High Risk Of Disease Progression Research Articles

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.

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.

Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression

Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.

Therapeutic Effects, Side Effects, and Adverse Effects of Neuropsychiatric Drugs in the Context of Treating Cancer-Related Anorexia With Olanzapine and Mirtazapine.

Drugs have actions that may be classified as therapeutic effects and side effects; side effects are actions that do not contribute to therapeutic benefit. Some side effects are neutral; others, experienced as undesirable or unpleasant, are recorded as adverse effects. Some drug actions are therapeutic for some disorders and adverse for others; or therapeutic during acute illness and adverse during maintenance treatment. As an example, anticholinergic action may be adverse when a tricyclic antidepressant is used to treat depression but therapeutic when the drug is used to treat irritable bowel syndrome with diarrhea. In clinical practice, side or adverse effects of a drug may be leveraged to manage troublesome symptoms. As an example, the sedative effect of a low dose of trazodone may be useful for some patients with insomnia. With this background, studies have examined whether the increase in appetite and weight associated with olanzapine and mirtazapine may be effective against anorexia and cachexia associated with cancer and cancer chemotherapy. The subject is important because cachexia may be present in 30%-50% of patients with cancer (with higher prevalence in patients with more advanced cancer) and because the presence of cachexia is associated with a higher risk of disease progression and mortality. Many randomized controlled trials (RCTs) have examined pharmacologic interventions such as progestins, corticosteroids, anamorelin, and medical cannabis for cancer related cachexia; most results have been disappointing. A recent RCT found that olanzapine (2.5 mg/d for 12 weeks) improved appetite, weight, other nutritional parameters, and quality of life in patients with locally advanced or metastatic cancer treated with chemotherapy. Another RCT, however, found that mirtazapine (30 mg/d for 8 weeks) brought no nutritional or anthropometric gain in patients with cancer and anorexia. It is concluded that olanzapine but not mirtazapine merits further investigation in patients with cancer who have anorexia and cachexia.

IgA Nephropathy – Current and Future Perspectives in Treatment

Abstract Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy in our adult population and is associated with a high lifetime risk of kidney failure. Recent years have succeeded in describing the pathogenesis of IgAN at the molecular level, where immune complexes containing specific galactose deficient IgA1 play an essential role. The gold standard in the diagnosis of IgAN remains renal biopsy followed by determination of a prognostic score using the Oxford classification. A fundamental goal in the management of patients with IgAN is to optimize supportive therapy involving active lifestyle modification and renoprotective medications. The reno-protective drug menu has recently been expanded to include effective sodium-glucose cotransporter 2 inhibitors (SGLT2i), and additional agents are on the way. However, despite maximal supportive therapy, a wide range of patients remain at high risk of disease progression and require the deployment of immunomodulatory drugs. To date, however, we do not have high potency agents that are well tolerated and safe. This has led to the initiation of many studies to target the inflammatory process at different pathogenetic levels. In this article, we summarize the current standards in the treatment of IgAN and present new promising options in the management of this disease.

Disease progression of side-branch intraductal papillary mucinous neoplasms following solid organ transplant

BackgroundBranch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation. MethodsA prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not. ResultsBetween 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6–6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11). ConclusionMalignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression.

Nirmatrelvir/Ritonavir (Paxlovid) Use Among Individuals at Risk of Severe COVID-19: An Analysis of the National COVID Cohort Collaborative (N3C).

Paxlovid is effective in reducing COVID-19 hospitalization and mortality. This study characterized Paxlovid use and evaluated racial/ethnic disparities over time among community-dwelling adults at high risk of progression to severe COVID-19 disease. This retrospective cohort study used the National COVID Cohort Collaborative (N3C) data and included individuals aged 18 years or older diagnosed with COVID-19 between January 2022 and December 2023. The study cohort included nonhospitalized individuals who were at high risk of COVID-19 progression, and selected the first COVID-19 episode in each quarter, including reinfection episodes. Paxlovid use was defined as receiving Paxlovid within ±5 days of a COVID-19 diagnosis. We used descriptive statistics to characterize Paxlovid use overall and by calendar quarter and race/ethnicity. We used a generalized estimating equations (GEE) models to quantify the association of race/ethnicity with Paxlovid use controlling for age, gender, and clinical characteristics. Among 1 264 215 individuals at high risk of disease progression (1 404 607 episodes), Paxlovid use increased from 1.2% in January-March 2022 to 35.1% in October-December 2023. Paxlovid use was more common among non-Hispanic White individuals (23.9%) than non-Hispanic Black (16.5%) and Latinx/e (16.7%) patients. After adjusting age, gender, and clinical characteristics, Paxlovid use was less likely among non-Hispanic Black (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.68-0.70) and Latinx/e (OR 0.72, CI 0.71-0.73) patients than non-Hispanic White patients. Among a large, diverse cohort of community-dwelling individuals with COVID-19, nearly two out of three eligible individuals did not receive Paxlovid, and minoritized racial/ethnic groups were less likely to use Paxlovid than their non-Hispanic White individuals.

Central Nervous System Prophylaxis Utilization in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Within a Large Community Health System.

The impact of central nervous system (CNS) prophylaxis in diffuse large B-cell lymphoma (DLBCL) is contentious. The CNS International Prognostic Index (IPI) calculator offers prognostic guidance in identifying those patients who may be at highest risk of disease progression or relapse to the CNS. However, it is unclear whether this tool has guided clinician decision-making in a real-world setting. Studies have suggested that CNS prophylaxis may not offer clinically significant benefit in terms of preventing CNS disease progression. Given this, we investigated the utilization of CNS prophylaxis within our own population and documentation of the CNS-IPI score. We retrospectively evaluated patients with newly diagnosed DLBCL between January 1, 2014, and December 31, 2017. Patients were assessed for receipt of CNS prophylaxis in the form of intrathecal (IT) chemotherapy and/or high-dose intravenous (IV) methotrexate. CNS-IPI scores were calculated for all patients who received CNS prophylaxis or those who experienced CNS disease. Long-term outcomes at five years from diagnosis included CNS progression/relapse and survival. Of 234 patients who met criteria, 20 (8.6%) received either IV methotrexate or IT chemotherapy; most received IT methotrexate. No patients in the IT prophylaxis group developed CNS disease, while two of eight IV methotrexate patients experienced CNS disease involvement. The incidence of CNS progression was 3.7% in the no prophylaxis group and 10% in those who received prophylaxis. This study revealed low utilization of CNS prophylaxis and CNS-IPI documentation in a community hospital system. Given large differences between groups, claims of CNS prophylaxis efficacy are unable to be made. CNS relapse rates were consistent with existing literature and promote continued evaluation of the utility of current CNS prophylaxis approaches in DLBCL. New unambiguously effective therapeutic approaches are needed and may encourage a higher rate of standardized use.

Clinicopathological and molecular genetic features of neuromuscular choristoma-associated desmoid type fibromatosis

Objective: To investigate the clinicopathological and genetic characteristics of neuromuscular choristoma-associated desmoid type fibromatosis (NMC-DF). Methods: The clinical morphological and immunohistochemical features of 7 NMC-DF cases diagnosed from January 2013 to January 2023 in Beijing Jishuitan Hospital were retrospectively analyzed. A series of neuromuscular choristoma and neuromuscular choristoma-associated desmoid type fibromatosis were evaluated for CTNNB1 mutations, and hotspot mutations for CTNNB1 were tested in 4 NMC-DF cases using Sanger sequencing. Results: The tumors were collected from 3 females and 4 males, aged 1 to 22 years (mean 7.1 years), involving the sciatic nerve (n=4), brachial plexus (n=2) or multiple nerves (n=1). The course of the disease spanned from 3 months to 10 years. Two cases were recurrent tumors. All the 7 NMC cases showed endoneurial intercalation of mature skeletal muscle fibers among the peripheral nerve fascicles, and the histologic features of the NMC-DF were strikingly similar to the conventional desmoid-type fibromatosis. By immunohistochemistry, all NMC and NMC-DF cases showed aberrant nuclear staining of β-catenin (7/7), the muscle cells in NMC were intensely immunoreactive for desmin, and the admixed nerve fibers were highlighted by NF and S-100 (7/7). Four NMC and NMC-DF had CTNNB1 mutations, 3 c.121A>G (p.T41A) and 1 c.134C>T (p.S45F). Follow-up of the 7 cases, ranging from 22 to 78 months, showed tumor recurrence in 2 patients at 3 and 8 months respectively after the first surgical resection, of which 1 patient underwent above-knee amputation. No recurrence occurred in other cases with tumor excision and neurological reconstruction surgery. There was no metastasis occurred in the 7 cases. Conclusions: NMC is a rare congenital lesion with differentiated mature skeletal muscle tissue found in peripheral nerve fascicles, and approximately 80% of patients with NMC develop a soft tissue fibromatosis. CTNNB1 mutation in the Wnt signaling pathway may be involved in the pathogenesis of NMC and NMC-DF, and S45F mutations seems to have a higher risk of disease progression.

Value of Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) in Assessing Liver Fibrosis in Metabolic Dysfunction-Associated Liver Disease: A Comprehensive Review of its Serum Biomarker Role.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.

Muscle MRI as a biomarker of disease activity and progression in myotonic dystrophy type 1: a longitudinal study

IntroductionMyotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by myotonia and progressive muscular weakness and atrophy. The aim of this study was to investigate the usefulness of longitudinal muscle MRI in detecting disease activity and progression in DM1, and to better characterize muscle edema, fat replacement and atrophy overtime.Materials and methodsThis is a prospective, observational, longitudinal study including 25 DM1 patients that performed at least two muscle MRIs. Demographic and genetic characteristics were recorded. Muscular Impairment Rating Scale (MIRS) and MRC score were performed within 3 months from MRIs at baseline (BL) and at follow-up (FU). We analysed 32 muscles of lower body (LB) and 17 muscles of upper body (UB) by T1 and STIR sequences. T1-, STIR- and atrophy scores and their variations were evaluated. Correlations between MRIs’ scores and demographic, clinical and genetic characteristics were analysed.ResultsEighty (80%) of patients showed fat replacement progression at FU. The median T1 score progression (ΔT1-score) was 1.3% per year in LB and 0.5% per year in UB. The rate of fat replacement progression was not homogenous, stratifying patients from non-progressors to fast progressors (> 3% ΔT1-score per year). Half of the STIR-positive muscles at BL showed T1-score progression at FU. Two patients with normal MRI at baseline only showed STIR-positive muscle at FU, marking the disease activity onset. STIR positivity at baseline correlated with fat replacement progression (ΔT1-score; p < 0.0001) and clinical worsening at FU (ΔMRC-score; p < 0.0001). Sixty-five (65%) of patients showed STIR- and fat replacement-independent muscle atrophy progression, more evident in UB.ConclusionsMuscle MRI represents a sensitive biomarker of disease activity, severity, and progression in DM1. STIR alterations precede fat replacement and identify patients with a higher risk of disease progression, while T1-sequences reveal atrophy and fat replacement progression before clinical worsening.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study

Objective To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. Methods Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18–64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. Results Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3–1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). Conclusion Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

MicroRNA and renal fibrosis in autosomal dominant polycystic kidney disease: a longitudinal study.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are stillneeded. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss. We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV). The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m2/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm3) and height-adjusted total fibrotic volume (cm3/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm3) and height-adjusted total kidney volume (cm3/m). The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals, or no treatment: a retrospective cohort study

BackgroundThe clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland.MethodsRetrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021–October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed.ResultsIn total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients.ConclusionsSotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.

Social Factors Associated with the Risk of Glaucoma Suspect Conversion to Glaucoma: Analysis of the Nationwide All of Us Program

To examine social factors associated with the 5-year risk of glaucoma suspects (GS) converting to open-angle glaucoma (OAG). Retrospective cohort analysis. We screened for participants diagnosed with GS in the All of Us database. Cases that converted to OAG within 5 years of GS diagnosis (the "conversion group") were compared with control cases that did not convert. Demographic, socioeconomic and healthcare utilization data of the cases were extracted and compared between the conversion group and the control group. Multivariable Cox proportional hazards modeling was used to identify potential factors associated with the risk of conversion. Hazard ratios (HRs) of significant factors associated with the risk of conversion. A total of 5274 GS participants were identified, and 786 (15%) cases converted to OAG within 5-year follow-up. The two groups showed significant differences in age, race, gender, employment status, income/education level, history of intra-ocular surgery, and healthcare utilization patterns. In the multivariable model, African American/Black race (HR [95% confidence interval] =1.70 [1.44-2.00]), older age at GS diagnosis (1.17 [1.09-1.25]), male gender (1.30 [1.13-1.50], no history of recreational drug use (1.23 [1.07-1.42]), history of intra-ocular surgery (1.60 [1.02-1.53]) and having more reasons for delayed healthcare access (2.27 [1.23-4.18]) were associated with a greater hazard of conversion, while being employed (0.71 [0.60-0.86]) was associated with a smaller hazard of conversion (P<0.05 for all). Several social factors were associated with the conversion from GS to OAG, which may help to identify patients at higher risk of disease progression. Future studies are needed to examine the basis for these findings and the potential interventions that could address them.

The Prognostic Value of Proliferative Activity in Cutaneous Melanoma: A Pilot Study Evaluating the Mitotic Rate and Ki67 Index to Predict Patient Outcomes.

Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 patients diagnosed with cutaneous melanomas between 2013 and 2018 in order to evaluate progression-free survival and overall survival. Multivariate Cox proportional hazards regression was performed by considering both clinical histopathological and immunohistochemical features. The mitotic rate was significantly independently associated with both outcomes, while the Ki67 index was not an independent prognostic factor. However, the Ki67 predictive accuracy could be improved by establishing both a cut-off value and a standardized protocol for evaluating its expression. Until these desiderata are met, the mitotic rate remains superior to the Ki67 index for predicting prognosis in cutaneous melanomas, as also has the advantage of being easily interpreted in a standard histopathological examination regardless of the pathologist's experience and with no further financial expenses. Importantly, this is one of very few articles that has shown perineural invasion to be an independent prognostic factor for both progression-free survival and overall survival in cutaneous melanomas. As a consequence, this parameter should become a mandatory feature in the histopathological evaluation of cutaneous melanomas as it can improve the identification of patients who are at high risk for disease progression.

Role of dynamic ctDNA monitoring in cervical and anal epidermoid carcinomas under curative chemoradiation.

3141 Background: Cervical and anal canal squamous cell carcinoma (SSC) are a significant health problem in underdevelopment countries. Definitive chemoradiation (CRT) is the standard-of-care (SOC) approach for curative treatment in locally advanced disease. Due to the common substantial local inflammation during CRT, the conventional clinical image cannot identify non-responders early. In this scenario, the evaluation of circulating tumor DNA (ctDNA) is a promising tool for real-time tumor response monitoring. Methods: We performed a prospective multicentric cohort study of patients treated between 2020 and 2023 in tertiary oncologic centers in Brazil to evaluate the role of ctDNA dynamic monitoring in epidermoid cervical (CC) and anal cancer (AC) T1-4, N0-1, M0 by AJCC 8th edition and candidates to complete curative CRT. The cDNA was assessed by Signatera test at D1, D29, immediately post-treatment, 8 weeks (w) post-CRT, 24w post-CRT, every 6 months (m) in the first 1-2 years(y), and yearly at 3-5y of follow-up (FUP). The primary endpoint was to estimate the correlation of ctDNA with a tumoral response assessed by conventional routine image and clinical evaluation at 8w. Secondary endpoints included a correlation between ctDNA results at different time points with progression-free survival (PFS) and overall survival (OS). The predictive potential of the biomarker was evaluated using receiving operating characteristic (ROC) curve analysis. Results: We included 33 patients, and 27 were evaluable with ctDNA, with a median FUP of 10m. The majority were female (n=23, 85.1%), and 3 (11%) were HIV-positive(+). Most patients presented with positive nodes and stage III disease (n=18, 66.6%). In the AC group (n=15), the majority received CRT with capecitabine and cisplatin (n=12, 55.5%); in the CC group (n=12), all pts received cisplatin. All pts tested expressed ctDNA+ before treatment. At 8w, images had a sensitivity of 42.8% and specificity of 100% for disease progression (area under the curve [AUC] 0.714), while ctDNA yielded a sensitivity of 85.7% and specificity of 89.4% (AUC 0.875). The ctDNA+ immediately after CRT ended (32%) was consistent with ctDNA+ at 8w (30.7%) and 24w (30%). Pts with ctDNA+ immediately post CRT have a higher risk of disease progression with PFS of 8.2m in ctDNA+ and not reached in ctDNA- group (HR:17.5; IC95%:1.9-157.3; p=0.01). Data are immature for OS analysis. Conclusions: CtDNA immediately post-CRT has a high predictive value in patients with anal and cervical tumors in early access CRT non-responders, who are at a high risk of disease progression. This biomarker should be considered for tailoring strategies of treatment escalation in this population.

#2632 Quality of life and fatigue burden in individuals living with Complement 3 Glomerulopathy – a real-world study

Abstract Background and Aims C3 glomerulopathy (C3G) has an estimated incidence of 1 to 2 per million per year and is associated with a high risk of disease progression, with approximately 50% of patients reaching kidney failure within ten years of diagnosis; despite this, there are currently limited treatment options available. The impact of C3G on patient fatigue and quality of life (QoL) is well understood but not well described in large scale real-world settings; this study aims to address this. Method Data were drawn from the Adelphi C3G Disease Specific Programme™, a cross-sectional survey with retrospective data collection of C3G-treating nephrologists in France, Germany, Italy, Spain, the United Kingdom (EU5), China, Japan, and the United States (US) from August 2022 – April 2023. Nephrologists completed surveys for 1–9 consecutively consulted C3G patients, reporting patient demographics, treatment history, symptoms and QoL. Patients for whom nephrologists completed a form were then invited to complete a voluntary follow-up questionnaire to capture impact of C3G across QoL metrics including the 5-level EQ-5D version [EQ-5D-5L] (which captures QoL at the time of survey) and the Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue (which captures typical impact of fatigue across the 7 days prior to survey completion). Analyses were descriptive. Results Overall, 111 nephrologists reported on 385 patients (EU5 n=189, China n=60, Japan n=36, US n=100). At the time of the survey, median (interquartile range; IQR) patient age was 42.0 (30.0, 55.0) years and 59% of patients were male. Median (IQR) proteinuria was 1.4 g/24 hr (0.8 g/24 hr-3.0 g/24 hr) and eGFR was 50.0 mL/min/1.73m2 (32.00 mL/min/1.73m2 -70.00 mL/min/1.73m2). Of the 385 patients with physician reported data, 118 patients completed their own matched questionnaire, the majority of which were based in China (EU5 n=33, China n=60, Japan n=6, US n=19). Among these patients who completed the EQ-5D 74% experienced anxiety and/or depression, 65% felt pain and/or discomfort and 63% experienced problems doing their usual activities. QoL was also impacted across the further 2 domains: 42% experienced mobility problems and 30% experienced self-care problems (washing or dressing themself). Fatigue as measured by the FACIT fatigue was commonly reported across all patients; 93% of patients felt tired, 91% felt fatigued, 84% felt listless and 82% felt weak all over. The majority (77%) also reported that they needed to sleep during the day. Fatigue impacted all aspects of the patients’ lives; 47% reported feeling too tired to eat, 62% required some help to conduct their usual activities, 71% struggled to start things because they are tired, 74% struggled to finish things because they are tired and 78% reported limiting their social activities due to their fatigue. Most patients (69%) also reported feeling some level of frustration due to tiredness preventing them from doing what they want to do, and 3% felt they could not do their usual activities at all. All the above results on anxiety and depression, pain and discomfort and fatigue were relatively similar across all regions, with EU5 generally reporting a slightly lower frequency. Conclusion Chronic kidney disease (CKD) such as C3G places a substantial burden on patients’ QoL. Living with C3G has a clear impact on all aspects of the patients’ lives, encompassing both an emotional impact (e.g., anxiety/depression and frustration), as well as a physical impact (e.g., pain/discomfort, mobility and fatigue). More efficacious treatment options are needed to treat the cause of C3G to improve patients’ daily lives, increase their QoL, and to reduce the impact of living with C3G.

#457 Sparsentan has direct effects on the glomerular capillary wall to attenuate increased permeability after exposure to nephrotic syndrome plasma

Abstract Background and Aims The glomerular endothelial glycocalyx (eGlx), a luminal layer of proteoglycans, glycoproteins and glycolipids, forms the first part of the glomerular filtration barrier (GFB). Nephrotic syndrome (NS) describes a group of pathologies of the renal glomerulus that result in proteinuria and is associated with glomerular endothelial dysfunction. Current treatments are broad and non-specific. Sparsentan is a single-molecule dual endothelin type-A and angiotensin II type 1 receptor antagonist that has received accelerated approval in the United States for the reduction of proteinuria in adults with IgA nephropathy at high risk of disease progression. Our validated glomerular permeability assay directly measures the albumin permeability (Ps’alb)of capillary loops within individually trapped glomeruli [1]. This ex vivo assay is independent of haemodynamic factors and tubular albumin handling – factors known to affect urine protein concentrations. This work examines whether sparsentan could reduce glomerular albumin permeability in NS, by preserving the eGlx to maintain the GFB. Method Human NS plasma samples were collected under ethical consent from 3 patients that had undergone plasma exchange from periods when they were in relapse (RL), or subsequent remission (RM). Adult male Sprague Dawley rats (175–200 g) were perfused with 4% Ringer BSA solution. Glomeruli were isolated on ice by graded sieving from the cortex of each kidney. Glomeruli were incubated, in the presence of AF488-conjugated BSA (AF488-BSA, 30 μg/ml) and R18 (36.5 μg/ml), with 10% plasma from NS patients for 1 hour, and simultaneously treated with sparsentan (0.1 μM, 1 μM and 10 μM) or vehicle. The glomerular Ps’alb assay was used to measure changes in albumin permeability. We applied a fluorescence profile peak-to-peak confocal imaging technique to treated glomeruli to assess glomerular eGlx thickness [2]. Results Human NS patients in RL had a significantly greater proteinuria compared to RM (RL, 10, 000 ± 1, 354 mg/g; RM, 95.3 ± 59.7 mg/g, P = 0.017). Incubation of rat glomeruli with RL plasma induced a significant increase in Ps’alb (RM+vehicle, 6.0 × 10−7 ± 0.12 × 10−7 cm/s; RL+vehicle, 10.9 × 10−7 ± 0.84 × 10−7 cm/s, P &amp;lt; .001) with a significant reduction in glomerular eGlx thickness (RM+vehicle, 210 ± 21.2 nm; RL+vehicle, 109 ± 7.9 nm, P = .027), compared to rat glomeruli incubated with paired RM plasma. Sparsentan-treated RL incubated glomeruli were protected from both the increase in Ps’alb (RL+spars 10 µM, 6.3 × 10−7 ± 0.19 × 10−7 cm/s, P &amp;lt; .001) and the loss in glomerular eGlx (RL+spars 10 µM, 222 ± 8.5 nm, P = .013), to a level comparable to RM incubated glomeruli. The effect of sparsentan on Ps’alb was dose dependent (RL+spars 1 µM, 8.0 × 10−7 ± 0.46 × 10−7 cm/s; RL+spars 0.1 µM, 9.6 × 10−7 ± 0.22 × 10−7 cm/s) with Ps’alb changes correlating inversely with glomerular eGlx thickness (r² = 0.75, P &amp;lt; .0001). In RM glomeruli, sparsentan alone had no effect on Ps’alb compared with vehicle (RM+spars 10 µM, 6.2 × 10−7 ± 0.25 × 10−7 cm/s, P = .590), suggesting no effect on otherwise healthy capillaries. Conclusion We have shown that dual inhibition of endothelin and angiotensin receptors, with sparsentan, preserves the glomerular eGlx resulting in normalised glomerular permeability in NS. These findings suggest that the direct action of sparsentan on the GFB could help maintain barrier integrity in NS, in particular by glycocalyx protection.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (&amp;lt;2 g/g vs ≥2 g/g), eGFR (&amp;lt;45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR &amp;lt;1 g/g and &amp;lt;0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.