High Risk Of Progression Research Articles

The Onerous task of managing paroxysmal nocturnal hemoglobinuria in a Low resource setting: a case report. A hematologist’s experience

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a form of red cell membrane defect characterized by increased sensitivity to complement-mediated cell lysis, resulting in intravascular hemolytic anemia, passage of hemoglobin-containing urine, a high risk of venous thrombosis and progression to pancytopenia.The diagnosis of PNH is based on the flow cytometric (FCM) detection of peripheral blood cell clones. Such clones lack expression of the surface molecules linked to the glycosylphosphatidylinositol (GPI) anchors. The underlying defect is a somatic mutation of the short arm of the phosphatidylinositol glycan class A gene (PIG-A). Case report: We report a case of a 34-year-old male, with recurrent hemolytic anemia and dural venous sinus thrombosis found to have PNH by flow cytometry. He is currently on anticoagulation, iron and folate supplements, intermittent steroids for hemolytic episodes as we await complement inhibitors. Conclusion: As part of the diagnostic workup for patients presenting with recurrent hemolytic anemia and thrombosis in unusual sites, clinicians should include PNH on the list of differential diagnoses. Effort should be taken to characterize the red urine reported on the urine dipstick as blood/hemoglobin by microscopy to differentiate hematuria and hemoglobinuria and order for flow cytometry as this has implications on patient management. Keywords: Thrombosis; hemolysis; complement; paroxysmal nocturia; hemoglobinuria.

8473 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City

Abstract Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None. Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population. Presentation: 6/1/2024

6428 Update on Genetic F6428 actors of Nonalcoholic Fatty Liver Disease

Abstract Disclosure: H.M. Heshmati: None. Background: Nonalcoholic fatty liver disease (NAFLD) is a pandemic with a prevalence of 25% among the adult population worldwide. NAFLD is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and hepatocellular cancer. The pathogenesis of NAFLD is complex and multifactorial, involving metabolic, epigenetic, and genetic factors. Several medical conditions (e.g., obesity, type 2 diabetes, inflammation, insulin resistance, disrupted gut microbiome, and impaired intestinal barrier function) are important risk factors associated with and/or contributing to NAFLD. This review presents an update on the genetic factors of NAFLD identified by the genome-wide association studies (GWAS). Methods: A systematic search of literature was conducted using the search terms nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, hepatocellular cancer, obesity, type 2 diabetes, epigenetics, and genetics. Results: Evidence for the contribution of genetic factors to NAFLD is further emphasized by the ethnic differences in the prevalence of NAFLD (e.g., higher prevalence among Hispanic American compared to African American adults). Based on the results of the GWAS, several genetic modifiers are relevant to NAFLD development and progression. They include variations in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7), glucokinase regulatory protein (GCKR), programmed cell death protein 1 (PDCD1), and hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) genes (non-exhaustive list). These genetic modifiers interact with the metabolic and epigenetic factors for the development and progression of NAFLD and are responsible for the variability in the severity of NAFLD. The PNPLA3 gene variant (rs738409), which is the first and the best validated genetic modifier, is associated with a high risk of development and progression of NAFLD. The PDCD1 gene variant (rs7421861) is independently associated with hepatocellular cancer development. In contrast, the HSD17B13 gene variant (rs72613567) may have a protective effect for NAFLD risk. Conclusion: NAFLD is a multifactorial condition with a complex pathogenesis involving the interactions between metabolic, epigenetic, and genetic factors. The prevalence and risk of NAFLD differ across populations mainly due to genetic polymorphisms. Genetic factors relevant to NAFLD include variations in PNPLA3, TM6SF2, MBOAT7, GCKR, PDCD1, and HSD17B13 genes. A better understanding of these genetic modifiers and their mechanisms of action should allow a better risk prediction of the development of NAFLD and its progression to cirrhosis and hepatocellular cancer and help the development of new and selected therapies for NAFLD. Presentation: 6/3/2024

9253 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City

Abstract Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None. Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population. Presentation: 6/1/2024

Characteristics of risk factors and molecular genetic parameters in children with chronic kidney disease

Introduction. Information about the health status of children with nephrological pathology includes many manifestations of functional system disorders. However, early diagnosis of chronic kidney disease (CKD) is rarely carried out due to the lack of reliable predictors of this process.The aim: To analyze the association of anamnestic signs, laboratory and genetic research results with chronic kidney disease in children to identify potential predictors of the disease.Material and Methods. The data were obtained from a single-center retrospective catamnestic cohort study (2011–2022). The main group included 128 children with chronic kidney disease aged 1 to 17 years. The comparison group consisted of 30 children without diagnosed kidney pathology aged from 1 to 17 years. There were no statistically significant differences in sex and age between the two groups. The informative value of more than 150 features, including anamnestic ones, the state of the mother’s health during pregnancy, antenatal and perinatal factors, features of the child’s development and manifestation of the disease, the results of clinical, laboratory, and genetic research methods were evaluated. An integrated approach to the study included methods for hypotheses testing on statistical significance of indicators differences, regression analysis, and ROC analysis.Results. Hereditary burden of nephrological pathology in the family, unfavorable course of pregnancy (anemia, toxicosis of the first half), obstetric and somatic pathology in the mother, the serial number of childbirth are associated with the subsequent development of CKD. Erythrocytes in the urine and daily protein loss were detected only in the group of children with CKD. In this group, a decrease in the number of red blood cells, increased erythrocyte sedimentation rate (ESR), allergies at an early age, otitis media, persistent viral and bacterial infections, and a number of signs of connective tissue dysplasia were more common. The main group statistically significantly differed from the comparison group by a number of polymorphic genetic markers. It can be assumed that the polymorphisms AGT1 Thr174Thr, AGT2 Thr235Thr, NO3 C786T are associated with a predisposition to CKD, and the products of polymorphisms AGT1 Thr174Met, AGT2 Met235Met, R1 AGT2 C1166C, NO3 T786T may have a protective effect according to development of CKD.Conclusion. The risk factors for CKD identified in this study can be used to develop software to support medical decision making for early detection of children at high risk of disease progression.

Management of acute kidney disease in type 2 diabetes: the potential role of GLP-1 RAs and SGLT2-Is.

Acute kidney disease (AKD) is defined as subacute damage and/or loss of kidney function occurring 7 to 90days after acute kidney injury (AKI), and bearing a high risk of progression to chronic kidney disease. Current management of AKD is non-specific and includes prevention of repeated AKI, early and regular follow-up by a nephrologist, resumption and dose adjustment of statins and renin-angiotensin system inhibitors, optimization of blood pressure control, nutrition management, and nephrotoxin avoidance. Recently, SGLT2i and GLP1- RAs have emerged as potential therapeutic tools preventing the transition from acute to chronic kidney disease due to their efficacy in preserving renal function.

Predicting Disease Progression in Inoperable Localized NSCLC Patients Using ctDNA Machine Learning Model.

There is an urgent clinical need to accurately predict the risk for disease progression in post-treatment NSCLC patients, yet current ctDNA mutation profiling approaches are limited by low sensitivity. We represent a non-invasive liquid biopsy assay utilizing cfDNA neomer profiling for predicting disease progression in 44 inoperable localized NSCLC patients. A total of 97 plasma samples were collected at various time points during or post-treatments (TP1: 39, TP2: 33, TP3: 25). cfDNA neomer profiling, generated based on target sequencing data, was used to fit survival support vector machine models for each time point. Leave-one-out cross-validation (LOOCV) was performed to evaluate the models' predictive performances. Our cfDNA neomer profiling assay showed excellent performance in detecting patients with a high risk for disease progression. At TP1, the high-risk patients detected by our model showed an increased risk of 3.62 times (hazard ratio [HR] = 3.62, p = 0.0026) for disease progression, compared to 3.91 times (HR = 3.91, p = 0.0022) and 4.00 times (HR = 4.00, p = 0.019) for TP2 and TP3. These neomer profiling determined HRs were higher than the ctDNA mutation-based results (HR = 2.08, p = 0.074; HR = 1.49, p = 0.61) at TP1 and TP3. At TP1, the predictive model reached 40% sensitivity at 92.9% specificity, outperforming the mutation-based method (40% sensitivity at 78.6% specificity), while the combination results reached a higher sensitivity (60%). Finally, the longitudinal analysis showed that the combination of neomer and ctDNA mutation-based results could predict disease progression with an excellent sensitivity of 88.9% at 80% specificity. In conclusion, we developed a cfDNA neomer profiling assay for predicting disease progression in inoperable NSCLC patients. This assay showed increased predicting power during and post-treatment compared to the ctDNA mutation-based method, thus illustrating a great clinical potential to guide treatment decisions in inoperable NSCLC patients. ClinicalTrials.gov: NCT04014465.

Upregulation of long non-coding RNA ENSG00000267838 is related to the high risk of progression and non-response to chemoradiotherapy treatment for cervical cancer

Cervical cancer (CC) is a global public health concern, primarily caused by persistent infection with oncogenic types of human papillomavirus (HPV). The World Health Organization (WHO) has established a plan to eliminate CC as a public health issue by the year 2100. However, the implementation of the HPV vaccine is impeded by vaccine restrictions and misinformation despite its demonstrated effectiveness. The CC treatment is influenced by the disease stage, with an unfavorable prognosis for those in advanced stages. This study aimed to investigate the potential of long non-coding RNAs (lncRNAs) in CC by identifying and characterizing related lncRNAs, elucidating their regulatory mechanisms and molecular interactions, and analyzing their expression patterns in patients with diverse responses to chemoradiotherapy. Non-stem cells from CC were isolated using flow cytometry sorting and used for total RNA extraction. The RNA was used to build libraries that were subsequently sequenced using the Illumina Nextseq 550.417 lncRNAs that showed differentially expressed between CC patients who responded or not to treatment. Further analysis demonstrated that these lncRNAs significantly interact with several molecules, which play crucial roles in CC progression and therapeutic resistance. Statistical analysis correlated the expression profile of these lncRNAs with treatment efficacy. Three lncRNAs, ENSG00000267838, ENSG00000266340, and FRMD6-AS1, were identified with positive expression related to non-response to chemoradiotherapy and worse progression-free survival in CC patients. Specifically, lncRNA ENSG00000267838 has its up-regulation related to non-response and down-regulation to response to chemoradiotherapy treatment.

Progression from Non-alcoholic Steatohepatitis to Advanced Liver Diseases and Mortality Among Medicare Patients.

Non-alcoholic steatohepatitis (NASH) may progress to more advanced liver disease. This study aimed to characterize NASH progression and mortality in the Medicare population. Patients with NASH in 100% Medicare fee-for-service claims accrued from2015-2021 who were≥66years old at index diagnosis, continuously enrolled for≥12months prior to and≥6months following index (unless death), and had no evidence of other causes of liver disease were included. Diagnosis codes defined severity states: non-cirrhotic NASH, compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), and liver transplant (LT). Survival analyses of disease progression and mortality were conducted for each state and by year of progression (Y1-5). Cox proportional hazards models assessed risk factors of worsening disease. Mean age and follow-up were 72.2 and 2.8years in 14,806 unique patients (n=12,990 NASH; 1899 CC; 997 DCC; 209 HCC; 140 LT). Progression rates were highest for patients with CC (11-37% for Y1-5), followed by DCC (3-18%), NASH (3-12%), and HCC (2-4%). Mortality rates were highest for patients with HCC (41-85% for Y1-5), followed by DCC (41-76%), LT (7-33%), CC (6-26%), and NASH (2-12%). Patients with any disease progression had a 5-year mortality rate more than double that of patients without progression (41% vs. 16%). Delayed progression from NASH was associated with lower mortality risk; the 5-year mortality rate was 26% lower for patients with progression in Y2 vs. Y1 (32% vs. 43%) and further decreased for progression in Y3-Y5. Risk factors included age, nursing home use, congestive heart failure, coagulopathy, fluid/electrolyte disorders, and unexplained weight loss. Medicare patients≥66years with NASH experience high risk of disease progression associated with increased mortality rates. Slower disease progression is associated with lower mortality rates, suggesting that therapies that can delay or prevent NASH progression may reduce morbidity and mortality.

Measurable residual disease by mass spectrometry and next-generation flow to assess treatment response in myeloma

AbstractQuantitative immunoprecipitation mass spectrometry (QIP-MS) allows the identification of the M-protein in patients with multiple myeloma (MM) otherwise in complete response, and could be considered suitable for measurable residual disease (MRD) evaluation in peripheral blood. In the context of the GEM2012MENOS65 and GEM2014MAIN trials, we compared the performance of QIP-MS in serum with next-generation flow (NGF) cytometry in bone marrow to assess MRD in paired samples obtained postinduction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate 2 groups of patients with significantly different progression-free survival; when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared with sustaining or converting to MRD positivity. Reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieves similar prognostic value based in single time point assessments and kinetics. Thus, the minimally invasive nature of MRD monitoring by MS represents a breakthrough in highly sensitive response assessment in MM. The trials were registered at www.clinicaltrials.gov as #NCT01916252 (GEM2012MENOS65) and at EudraCT as #2012-005683-10; and as #NCT02406144 (GEM2014MAIN) and at EudraCT as 2014-00055410.

Differences in Clinical Outcomes and Survival Among Primary, Secondary, and Concomitant Carcinoma In Situ of the Bladder.

Carcinoma in situ (CIS) is a flat, high-grade, and aggressive form of urothelial carcinoma with a high risk of progression to muscle-invasive disease and metastasis. This study aimed to investigate differences in clinical outcomes and survival among patients with primary, secondary, and concomitant CIS of the bladder. A total of 209 patients diagnosed with CIS between 2010 and 2022 in our department with a minimum follow-up of 12 months were retrospectively analyzed. Patients with muscle-invasive cancer at diagnosis, those with recurrence within one month after diagnosis, and those with primary malignant melanoma were excluded. The recurrence, progression, and cancer-specific mortality rates of patients receiving Bacillus Calmette-Guérin therapy for CIS were analyzed. A total of 96 patients with primary (n = 18), secondary (n = 29), and concomitant CIS (n = 49) were included in the analysis. The median follow-up was 52.2 months. Patients with secondary CIS had a significantly higher recurrence rate than those with concomitant CIS (58.6% vs. 32.7%, p = 0.016). However, no significant difference in progression rates was observed among the three groups. Furthermore, no significant association was observed between CIS subtypes and recurrence-free survival (RFS) (HR = 1.45, 95% CI 0.96-2.46, p = 0.16) or progression-free survival (PFS) (HR = 2.20, 95% CI 0.99-4.87, p = 0.054). Secondary CIS had a significantly higher recurrence rate than concomitant CIS. However, no statistically significant association was observed between CIS subtypes and RFS or PFS.

Structural and functional alterations in hematological parameters among individuals at clinically high risk for acute lymphocytic leukemia

Abstract: Acute lymphocytic leukemia (ALL) is a diverse category of hematological malignancies defined by the clonal proliferation of immature lymphoid cells. While advances in diagnostic procedures and treatment modalities have improved results for many patients, a group of them exhibit clinical characteristics that indicate a high risk of disease progression and unfavorable consequences. Understanding the underlying molecular processes and developing accurate prognostic indicators in this high-risk group is critical for personalized treatment approaches and better patient outcomes. Hematological markers, immunophenotyping profiles, and chromosomal defects in people who were clinically high risk (CHR) for ALL are discussed in this review. Alterations in hematological markers, such as elevated white blood cell counts, decreased hemoglobin levels, and thrombocytopenia, are indicative of the aggressive nature of high-risk ALL. Immunophenotyping investigations revealed abnormal expression patterns of lineage-specific markers, indicating clonal proliferation and differentiation arrest. Furthermore, cytogenetic examination revealed frequent chromosomal defects, such as the Philadelphia chromosome and hyperdiploidy, which have been linked to a poor prognosis in ALL patients. The combination of hematological, immunophenotypic, and cytogenetic data gives a thorough knowledge of disease biology and assists in risk assessment for patients with CHR for ALL. The present review elucidates the intricate interaction of hematological, immunophenotypic, and cytogenetic abnormalities in persons at clinically high risk for ALL, emphasizing the importance of integrated diagnostic techniques to enhance patient outcomes and optimize treatment strategies.

Relationship between hypertransmission defect size and progression in eyes with intermediate age-related macular degeneration.

To determine the associations between the presence of various-sized hypertransmission defects (hyperTDs) and progression to incomplete retinal pigment epithelial (RPE) and outer retinal atrophy (iRORA) and complete RORA (cRORA) in eyes with intermediate age-related macular degeneration (iAMD). Optical coherence tomography (OCT) data from consecutive iAMD patients, were retrospectively reviewed. All of iAMD eyes with or without iRORA (but not cRORA) at baseline were included. Graders evaluated the presence of hyperTDs at baseline (small: 63-124 µm; medium: 125-249 µm; large: ≥250 µm in diameter on choroidal en face OCT) and the progression two years later. Of the 145 eyes that not developed neovascular AMD at two years, the eyes that progressed to or developed iRORA or cRORA included 13 eyes (10.7%), 5 eyes (83.3%), 9 eyes (81.8%), and 6 eyes (85.7%) in the groups with no, small, medium, and large hyperTDs at baseline, respectively (P-value < 0.001). The odds ratios (95% CI) for progression were 41.6 (4.5-383.6), 37.4 (7.3-192.0), and 49.9 (5.6-447.1) in the small, medium, and large hyperTDs groups, compared to no hyperTDs (P-value ≤ 0.001). Eyes with ≥2 hyperTDs also showed more frequent progression than eyes with one or no hyperTDs (100% vs. 16.4%; P-value < 0.001). While most iAMD eyes with no hyperTDs remained stable on OCT over two years, eyes with hyperTDs of any size appeared to be at a higher risk for progression. HyperTDs may provide an important OCT biomarker for identifying high-risk iAMD patients.

P53 Abnormal Oral Epithelial Dysplasias are Associated With High Risks of Progression and Local Recurrence—A Retrospective Study in a Longitudinal Cohort

Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by 2 pathologists (Y.C.K.K., C.F.P.) blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (P < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence–free survival compared with p53 wild-type OED (P = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade.

Current status and clinical outcomes of pharmacotherapies according to SARS-CoV-2 mutations in patients with mild-to-moderate COVID-19: a retrospective single center study

BackgroundDuring the pandemic period, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutated, leading to changes in the disease’s severity and the therapeutic effect of drugs accordingly. This study aimed to present the actual use of therapeutics and clinical outcomes based on the prevalence of each variant using real-world data.MethodsWe analyzed the electronic medical records of adult patients admitted to Busan Medical Center after confirming coronavirus disease 2019 (COVID-19) from February 1, 2020, to June 30, 2022. Patients with mild-to-moderate COVID-19 who were at a high risk of disease progression were selected as study subjects, and the time period was classified according to the variants as ancestral strain, Delta variant, or Omicron variant. We compared drug use status and clinical outcomes by time period.ResultsAmong all 3,091 patients, corticosteroids were the most commonly used therapy (56.0%), being used most frequently in the Delta variant (93.0%), followed by the Omicron variant (42.9%) and ancestral strain (21.2%). Regdanvimab accounted for the majority of therapeutic use in the Delta variant (82.9%) and ancestral strain (76.8%), whereas remdesivir was most frequently used during the Omicron variant period (68.9%). The composite outcomes of death or disease aggravation were ranked in the order of the Delta variant, Omicron variant, and ancestral strain (14.5, 11.9, and 6.0%, respectively, P < 0.001).ConclusionRegdanvimab was primarily used during the ancestral strain period, regdanvimab plus corticosteroids during the Delta variant period, and remdesivir during the Omicron variant period. The rate of death or disease aggravation was highest in the Delta variant, followed by the Omicron variant and the ancestral strain.

FIB-4 Reliability in Patients With Severe Obesity: Lower Cutoffs Needed?

Liver biopsy is the gold standard to evaluate hepatic fibrosis; however, it has many drawbacks, especially in patients with severe obesity. Noninvasive testing such as the FIB-4 score is increasingly being used as the initial screening tool to identify patients at risk for advanced fibrosis. The broader applicability of FIB-4 and the precision of its cutoff values remain uncertain in metabolic dysfunction-associated steatotic liver disease and patients with severe obesity. Our study explored the correlation between FIB-4 scores and intraoperative liver biopsy in patients with severe obesity undergoing bariatric surgery. A total of 632 patients with severe obesity underwent preoperative vibration-controlled transient elastography and intraoperative liver biopsy during bariatric surgery from January 2020 to August 2021. Variables collected included patient demographics, laboratory values, abdominal ultrasound, vibration-controlled transient elastography, and liver biopsy results. ANOVA 1-way test, χ 2 tests, and Fisher exact tests were used for quantitative and qualitative variables, respectively. The 95% CIs for the mean FIB-4 scores were used to generate surrogate cutoff values. The proposed FIB-4 cutoffs for F0-1, F2, F3, and F4 were 0.62 (CI: 0.59, 0.64), 0.88 (0.74, 1.01), 1.24 (0.94, 1.54), and 1.53 (0.82, 2.24), respectively. Area under the curve (AUC) methods were used to compare traditional to proposed cutoff values. Applying the traditional FIB-4 cutoffs to approximate advanced fibrosis yielded an AUC of 0.5748. Use of the proposed FIB-4 cutoffs increased the AUC to 0.6899. The proposed FIB-4 cutoffs correctly identified 40 patients with biopsy-proven advanced fibrosis (F3-F4), all of which would have been missed using traditional cutoffs. Our study revealed that the use of the currently accepted FIB-4 cutoffs as the screening modality for identifying patients with advanced fibrosis due to metabolic dysfunction-associated steatotic liver disease is insufficient and will result in missing patients with histologically confirmed advanced fibrosis. Use of the revised FIB-4 scores should be considered to diagnose patients with severe obesity at high risk of liver disease progression.

Lab-on-a-chip models of cardiac inflammation.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with numerous inflammatory cell etiologies associated with impaired cardiac function and heart failure. Inflammatory cardiomyopathy, also known as myocarditis, is an acquired cardiomyopathy characterized by inflammatory cell infiltration into the myocardium with a high risk of progression to deteriorated cardiac function. Recently, amidst the ongoing COVID-19 pandemic, the emergence of acute myocarditis as a complication of SARS-CoV-2 has garnered significant concern. Given its mechanisms remain elusive in conjunction with the recent withdrawal of previously FDA-approved antiviral therapeutics and prophylactics due to unexpected cardiotoxicity, there is a pressing need for human-mimetic platforms to investigate disease pathogenesis, model dysfunctional features, and support pre-clinical drug screening. Traditional in vitro models for studying cardiovascular diseases have inherent limitations in recapitulating the complexity of the in vivo microenvironment. Heart-on-a-chip technologies, combining microfabrication, microfluidics, and tissue engineering techniques, have emerged as a promising approach for modeling inflammatory cardiac diseases like myocarditis. This review outlines the established and emerging conditions of inflamed myocardium, identifying key features essential for recapitulating inflamed myocardial structure and functions in heart-on-a-chip models, highlighting recent advancements, including the integration of anisotropic contractile geometry, cardiomyocyte maturity, electromechanical functions, vascularization, circulating immunity, and patient/sex specificity. Finally, we discuss the limitations and future perspectives necessary for the clinical translation of these advanced technologies.

Hysterectomy Rate Following Endometrial Ablation in Ontario: A Cohort Analysis of 76,446 Patients

Background: Endometrial Ablation (EA) is an alternative to hysterectomy for the management of abnormal uterine bleeding (AUB); however, it does not eliminate the need for future surgical re-intervention. Objectives: The primary objective of this study was to establish long-term clinical outcomes including the risk of hysterectomy in women who had undergone a primary EA. Materials and Methods: This is a retrospective population-based cohort study utilising administrative data from the Canadian province of Ontario. This study assesses patients undergoing surgery in a publicly funded health care system. Main Outcome Measures: We assessed women in Ontario undergoing a primary EA over a 15-year period. The primary outcome was hysterectomy within 5 years of primary EA. Secondary outcomes included myomectomy and repeat EA. All outcomes were also reported for 1, 3, 5, 10 and 15 years of follow-up. Logistic regression was used to establish predictors of hysterectomy within 5 years of primary EA. Results: A total of 76,446 primary EAs were evaluated from 2002-2017, with 16,480 (21.56%) undergoing a subsequent surgical intervention. The average age of primary EA was 43.8 (+/- 6.3) years. Within 5 years, the evaluable cohort was 52,464, with 8,635 (16.46%) of women having proceeded to hysterectomy, 664 (1.27%) to myomectomy, and 2,468 (2.8%) to repeat ablation. By 15-years follow-up, the evaluable cohort was 1,788, with 28.75% had undergone a hysterectomy, 2.01% a myomectomy, and 5.20% a repeat EA. On logistic regression analysis, advancing age at time of EA was associated with significantly decreased odds of hysterectomy (OR=0.94, 95% CI 0.935-0.944, p&lt;.0001) as was increasing surgical experience (OR=0.997, 95% CI 0.994-1.000, p=.022). Conversely, complex diagnosis (OR=1.102, 95% CI 1.042-1.164, p&lt;.0001) and previous abdominal surgery (OR=1.288, 95% CI 1.222-1.357, p&lt;0.0001) were associated with increased risk of subsequent hysterectomy. Conclusion: Primary EA is associated with a high risk of progression to subsequent hysterectomy or other surgical intervention, without evidence of plateau of risk with long term follow-up. What is new? This study has the longest follow-up assessing hysterectomy outcomes in women undergoing a primary EA, with 28.75% of women having undergone a hysterectomy within 15 years of their EA.

Hysterectomy Rate Following Endometrial Ablation in Ontario: A Cohort Analysis of 76,446 Patients

Background: Endometrial Ablation (EA) is an alternative to hysterectomy for the management of abnormal uterine bleeding (AUB); however, it does not eliminate the need for future surgical re-intervention. Objectives: The primary objective of this study was to establish long-term clinical outcomes including the risk of hysterectomy in women who had undergone a primary EA. Materials and Methods: This is a retrospective population-based cohort study utilising administrative data from the Canadian province of Ontario. This study assesses patients undergoing surgery in a publicly funded health care system. Main Outcome Measures: We assessed women in Ontario undergoing a primary EA over a 15-year period. The primary outcome was hysterectomy within 5 years of primary EA. Secondary outcomes included myomectomy and repeat EA. All outcomes were also reported for 1, 3, 5, 10 and 15 years of follow-up. Logistic regression was used to establish predictors of hysterectomy within 5 years of primary EA. Results: A total of 76,446 primary EAs were evaluated from 2002-2017, with 16,480 (21.56%) undergoing a subsequent surgical intervention. The average age of primary EA was 43.8 (+/- 6.3) years. Within 5 years, the evaluable cohort was 52,464, with 8,635 (16.46%) of women having proceeded to hysterectomy, 664 (1.27%) to myomectomy, and 2,468 (2.8%) to repeat ablation. By 15-years follow-up, the evaluable cohort was 1,788, with 28.75% had undergone a hysterectomy, 2.01% a myomectomy, and 5.20% a repeat EA. On logistic regression analysis, advancing age at time of EA was associated with significantly decreased odds of hysterectomy (OR=0.94, 95% CI 0.935-0.944, p&lt;.0001) as was increasing surgical experience (OR=0.997, 95% CI 0.994-1.000, p=.022). Conversely, complex diagnosis (OR=1.102, 95% CI 1.042-1.164, p&lt;.0001) and previous abdominal surgery (OR=1.288, 95% CI 1.222-1.357, p&lt;0.0001) were associated with increased risk of subsequent hysterectomy. Conclusion: Primary EA is associated with a high risk of progression to subsequent hysterectomy or other surgical intervention, without evidence of plateau of risk with long term follow-up. What is new? This study has the longest follow-up assessing hysterectomy outcomes in women undergoing a primary EA, with 28.75% of women having undergone a hysterectomy within 15 years of their EA.

Disease severity and activity in bronchiectasis: A paradigm shift in bronchiectasis management.

Bronchiectasis has an increasing prevalence and substantial clinical and economic burden. Therefore, physicians should identify patients with bronchiectasis at high risk of disease progression to ensure optimal management in advance. The heterogeneity of bronchiectasis means it is unlikely that any single parameter could identify high-risk patients, therefore disease severity is usually assessed using validated composite tools, such as the Bronchiectasis Severity Index, FACED, and Bronchiectasis Aetiology Comorbidity Index, to predict long-term outcomes in bronchiectasis. Disease severity, however, implies an advanced process with lung destruction. Earlier intervention may prevent disease progression and improve outcomes. To identify patients at risk, rather than patients with established advanced disease, we need to shift our focus from disease severity to disease activity. Disease activity denotes the activation level of underlying pathophysiological processes and can be measured using clinical presentations and biomarkers. This review discusses a paradigm shift in bronchiectasis management, focusing on disease activity rather than severity, to prevent disease progression.