Natural History Of Patients Research Articles

Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial.

LMNA-related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM-DCM trial evaluated a potential disease-modifying therapy for LMNA-related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM-DCM to descriptively characterize the phenotype and progression of LMNA-related DCM in a contemporary cohort of patients using common heart failure (HF) measures. REALM-DCM enrolled patients with stable LMNA-related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Between 2018 and 2022, 77 patients took part in REALM-DCM. The median patient age was 53years (range: 23-72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at baseline were 42% (23-62), 403m (173-481), 67 (18-97) and 866pg/mL (57-5248), respectively. LVEF, 6MWT distance and KCCQ-OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413m; and KCCQ-OS score: 43 vs. 70), whereas NT-proBNP concentration was higher (1216 vs. 799pg/mL). Median follow-up was 73weeks (range: 0.4-218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ-OS and NT-proBNP values during follow-up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF-related hospitalization or urgent care visit) or all-cause death; six had NYHA Class II and four had NYHA Class III at baseline. All-cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Findings confirm the significant morbidity and mortality associated with LMNA-related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ-OS score and NT-proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA-related DCM. NCT03439514.

Epidemiology of Elderly Onset IBD: A Nationwide Population-Based Cohort Study

We examined the incidence and natural history of patients with very elderly onset (herein referred to as very late-onset) inflammatory bowel diseases (IBDs) (≥ 70 years of age at diagnosis), compared with patients diagnosed between 60 and 69 years of age in Denmark. In the Danish National Patient Register, between 1980 and 2018, we identified all individuals ≥ 60 years of age with newly diagnosed Crohn's disease (CD) and ulcerative colitis (UC) and examined trends in incidence, cumulative risk of hospitalization, treatment patterns, IBD-related surgery, serious infection, cancer and cardiovascular and venous thromboembolic risks among very late-onset (70-79 years of age or 80+ years) vs late-onset (60-69 years of age) IBD, using nonparametric competing risk analysis treating death as competing risk. We identified 3459 patients with onset of CD at ≥60 years of age (47% ≥ 70 years of age) and 10,774 patients with onset of UC ≥60 years of age (51% ≥ 70 years of age). Over the last 3 decades, incidence changes for very late-onset and late-onset IBD have followed the same patterns. Also, both for CD and UC, cumulative incidence of IBD-related hospitalization and corticosteroid use was comparable in very late-onset vs late-onset patients. However, the burden of disease-modifying therapy, either immunomodulator or tumor necrosis factor antagonist use, and major IBD-related surgery was significantly lower in patients with very late-onset than in late-onset IBD. On the other hand, the 5-year risk of serious infections and cardiovascular events was higher in patients with very late-onset IBD. This nationwide cohort study shows that patients diagnosed with very late-onset (≥ 70 years of age) IBD have a higher relative burden of disease- and aging-related complications, with limited use of steroid-sparing strategies and surgery, compared with late-onset IBD.

Natural history of initially asymptomatic severe aortic stenosis: a one-stage meta-analysis.

Current guidelines on the management strategy for patients with asymptomatic severe aortic stenosis (AS) remain unclear. This uncertainty stems from the lack of data regarding the natural history of these patients. To address this gap, we performed a systematic review and meta-analysis examining the natural history of asymptomatic severe AS patients receiving conservative treatment. The PubMed, Cochrane, and Embase databases were searched from inception to 24 January 2024 using the keywords "asymptomatic" AND "aortic" AND "stenosis". We included studies examining patients with asymptomatic severe AS. In interventional trials, only data from conservatively managed arms were collected. A one-stage meta-analysis was conducted using individual patient data reconstructed from published Kaplan-Meier curves. Sensitivity analysis was performed for major adverse cardiovascular outcomes in patients who remained asymptomatic throughout follow-up. A total of 46 studies were included (n = 9545). The median time to the development of symptoms was 1.11years (95% CI 0.90-1.53). 49.36% (40.85-58.59) of patients who were asymptomatic had suffered a major adverse cardiovascular event by 5years. The median event-free time for heart failure hospitalization (HFH) was 5.50years (95% CI 5.14-5.91) with 36.34% (95% CI 33.34-39.41) of patients experiencing an HFH by year 5. By 5years, 79.81% (95% CI 69.26-88.58) of patients developed symptoms (angina, dyspnoea, syncope and others) and 12.36% (95% CI 10.01-15.22) of patients died of cardiovascular causes. For all-cause mortality, the median survival time was 9.15years (95% CI 8.50-9.96) with 39.43% (CI 33.41-36.40) of patients dying by 5years. The median time to AVR was 4.77years (95% CI 4.39-5.17), with 52.64% (95% CI 49.85-55.48) of patients requiring an AVR by 5years. Our results reveal poor cardiovascular outcomes for patients with asymptomatic severe AS on conservative treatment. A significant proportion eventually requires an AVR. Further research is needed to determine if early intervention with AVR is more effective than conservative treatment.

Long-Term Natural History of Presumptive Diverticular Hemorrhage.

The natural history of patients with well-documented presumptive diverticular hemorrhage (TICH) is unknown. Our aims are to report (i) rebleeding rates and clinical outcomes of presumptive TICH patients with and without rebleeding, (ii) conversion to definitive TICH during long-term follow-up (F/U), and (iii) risk factors of presumptive diverticular (TIC) rebleeding. This was a retrospective cohort study of prospectively collected results of presumptive TICH patients from 1994 to 2023. Presumptive TICH was diagnosed for patients with TICs without stigmata of recent hemorrhage and no other cause of bleeding found on anoscopy, enteroscopy, capsule endoscopy, computed tomography angiography, or tagged red blood cell scan. Patients with ≤6 months of F/U were excluded. Of 139 patients with presumptive TICH, 104 were male and 35 female. The median age was 76 years. There were no significant differences in baseline demographics of rebleeders and non-rebleeders. During long-term median F/U of 73 months, 24.5% (34/139) rebled. A total of 56% (19/34) of rebleeders were diagnosed as definitive TICH, and they had significantly higher rates of readmission ( P < 0.001), reintervention ( P < 0.001), and surgery ( P < 0.001). During F/U, there were significantly higher rates of newly diagnosed hypertension and/or atherosclerotic cardiovascular disease in rebleeders ( P = 0.033 from a logistic model). All-cause mortality was 42.8%, but none was from TICH. For presumptive TICH during long-term F/U, (i) 75.5% did not rebleed and 24.5% rebled. (ii) 56% of rebleeders were diagnosed as definitive TICH. (iii) New development of hypertension and atherosclerotic cardiovascular disease were risk factors of TIC rebleeding.

Familial Mediterranean fever in patients with inflammatory bowel diseases: A nationwide study from the epi-IIRN.

Inflammatory Bowel Diseases (IBD) and Familial Mediterranean Fever (FMF) are auto-inflammatory diseases with common clinical and biological features. We aimed to determine their association and characterize the natural history in patients with both diagnoses. Utilizing data from the epi-IIRN cohort, which includes 98% of Israel's population, we calculated the adjusted prevalence of FMF among IBD patients vs non-IBD controls. Case ascertainment of IBD was determined according to validated algorithms and for FMF by ICD-9 codes and colchicine purchase. In total, 34 375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93 602 matched controls. Among IBD patients, 157 (0.5%) had FMF compared with 160 (0.2%) of non-IBD controls (OR = 2.68 [95%CI 2.2-3.3]; p< 0.001). Pediatric-onset IBD had a higher prevalence of FMF compared with adult-onset IBD (30/5,243 [0.6%] vs 127/29 132 [0.4%]), without statistical significanse (OR = 1.31 [0.88-1.96]; p= 0.2). FMF was more prevalent in CD (114/19 264 [0.6%]) than UC (43/15 111 [0.3%]; OR = 2.1 [1.5-3.0]), p< 0.001). FMF diagnosis preceded that of IBD in 130/157 cases (83%). FMF was associated with a more severe disease activity in UC patients at diagnosis, but not in CD patients. Outcomes were comparable between patients with CD+FMF vs CD alone; however in patients with UC+FMF, time to biologic treatment was shorter. FMF is more prevalent in IBD patients than in the general population, particularly in CD. The diagnosis of FMF precedes the diagnosis of IBD in most cases, and may be associated with a more severe course in UC.

Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis

Indigo naturalis is an effective treatment for ulcerative colitis. However, long-term use of indigo naturalis causes adverse events, such as pulmonary hypertension. The natural history of patients with ulcerative colitis who discontinued indigo naturalis after induction therapy is unknown. Moreover, the clinical features of patients who relapsed within 52 weeks after the discontinuation of indigo naturalis are unclear. This study aimed to assess the clinical outcomes of patients with ulcerative colitis after discontinuation of indigo naturalis and to identify potential markers responsible for relapse. This single-center retrospective study investigated the follow-up of 72 patients who achieved a clinical response 8 weeks after indigo naturalis treatment. We observed relapse in patients with ulcerative colitis after the discontinuation of indigo naturalis. We analyzed the factors predicting long-term outcomes after discontinuation of indigo naturalis. Relapse was observed in 24%, 57%, and 71% of patients at 8, 26, and 52 weeks, respectively. There were no predictive markers in patients who relapsed within 52 weeks after the discontinuation of indigo naturalis. The ulcerative colitis relapse rate after indigo naturalis discontinuation was high. Follow-up treatment is required after the discontinuation of indigo naturalis in patients with ulcerative colitis.

The Role of Transjugular Intrahepatic Portosystemic Shunt for the Management of Ascites in Patients with Decompensated Cirrhosis.

The development and progression of ascites represent a crucial event in the natural history of patients with cirrhosis, predisposing them to other complications and carrying a heavy impact on prognosis. The current standard of care for the management of ascites relies on various combinations of diuretics and large-volume paracenteses. Periodic long-term albumin infusions on top of diuretics have been recently shown to greatly facilitate the management of ascites. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS), an artificial connection between the portal and caval systems, is indicated to treat patients with refractory ascites. TIPS acts to decrease portal hypertension, thus targeting an upstream event in the pathophysiological cascade of cirrhosis decompensation. Available evidence shows a significant benefit on ascites control/resolution, with less clear results on patient survival. Patient selection plays a crucial role in obtaining better clinical responses and avoiding TIPS-related adverse events, the most important of which are hepatic encephalopathy, cardiac overload and failure, and liver failure. At the same time, some recent technical evolutions of available stents appear promising but deserve further investigations. Future challenges and perspectives include (i) identifying the features for selecting the ideal candidate to TIPS; (ii) recognizing the better timing for TIPS placement; and (iii) understanding the most appropriate role of TIPS within the framework of all other available treatments for the management of patients with decompensated cirrhosis.

Surgical Management of a Thalamic Arteriovenous Malformation in a Young Male in a Low Resource Setting: An Illustrative Case Report

Introduction: The natural history of patients with arteriovenous malformations (AVMs) suggests that 10-17% die due to hemorrhage and 40-50% experience serious physical deterioration of their working capacity in their 20-40-year period after presentation and treatment. Deep basal ganglia and thalamus lesions account for 3-12% of all AVMs and some literature suggests that these lesions have a more hostile clinical course. Case Presentation: 16-year-old male, a student with no known chronic illnesses came to our hospital as a referral from Lubaga hospital. He presented with fifteen days’ history of sudden onset of severe headache with no known relieving or exacerbating factors. This was associated with episodes of vomiting, altered mentation, right sided weakness, however there was no history of convulsions, blurring of vision or trauma. This was the first time for this kind of presentation. On admission: He was lethargic, moderately dehydrated, not pale nor jaundiced. BP was 109/52mmHg, HR of 60bpm, SPO2=96% on room air. Glasgow Coma Scale score of 14/15, V=4, PEAL, soft neck, normal muscle bulky with a power of 2/5 on the left side and 4/5 on the right side. Successful surgical resection of the AVM was done at Mbarara regional referral Hospital-Uganda. Currently the patient is back in the community and has returned to school. Conclusion: Children who present with intracranial hemorrhage from a previously undiagnosed AVM have a 12% chance of sudden death. Clinical triggers of hemorrhage are unpredictable, and all fatal cases were in locations with high risk of potential herniation. These data support a proactive, aggressive approach toward definitive treatment of AVMs in children and adults. Patients with diagnosed AVM can once again get a chance to survive like other children in the community in LMICs like Uganda by undergoing open surgery, although advanced opportunities are still limited.

The Disease Spectrum and Natural History of Patients With Abdominal Bloating or Distension: A Longitudinal Study.

Abdominal bloating or distension (AB/D) is a common complaint in the outpatient of gastroenterology department. Since the potential contributors are numerous and complex, a longitudinal study on the disease spectrum and natural history of patients was performed to better understand the key factors of AB/D. Consecutive patients with the chief complaint of AB/D referred to the outpatient clinic were screened. Functional gastrointestinal disorders (FGIDs) were diagnosed according to Rome IV criteria. A 3-year follow-up was performed to seek for the changes in symptoms as well as disease spectrum. A total of 261 participants were enrolled and 139 completed the follow-up. Most patients suffered from moderate to severe symptoms more than 1 day per week. Common causes of AB/D were FGIDs (51.7%) and organic diseases (17.2%). The latter group was older with lower body mass index (BMI). Functional dyspepsia was the most common type of FGIDs in AB/D. The symptoms of 18.0% of participants failed to improve at the end of the 3-year follow-up, and those diagnosed with FGIDs were most likely to continue to suffer. Abdominal pain was a positive predictive factor for good prognosis in the FGIDs group. Besides, only 22.7% of participants had a consistent diagnosis of FGIDs during follow-up. FGIDs are the most common diagnosis in patients with AB/D. Symptoms were especially hard to be improved. Classification diagnoses of FGIDs in AB/D patients fluctuated significantly over time.

Evaluation of autoimmune liver disease natural history in patients referred to Middle East Liver Diseases (MELD) center

BackgroundAutoimmune liver diseases (AILD) are increasing and common forms of chronic liver disease (CLD) with different clinical responses and characteristics which can result in cirrhosis. This study aimed to investigate the natural history and characteristics of AILD in an Iranian population.MethodsPatients with AILD [Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Overlap Syndrome (OS)] referred to Middle East Liver Diseases (MELD) center, Tehran, Iran, between January 2002 and December 2022 were included in this retrospective cohort study. The main features of natural history (the trends of liver functional tests (LFT), Auto-Antibodies, response to treatment and cirrhotic status) along with demographic data were studied.ResultsTwo hundred sixty-five patients (160 (60.4%) AIH, 37 (14.0%) PBC, 20 (7.5%) PSC, 48 (18.1%) overlap syndrome) with a median follow-up time of 5 years (IQR 4 to 8 years) were included. Baseline laboratory tests revealed that patients with AIH exhibit elevated transaminase levels. However, patients suffering from PBC and PSC displayed increased alkaline phosphatase levels. Conversely, in overlap syndrome patients, both transaminases and alkaline phosphatase were observed at high levels. Autoantibodies represented themselves as important diagnostic markers for the AIH and PBC but not for PSC. The complete response occurred in 112 (70%) of and 28 (58.4%) patients with AIH and overlap syndrome respectively and 21 patients 11 (6.9%) of AIH and 10 (20.8%) of overlap syndrome) were non-responders. Other patients in these two categories were considered as insufficient responders. On the other side, 32 (91.9%) and 8 (40%) of patients with PBC and PSC biochemically responded to Ursodeoxycholic Acid (UDCA). Unpredictably, cirrhosis regression was observed in some AIH and PBC patients.ConclusionAppropriate medication management for AILD patients may leads to regression from cirrhosis and improvement of manifestations; while discontinuation of medication may cause relapses. However, patient suffering from PSC showed limited response to treatment.

Characteristics and Survival Outcomes of Patients With Metastatic RET Fusion-Positive Solid Tumors Receiving Non-RET Inhibitor Standards of Care in a Real-World Setting.

RET fusions are oncogenic drivers across different solid tumors. However, the genomic landscape and natural history of patients with RET fusion-positive solid tumors are not well known. We describe the clinical characteristics of RET tyrosine kinase inhibitor (TKI)-naïve patients with RET fusion-positive solid tumors (excluding non-small-cell lung cancer [NSCLC]), treated in a real-world setting and assess the prognostic effect of RET fusions. Data for RET TKI-naïve patients with metastatic solid tumors (excluding NSCLC) who had ≥one Foundation Medicine comprehensive genomic profiling test (January 1, 2011-March 31, 2022) were obtained from a deidentified nationwide (US-based) clinicogenomic database. The primary objective of this study was to compare the overall survival (OS) of patients with RET fusion-positive tumors versus matched patients with RET wild-type (RET-WT) tumors. Patients with RET-WT solid tumors were matched (4:1) to patients with RET fusion-positive tumors on the basis of preselected covariates. The study population included 26 patients in the RET fusion-positive cohort, 7,220 patients in the RET-WT cohort (before matching), and 104 patients in the matched RET-WT cohort. Co-occurring genomic alterations were rare in the RET fusion-positive cohort. Median OS was consistently lower in patients with RET fusion-positive tumors versus those with RET-WT tumors, using three different analyses (hazard ratios, 2.0, 1.7, and 2.2). These data suggest that RET fusions represent a negative prognostic factor in patients with metastatic solid tumors and highlight the need for wider genomic testing and use of RET-specific TKIs that could improve patient outcomes. Our study also highlights the value of real-world data when studying rare cancers or cancers with rare genomic alterations.

Genotypic diversity and long-term impact of human bocavirus on diarrheal disease: Insights from historical fecal samples in Brazil.

This study aimed to investigate the frequency and genotypic diversity of human bocavirus (HBoV) in historical fecal samples collected before 2005 in Brazil and understand its natural history in patients with diarrhea. Between 1998 and 2005, 3347 samples were tested for HBoV by RT-PCR, with a detection rate of 5.8% (195/3347). Coinfection with norovirus (NoV) and human adenovirus (HAdV) was found in 34.9% (68/195), indicating HBoV's potential role as a causative agent of diarrheal disease. The detection rate varied over the years (p < 0.05), suggesting natural oscillatory fluctuations. HBoV was more prevalent in fall and winter, with higher positivity in children ≤5 years (p < 0.05), reinforcing that HBoV is an important pathogen in childhood diarrhea. Genotyping (32.8%; 64/195) revealed the circulation of HBoV-1 (79.7%, 51/64), HBoV-3 (12.5%, 8/64), HBoV-2 (6.2%, 4/64), and the rare HBoV-4 (1.6%, 1/64). Difference in HBoV-1 and HBoV-2/-3 mono-infections prevalence (p < 0.05), suggests a potential role of HBoV-1 in the pathogenicity of diarrheal disease. The study highlights HBoV's lasting impact on viral gastroenteritis in Brazil and emphasizes its genotypic diversity. Recommending screening for HBoV in public health laboratories is crucial for understanding its role in gastrointestinal diseases. The data also contribute to understanding the molecular characterization of enteric viruses in historical fecal samples.

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort.

Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.

Accelerated Progression in Lower-Risk Myelodysplastic Neoplasms: Attenuated Cell Cycle, DNA Damage Response, and Augmented Oncogenic Transcriptome Signatures

Patients with myelodysplastic neoplasms (MDS) face the risk of transformation to acute myeloid leukemia (AML). Although prognostic scoring systems exist for risk stratification and treatment decision making in MDS patients (Garcia-Manero G. Am J Hematol. 2023;98(8):1307-1325), disease management remains challenging due to the heterogeneity of clinical courses and long-term outcomes. The natural history of patients with lower-risk MDS (LR-MDS) is very heterogeneous and some LR-MDS patients experience rapid progression despite a generally favorable prognosis. The aim of our study was to uncover the molecular mechanisms underlying accelerated progression in hematopoietic stem/progenitor cells of patients with LR-MDS regardless of driver mutations. We focused on the transcriptome of bone marrow (BM) CD34 + cells from diagnostic samples using RNA-seq and used various bioinformatic pipelines to examine differentially expressed protein-coding genes, and long non-coding RNAs (lncRNAs) as well as differential alternative splicing events. RNA-seq dataset of CD34 + ribodepleted RNA samples from 53 LR-MDS patients without accelerated progression (stMDS) and 8 who progressed within 20 months (prMDS) showed 845 differentially expressed genes (ІlogFCІ &amp;gt; 1, FDR &amp;lt; 0.01) between these groups. CD34 + cells of prMDS exhibited a transcriptional pattern of quiescent-like cell state with overall decreased metabolism signatures and significantly reduced lineage differentiation compared to stMDS CD34 + cells. Gene set enrichment analysis (GSEA) showed that cell cycle- and cell cycle checkpoint- associated genes and activation of ATR in response to replication stress were all significantly under-represented in prMDS CD34 + BM (Fig. 1A). Cellular pathways from GO Biological Processes associated with cellular responses to stress and DNA damage responses (DDR) were downregulated in prMDS compared to stMDS. The only GO terms that were significantly upregulated in prMDS were processes related to cell-matrix adhesion or cell-cell adhesion. Indeed, key transcription factor controlling changes in cell-cell adhesion, ZEB1, was significantly overexpressed in prMDS BM CD34 + cells, whereas E-cadherin expression ( CDH1) was decreased; the expression levels of CDH1 and ZEB1 showed a significant moderate negative correlation (Fig. 1B). Additionally, prMDS samples exhibited high levels of aberrant splicing and global lncRNA expression. Analysis of aberrant transcripts, deregulated lncRNAs and their targets suggested their contribution to the attenuation of DDR pathways in prMDS. Given that the downregulation of DDR gene expression was the major feature distinguishing the prMDS CD34 + cell transcriptome from that of stMDS in our cohort, we selected - from the transcriptional profile of the top 50 downregulated genes in GSEA - a prognostic DDR-associated gene signature consisting of 19 genes. Using regularized Cox regression analysis of the expression profile of 19 DDR-associated genes, the probability of a progression-free disease was calculated in our cohort. High DDR gene expressors had a significantly higher probability of progression-free disease (p &amp;lt; 0.001) compared to low DDR gene expressors (Fig. 2A). Among the top 50 upregulated genes in the prMDS vs. stMDS samples, ranked by GSEA, overexpression of previously identified markers of leukemic progression and/or poor MDS/AML survival ( SPNS2, MN1, DOCK1 and others) was demonstrated. Interestingly, overexpression of NEK3, a gene not previously associated with MDS/AML progression, showed a predictive power for accelerated progression in LR-MDS with the best significance of curve separation among the genes tested (Fig. 2B). Furthermore, NEK3 expression was an independent prognostic factor (p&amp;lt;0.001) for progression-free disease in a multivariate analysis of important clinical and genetic factors. To conclude, our data suggest that DDR gene expression signature and NEK3 expression appear to be a significant predictor of LR-MDS progression and may be applicable at the time of diagnosis for the prognostic stratification of patients with LR-MDS, regardless of their mutational status. Supported by AZV (NU21-03-00565) and (NU23-03-00401); MH CZ-DRO (UHKT, 00023736); Program EXCELES, ID Project No. LX22NPO5102, and UP Young Researcher Grant Competition, ID Project JG_2023_016.

Clinical Characteristics and Outcomes in Young-Onset Multiple System Atrophy.

Young-onset multiple system atrophy (YOMSA) is defined as the onset of multiple system atrophy (MSA) before the age of 40 years old. YOMSA is rare and there is much uncertainty of the phenotype and natural history in patients with YOMSA. The objective is to evaluate the characteristics and disease course of patients with YOMSA. We retrospectively reviewed medical records of patients with MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients with YOMSA and evaluated clinical characteristics, autonomic function testing results, and disease course. Of 1496 patients with a diagnosis of clinically probable or clinically established MSA, 20 patients had YOMSA. The median age of onset was 39.1 (interquartile range [IQR] = 37.1, 40.1) years; 13 patients (65%) were male. MSA-parkinsonism was the most common subtype (65%). The median duration of symptom onset to YOMSA diagnosis was 4.9 (IQR = 3.7, 9) years. At the time of medical record review, 17 patients were deceased with a median survival of 8.3 (IQR = 7, 10.9) years. Univariate analysis showed that initial onset of autonomic failure predicted unfavorable survival (hazard ratio = 2.89, P = 0.04) compared to those who presented with motor impairment only at onset. At the time of YOMSA diagnosis, composite autonomic severity score was available in 19 patients with a median of 5 (IQR = 4, 6.5). YOMSA resembles MSA in most aspects including phenotype and prognosis, although the diagnosis is usually delayed. The presence of autonomic failure at symptom onset may be a poor predictor for survival.

Adverse outcomes according to metabolic status in obese and overweight patients with atrial fibrillation: a report from the GLORIA-AF Phase II and III Registry

Abstract Background The "obesity paradox" has been repeatedly described in atrial fibrillation (AF). Metabolic status has been proposed as a potential determinant of cardiovascular risk, particularly in overweight and obese patients, whereby ‘metabolically healthy’ and ‘metabolically unhealthy’ overweight/obesity subgroups can be defined. Purpose We aimed to explore the association between metabolic status, body mass index (BMI) and natural history of patients with recently diagnosed AF. Methods Eligible patients for GLORIA-AF registry Phases II and III were adults (age ≥18) with a recent diagnosis of AF (&amp;lt;3 months before enrolment, or &amp;lt;4.5 months in Latin America) and a CHA2DS2VASc score ≥1. For this analysis, we included patients with BMIs between 18.5 and 60 kg/m2 and with complete data on determinants of metabolic status (hypertension, diabetes mellitus (DM) and hyperlipidemia). We categorised patients according to BMI (normal weight [18.5-24.9 kg/m2], overweight [25.0-29.9 kg/m2], obesity [30.0-60.0 kg/m2]) and metabolic status (unhealthy status defined as the presence of at least one factors among hypertension, DM and hyperlipidemia; healthy status defined as having none of these three factors). We analysed the odds of receiving oral anticoagulant (OAC) and other treatments, as well as the risk of major adverse outcomes, using multivariable Cox regression analyses with a primary outcome of a composite of all-cause death and major adverse cardiovascular events (MACE). Results 24,828 (mean age 70.1±10.3, females 44.6%) patients were included. The most represented group was the overweight unhealthy (8,161, 32.9%), followed by obese unhealthy (7,485, 30.1%), normal weight unhealthy (5,115, 20.6%), normal weight healthy (1,778, 7.2%), overweight healthy (1,508, 6.1%), and obese healthy (781, 3.1%). Among the obese patients, females were mostly metabolically healthy (51.0% vs. 44.9%). Higher BMI was associated with metabolic unhealthy status, and higher odds of receiving OAC (Figure 1; OR (95%CI) for OAC prescription in obese vs. normal weight patients: 2.22 [2.00-2.45]) and other treatments. Compared to normal weight healthy patients, normal weight unhealthy patients showed a higher risk of the primary composite outcome (adjusted Hazard Ratio (aHR): 1.20, 95%CI: 1.01-1.42, p=0.039) and thromboembolism, while no significant difference for the risk of the primary outcome or thromboembolism was observed for the other groups (Figure 2). Metabolically healthy obese group was associated with a reduced risk of cardiovascular death (aHR: 0.35, 95%CI:0.14-0.88, p=0.026) and MACE (aHR:0.56, 95%CI:0.33-0.93, p=0.024). In all weight groups, unhealthy metabolic status was associated with an increased risk of major bleeding. Conclusions Increasing BMI was associated with poor metabolic status, and with more intensive therapeutic management. The risk of outcomes was heterogenous among BMI groups, with metabolically unhealthy subjects having a poorer prognosis.Odds of receiving OAC according to BMIAdjusted Cox regression analysis

Patterns of comorbidities and influence on the natural history of patients with atrial fibrillation: a latent class analysis from a prospective observational european AF registry

Abstract Background Patients with Atrial Fibrillation (AF) usually present with multiple comorbidities at diagnosis, and their combinations heterogeneously influence management and outcomes. While the effect of multimorbidity on the natural history of AF is well-known, the influence of patterns of multimorbidity is far less understood. Purpose To identify and analyse subgroups of AF patients according to their comorbidities, through a latent class analysis of a contemporary cohort of AF patients. Methods We used data from a European-wide prospective observational AF registry, and performed a latent class analysis, according to the presence of chronic diseases (including cardiovascular, respiratory, metabolic and other conditions); class membership was assigned according to the modal posterior probability. Multivariable logistic regression models were used to analyse odds of receiving oral anticoagulant (OAC) prescription and type of OAC received; the risk of the primary outcome of all-cause death and MACE was assessed using multivariable Cox-regression model. Results 9,613 AF patients were included in this analysis (mean age 68.9 ± 11.4 years, 40.2% females), and were grouped in 5 classes, which were different according to the burden of comorbidities: low morbidity pattern (46.1%), cardiovascular pattern (25.0%), metabolic pattern (11.3%), heart failure pattern (9.7%) and multisystemic pattern (8.0%) (Figure 1). Patients in the multisystemic pattern were older and more frequently frail and with polypharmacy compared to other classes. Compared to the low morbidity pattern, odds of receiving OAC was lower in those with cardiovascular pattern (OR [95%CI]: 0.73 [0.62-0.86]), heart failure pattern (OR [95%CI]: 0.60 [0.48-0.75] and multisystemic pattern (OR [95%CI]: 0.28 [0.22-0.36]), while those with metabolic pattern were more likely prescribed OAC (OR [95%CI]: 1.55 [1.20-2.00]). All patterns were less likely treated with NOAC compared to VKA (Figure 2). When analysing the risk of the primary composite outcome, all patterns except for the metabolic pattern were associated with higher hazard of events, with highest magnitude observed for the heart failure pattern (HR 2.68 [95%CI: 2.22-3.25]) and the multisystemic pattern (HR 2.67 [2.13-3.35]) (Figure 2). Conclusions Comorbidities are heterogeneously distributed in the AF population, and different phenotypes of AF patients may be identified according to the combination of other chronic diseases, with different OAC use for stroke prevention and an unequal impact on long-term prognosis. These findings reinforce the need for tailored preventive strategies to improve outcomes in AF patients, especially those with multimorbidity.Figure 1Figure 2

Clinical Outcomes in Metabolically Healthy and Unhealthy Obese and Overweight Patients With Atrial Fibrillation: Findings From the GLORIA-AF Registry

ObjectiveTo explore the association between metabolic status, body mass index (BMI), and natural history of patients with atrial fibrillation (AF). MethodsThe global, prospective GLORIA-AF Registry Phase II and III included patients with recent diagnosis of AF between November 2011 and December 2014 for Phase II and between January 2014 and December 2016 for Phase III. With this analysis, we categorized patients with AF according to BMI (normal weight [18.5 to 24.9 kg/m2], overweight [25.0 to 29.9 kg/m2], obese [30.0 to 60.0 kg/m2]) and metabolic status (presence of hypertension, diabetes, and hyperlipidemia). We analyzed risk of major outcomes using multivariable Cox regression analyses; the primary outcome was the composite of all-cause death and major adverse cardiovascular events. ResultsThere were 24,828 (mean age, 70.1±10.3 years; 44.6% female) patients with AF included. Higher BMI was associated with metabolically unhealthy status and higher odds of receiving oral anticoagulants and other treatments. Normal-weight unhealthy patients showed a higher risk of the primary composite outcome (adjusted hazard ratio [aHR], 1.20; 95% CI, 1.01 to 1.42) and thromboembolism, whereas a lower risk of cardiovascular death (aHR, 0.35; 95% CI, 0.14 to 0.88) and major adverse cardiovascular events (aHR, 0.56; 95% CI, 0.33 to 0.93) was observed in metabolically healthy obese individuals. Unhealthy metabolic groups were also associated with increased risk of major bleeding (aHR, 1.51 [95% CI, 1.04 to 2.20] and aHR, 1.96 [95% CI, 1.34 to 2.85] in overweight and obese groups, respectively). ConclusionIncreasing BMI was associated with poor metabolic status and with more intensive treatment. Prognosis was heterogeneous between BMI groups, with metabolically unhealthy patients showing higher risk of adverse events.

Retrospective Study of Treatment Patterns and Natural History of Patients with T1a/b N0 Triple-Negative Breast Cancers: A Single-Institution Experience

Introduction: T1a/b, node-negative (node−), triple-negative breast cancers (TNBCs) are underrepresented in randomized drug-approving clinical trials. Given their low incidence, the clinicopathological features, natural history, and treatment patterns of these tumors remain insufficiently understood. Methods: We conducted a single-institution retrospective cohort study of patients with T1a/b, N0, M0 TNBCs. Deidentified patient- and tumor-related data were collected and summarized. Kruskal-Wallis, χ2, or Fisher exact tests were used to evaluate associations of interest. Kaplan-Meier methods, log-rank tests, and Cox’s proportional hazards models were applied for survival analyses. Results: Of 108 cases of node– TNBCs measuring ≤2 cm, 34 node– T1a/b tumors were included in our analysis. All cases had an intermediate to high histological grade, and most had a Ki-67 score of ≥20%. All patients received adjuvant chemotherapy, and many underwent mastectomy (47%). Docetaxel combined with cyclophosphamide was the most common adjuvant chemotherapy regimen (75%). We did not observe significant associations between improved outcomes and treatment with anthracycline-containing regimens. Among patients with node– pT1a/b tumors, the estimated 3-year recurrence-free survival (RFS) and distant RFS rates were both 96.3% (95% CI: 76.5–99.5), and the overall survival rate was estimated to be 100% (95% CI: 100–100). There were no cases of local recurrences observed. Conclusions: In our cohort, all patients with T1a/b node– TNBCs were treated with adjuvant chemotherapy and had favorable outcomes even when treated with anthracycline-sparing regimens.

Role of nonneoplastic PVT in the natural history of patients with cirrhosis and first diagnosis of HCC.

HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, >50% <100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p < 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The "complete/progressive" evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p < 0.001). A higher competing risk of death emerged for "complete and progressive" PVT, both for HCC-related ( p < 0.001) and non-HCC-related ( p = 0.002) death. HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.