression. The platelet counts fluctuated, with a decrease observed during the acute phase (190 ± 50 × 10^9/L) and subsequent recovery during convalescence (240 ± 60 × 10^9/L). Inflammatory markers, such as C-reactive protein and interleukin-6, were elevated, peaking at 120 and 150 pg/mL, respectively, indicating systemic inflammation. Coagulation profiles showed abnormalities suggestive of COVID-19-associated coagulopathy, including elevated D-dimer levels (mean ± SD: 3.5 ± 1.2 µg/mL) and prolonged prothrombin time (15.8 ± 2.5 seconds). Longitudinal analysis of hematological parameters revealed associations between disease severity and clinical outcomes, with certain abnormalities correlating with an increased risk of complications and a poor prognosis. This study highlights the importance of monitoring hematological parameters in COVID-19 patients for risk stratification, prognostication, and guiding therapeutic interventions.

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

A Comprehensive Pan-Cancer Analysis of Cytochrome C Oxidase Assembly Factor 1 (COA1) Reveals Instrumental Role of Mitochondrial Protein Assembly in Cancer that Modulates Disease Progression and Prognostic Outcome.

Cytochrome c oxidase assembly factor 1 (COA1), a mitochondrial respiratory chain complex assembly factor protein of inner mitochondrial membrane (IMM), is involved in translating many mitochondrial components and assembling nuclear-encoded components within mitochondria. Given the lack of extensive research on COA1 in cancer, this study undertakes a comprehensive pan-cancer analysis of COA1, which is overexpressed across various cancer types, shedding light on its multifaceted role in tumorigenesis, prognosis, and tumor microenvironment (TME) modulation. Leveraging bioinformatics tools and public databases, we elucidated its potential as a diagnostic cancer biomarker as well as a target for novel anti-cancer therapeutics. Gene expression analysis using "TIMER2.0", "UALCAN" and "GEPIA2" platforms, supported by protein expression data, revealed a significant correlation between COA1 upregulation and poor prognosis in Kaplan-Meir analysis, underscoring its clinical relevance. Additionally, genetic mutation analysis of COA1 with the help of "cBioPortal" warrants further exploration into its functional significance. Moreover, our investigation of the tumor microenvironment unveiled the interplay of COA1 with fibroblast and T cell infiltration implicating the role of COA1 in the tumor immune microenvironment. Furthermore, COA1-related gene enrichment study in "GeneMANIA" and pathway cross-talk analysis with Gene Ontology (GO) gene sets established comprehensive clarifications about the molecular pathways and protein networks associated with COA1 deregulation. Overall, this study lays a sturdy foundation to support future research endeavors targeting COA1, unraveling the molecular mechanisms underlying COA1 deregulation, and exploring its therapeutic potential in cancer.

Prediction of peritoneal free cancer cells in gastric cancer patients by golden-angle radial sampling dynamic contrast-enhanced magnetic resonance imaging.

Peritoneal free cancer cells can negatively impact disease progression and patient outcomes in gastric cancer. This study aimed to investigate the feasibility of using golden-angle radial sampling dynamic contrast-enhanced magnetic resonance imaging (GRASP DCE-MRI) to predict the presence of peritoneal free cancer cells in gastric cancer patients. All enrolled patients were consecutively divided into analysis and validation groups. Preoperative magnetic resonance imaging (MRI) scans and perfusion were performed in patients with gastric cancer undergoing surgery, and peritoneal lavage specimens were collected for examination. Based on the peritoneal lavage cytology (PLC) results, patients were divided into negative and positive lavage fluid groups. The data collected included clinical and MR information. A nomogram prediction model was constructed to predict the positive rate of peritoneal lavage fluid, and the validity of the model was verified based on data from the verification group. There was no statistical difference between the proportion of PLC-positive cases predicted by GRASP DCE-MR and the actual PLC test. MR tumor stage, tumor thickness, and perfusion parameter Tofts-Ketty model volume transfer constant (Ktrans) were independent predictors of positive peritoneal lavage fluid. The nomogram model featured a concordance index (C-index) of 0.785 and 0.742 for the modeling and validation groups, respectively. GRASP DCE-MR could effectively predict peritoneal free cancer cells in gastric cancer patients. The nomogram model constructed using these predictors may help clinicians to better predict the risk of peritoneal free cancer cells being present in gastric cancer patients.

Paracrine Ovarian Cancer Cell-Derived CSF1 Signaling Regulates Macrophage Migration Dynamics in a 3D Microfluidic Model that Recapitulates In Vivo Infiltration Patterns in Patient-Derived Xenografts.

A high density of macrophages in the ovarian cancer microenvironment is associated with disease progression and poor outcomes. Understanding cancer-macrophage interaction mechanisms that establish this pro-tumorigenic microenvironment is critical for developing macrophage-targeted therapies. Here, 3D microfluidic assays and patient-derived xenografts are utilized to define the role of cancer-derived colony stimulating factor 1 (CSF1) on macrophage infiltration dynamics toward ovarian cancer cells. It is demonstrated that multiple ovarian cancer models promote the infiltration of macrophages into a 3D extracellular matrix in vitro in a cell density-dependent manner. Macrophages exhibit directional migration and increased migration speed under both direct interactions with cancer cells embedded within the matrix and paracrine crosstalk with cancer cells seeded in an independent microchannel. It is also found that platinum-based chemotherapy increases macrophage recruitment and the levels of cancer cell-derived CSF1. Targeting CSF1 signaling under baseline or chemotherapy-treatment conditions reduces the number of infiltrated macrophages. It is further shown that results obtained with the 3D microfluidic model reflect the recruitment profiles of macrophages in patient-derived xenografts in vivo. These findings highlight the role of CSF1 signaling in establishing macrophage-rich ovarian cancer microenvironments, as well as the utility of microfluidic models in recapitulating 3D tumor ecosystems and dissecting cancer-macrophage signaling.

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Liquid Chromatography-Mass Spectrometry Analytical Methods for the Quantitation of p-Cresol Sulfate and Indoxyl Sulfate in Human Matrices: Biological Applications and Diagnostic Potentials.

Indoxyl sulfate (IxS) and p-cresyl sulfate (pCS) are toxic uremic compounds with documented pathological outcomes. This review critically and comprehensively analyzes the available liquid chromatography-mass spectrometry methods quantifying IxS and pCS in human matrices and the biological applications of these validated assays. Embase, Medline, PubMed, Scopus, and Web of Science were searched until December 2023 to identify assays with complete analytical and validation data (N = 23). Subsequently, citation analysis with PubMed and Scopus was utilized to identify the biological applications for these assays (N = 45). The extraction methods, mobile phase compositions, chromatography, and ionization methods were evaluated with respect to overall assay performance (e.g., sensitivity, separation, interference). Most of the assays focused on human serum/plasma, utilizing acetonitrile or methanol (with ammonium acetate/formate or formic/acetic acid), liquid-liquid extraction, reverse phase (e.g., C18) chromatography, and gradient elution for analyte separation. Mass spectrometry conditions were also consistent in the identified papers, with negative electrospray ionization, select multiple reaction monitoring transitions and deuterated internal standards being the most common approaches. The validated biological applications indicated IxS and/or pCS were correlated with renal disease progression and cardiovascular outcomes, with limited data on central nervous system disorders. Methods for reducing IxS and/or pCS concentrations were also identified (e.g., drugs, natural products, diet, dialysis, transplantation) where inconsistent findings have been reported. The clinical monitoring of IxS and pCS is gaining significant interest, and this review will serve as a useful compendium for scientists and clinicians.

#308 The impact of multimorbidity on the effects of empagliflozin in chronic kidney disease (CKD): exploratory analyses from the EMPA-KIDNEY trial

Abstract Background and Aims Sodium-glucose co-transporter-2 (SGLT2) inhibitors slow kidney disease progression and reduce cardiovascular risk in patients with CKD. Multimorbidity is common in CKD and associated with poor prognosis. Multimorbidity may identify patients with most to gain from, or at increased risk of adverse effects of, such treatment, so uncertainty exists around the risk-benefit profile. We assessed the effects of empagliflozin according to baseline multimorbidity, polypharmacy and health-related quality of life in EMPA-KIDNEY trial participants. Method EMPA-KIDNEY was a double-blind, placebo-controlled randomised trial which compared empagliflozin 10 mg once daily versus placebo among 6609 patients with CKD (Clinicaltrials.gov: NCT03594110). Eligible patients had an eGFR of 20 to &amp;lt;45; or 45 to &amp;lt;90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio (uACR) ≥200 mg/g. Multimorbidity was defined by the presence or absence of eight self-reported conditions at randomisation (diabetes, heart failure, ischaemic heart disease [any history of myocardial infarction or angina], cerebrovascular disease [any history of stroke or transient ischaemic attack], peripheral arterial disease, atrial fibrillation, peripheral neuropathy and gout), in addition to CKD. Polypharmacy was derived from the number of concomitant medications recorded at randomisation. Health-related quality of life at randomisation was assessed using the EuroQoL EQ-5D-5L tool. To enable subgroup analyses, participants were categorised into approximate thirds of each variable's distribution. The relative effects of allocation to empagliflozin versus placebo on the trial's pre-specified efficacy and safety outcomes were assessed using Cox regression models adjusted for age, sex, region, eGFR, uACR and diabetes status. Tests for heterogeneity across subgroups were used to assess for any evidence that multimorbidity modifies relative treatment effects, and used to inform approaches to estimate absolute benefits. Results The median (Q1-Q3) number of comorbid conditions (other than CKD) recorded at randomisation was 1 (0-2); range 0-7. At randomisation, the median (Q1-Q3) number of concomitant medications recorded was 7 (5-10), range 0-36, and polypharmacy (≥5 medications) was prevalent in 5044/6609 (76%) of participants. There was considerable overlap between multimorbidity, polypharmacy and deficits in health-related quality of life (Fig. 1). Empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio 0.72, 95% CI 0.64-0.82). There was no evidence of heterogeneity relative effects by categories reflecting multimorbidity, nor by level of polypharmacy or self-reported quality of life at randomisation (P value for heterogeneity all &amp;gt;0.05; Fig. 2). Absolute benefits for the primary outcome were at least as large in the highest categories of multimorbidity or polypharmacy versus the lowest (and for those with poorer versus greater health-related quality of life). Safety outcomes were infrequent with no evidence of a difference in effect by baseline levels of multimorbidity, polypharmacy or quality of life, including no excess of symptomatic dehydration or fractures. Conclusion In EMPA-KIDNEY, the estimated absolute benefits of empagliflozin on kidney disease progression or cardiovascular death substantially outweigh potential for harm, irrespective of multimorbidity, polypharmacy or quality of life. The analyses encourage safe widespread use of SGLT2 inhibitors in CKD.

#150 Effect of dapagliflozin in patients with CKD depending on primary kidney disease

Abstract Background and Aims Multiple trials have reported that SGLT2 inhibitors reduce the risk of its primary composite outcome of kidney disease progression or cardiovascular death in a wide range of patients with CKD. Our aim was to compare effects on kidney outcomes among the different types of kidney diseases. Method Eligible patients with eGFRs ≥30-45, or ≥45-90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio of ≥300 mg/g, and receiving renin angiotensin system inhibitor, where indicated and tolerated were randomized to dapagliflozin 10 mg once daily vs placebo. Kidney disease progression was defined as a sustained ≥30% eGFR decline from randomization or to &amp;lt;10 mL/min/1.73 m2, start of maintenance dialysis or receipt of a kidney transplant, or renal death, and the effects of dapagliflozin were analyzed using a pre-specified Cox model. Testing for heterogeneity of effect between pre-specified kidney disease subgroups was performed, including exploratory analyses by specific glomerular disease etiologies. Results 362 participants were followed for a median of 2.0 years. 90 (24.8%) had diabetic kidney disease, 126 (34.8%) had glomerular disease, 94 (26%) had hypertensive or renovascular disease, and 52 (14.4%) had other or unknown causes. Overall, dapagliflozin reduced the risk of kidney disease progression by 34% (dapagliflozin 29/178 vs placebo 48/184; hazard ratio 0.62, 95% CI 0.51-0.78). This relative risk reduction appeared broadly similar in subgroup analyses by primary cause of kidney disease and by different types of glomerular disease. Conclusion Our study with a few numbers of patients with diabetic and non-diabetic causes of CKD showed that dapagliflozin reduced risk of kidney disease progression with relative risk reductions that were broadly similar across the different CKD etiologies.

#210 Effects of serum magnesium level on kidney disease progression and major cardiovascular outcome in patients with chronic kidney disease

Abstract Background and Aims Magnesium is known for its anti-inflammatory, anti-apoptotic, and anti-oxidative effects, potentially inhibiting renal fibrosis. Additionally, it is believed that magnesium can inhibit vascular calcification, potentially improving cardiovascular outcomes. However, this remains a topic of controversy. This study aims to investigate the association between serum magnesium levels and CKD progression as well as cardiovascular outcomes. Method We analyzed 1,893 patients from The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD), which is a prospective cohort study. These patients were categorized into three groups based on their baseline magnesium levels: Mg1 (hypomagnesemia, &amp;lt;1.8 mg/dL), Mg2 (normomagnesemia, 1.8-2.4 mg/dL), and Mg3 (hypermagnesemia, &amp;gt;2.4 mg/dL). The primary outcome was defined as meeting one or more of the following criteria during the follow-up period: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate. The secondary outcome was a composite of major adverse cardiovascular events (MACEs). We used Cox proportional hazard regression model. Results A total of 673 patients (35.6%) experienced the composite renal outcome. The Mg1 group showed significantly increased adverse renal outcomes compared to the Mg2 group (HR, 1.885; 95% CI, 1.137-3.124; p = 0.013), however, Mg3 group did not show a significant difference (HR, 0.927; 95% CI, 0.783-1.097; p = 0.379). The composite cardiovascular outcome occurred in 138 patients (7.3%). The risk of composite cardiovascular outcomes significantly increased in the Mg1 group compared to the Mg2 group (HR 3.472; 95% CI, 1.492-8.076; p = 0.003). However, we observed no statistically significant differences in the Mg3 group (HR 1.021; 95% CI, 0.689; p = 0.913). The cubic spline curves demonstrated a U-shaped association between serum magnesium levels and both renal and cardiovascular outcomes. Conclusion Hypomagnesemia is associated with the progression of renal disease and a significant increase in MACEs. Beyond a certain level, hypermagnesemia may also be associated with worsening renal and cardiovascular outcomes.

Diagnostic and prognostic significance of mast cell markers in HIV/AIDS: Current insights and future directions.

Human immunodeficiency virus (HIV) infection continues to pose significant global health challenges, necessitating advancements in diagnostic and prognostic approaches to optimize disease management. While primarily recognized for their roles in allergic responses, mast cells have emerged as potential markers with diagnostic and prognostic significance in the context of HIV/AIDS. This paper aims to synthesize current insights and delineate future directions regarding the utility of mast cell markers in diagnosing HIV infection, predicting disease progression, and guiding therapeutic strategies. Mast cells, equipped with distinct markers such as tryptase, chymase, carboxypeptidase A3, and c-kit/CD117 receptors, exhibit tissue-specific expression patterns that offer potential as diagnostic indicators for HIV infection. Understanding the dynamics of these markers in different tissues and body fluids holds promise for accurate HIV diagnosis, disease staging, and monitoring treatment responses. Moreover, the prognostic significance of mast cell markers in HIV/AIDS lies in their potential to predict disease progression, immune dysregulation, and clinical outcomes. The integration of mast cell markers into clinical applications offers promising avenues for refining diagnostic assays, patient monitoring protocols, and therapeutic strategies in HIV/AIDS. Future research directions involve the development of novel diagnostic tools and targeted therapies based on mast cell-specific markers, potentially revolutionizing clinical practice and enhancing patient care in the management of HIV/AIDS. Continued investigations into mast cell markers' diagnostic and prognostic implications hold immense potential to advance our understanding and improve outcomes in HIV/AIDS management.

Long-term comparison of image-guided thermal ablation vs. lobectomy for solitary papillary thyroid microcarcinoma: a multi-center retrospective cohort study.

Image-guided thermal ablation has been applied in patients with papillary thyroid microcarcinoma (PTMC) who refuse surgery or active surveillance. However, evidence to support ablation is limited by single-center designs and a lack of long-term data. The purpose of this study was to compare long-term outcomes between ablation and lobectomy for patients with solitary PTMC. This multi-center retrospective study included 1021 consecutive patients with solitary PTMC who underwent ablation ( n =444) or lobectomy ( n =577) at the four university-affiliated hospitals. The primary outcomes were disease progression [lymph node metastasis (LNM), recurrent tumors, persistent tumors and distant metastasis] and disease-free survival (DFS). Secondary outcomes were complications, hospitalization, procedure time, estimated blood loss and cost. The two groups were compared using propensity score matching. After matching, no significant differences were observed in disease progression (4.7% vs. 3.4%, P =0.307), LNM (1.6% vs. 1.6%, P =1.000), recurrent tumors (2.9% vs. 1.8%, P =0.269), persistent tumors(0.2% vs. 0%, P =0.317) and DFS (95.5% vs. 97.1%, P =0.246) between the ablation and lobectomy groups during the median follow-up of 96.5 months. The ablation group had significantly lower complication rates (0.7% vs. 5.2%, P <0.001), shorter post-treatment hospitalization {median [interquartile range (IQR)], 0 vs. 4.0 [3.0] days, P <0.001}, shorter procedure time [8.5 (2.8) vs. 90.0 (43.8) min, P <0.001], reduced estimated blood loss [0 vs. 20.0 (10.0) ml, P <0.001], and lower cost [$1873.2 (254.0) vs. $2292.9 (797.8), P <0.001] than the lobectomy group. This study revealed comparable disease progression and survival outcomes between ablation and lobectomy for solitary PTMC. Imaged-guided thermal ablation could be effective and safe alternatives to lobectomy for properly selected patients with PTMC.

Maternal and fetal outcomes in multiparous women with Cystic Fibrosis

BackgroundQuality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. MethodsA multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18–45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed – before, during, and after pregnancy. ResultsThe study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. ConclusionsMultiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.