Treatment Cohorts Research Articles

A retrospective claims data analysis of health care utilization and cost among patients receiving multi-injection intraarticular hyaluronic acid.

With the rising costs for knee arthroplasty, therapies that allow patients to avoid or delay surgery following knee osteoarthritis (KOA) may help in reducing overall health care costs. Multiple intraarticular hyaluronic acid (HA) products are available on the market, varying by formulation, molecular weight, and number of injections, but clinical and economic benefits may differ by product. OBJECTIVES: To evaluate the all-cause and KOA-related health care resource utilization (HCRU) and costs among newly diagnosed patients with KOA treated with multi-injection HA. A retrospective cohort study using a large commercial claims database (Merative MarketScan database) to identify patients with KOA treated with high molecular weight (HMW) (n = 11,200), medium molecular weight (MMW) (n = 10,225), or low molecular weight (LMW) HAs (n = 8,473) between 2016 and 2019. KOA-related and all-cause HCRU and costs were compared within 12 months after the index HA treatment date. The association between outcomes and HA treatments was evaluated using a doubly robust method to adjust for confounding factors. HCRU and costs among the propensity score-weighted HA groups were compared using generalized linear models. HMW HA patients were found to have lower adjusted KOA-related medical costs by $265.37 (P < 0.001) and pharmacy costs by $19.90 (P < 0.001) compared with LMW HA patients, as well as lower all-cause total medical costs by $130.42 (P = 0.013) and pharmacy costs by $63.33 (P < 0.001). HMW HA patients also had a lower adjusted KOA-related medical cost by $205.74 (P < 0.001) and pharmacy cost by $14.39 (P < 0.001) compared with MMW HA patients, as well as lower all-cause medical by $1,195.66 (P < 0.001) and pharmacy by $196.99 (P < 0.001). Three-injection treatment patients (HMW HA, 84%; MMW HA, 82%) had high completion rate, compared with the 5-injection treatment cohort (LMW HA, 48%). HMW HA patients had statistically significantly lower adjusted all-cause and KOA-related medical and pharmacy costs at 1 year follow-up compared with MMW HA and LMW HA patients. It is unclear if this is related to differences in molecular weight or specific mechanism of actions.

Abstract B053: SUMOylation and TIGIT inhibition: a novel immunotherapy combination for pancreatic cancer

Abstract Introduction: Immune checkpoint inhibitors have shown promise in many other solid tumors but have been disappointing in pancreatic ductal adenocarcinoma (PDAC). Preclinical work demonstrates that the immune checkpoint receptor TIGIT plays a key role in PDAC immune evasion and may be a better therapeutic target than the PD1 or CTLA4 axes. Post-translational small-ubiquitin-like modification (SUMOylation) regulates the activity of numerous proteins involved in cell proliferation. Our laboratory has shown that inhibition of SUMOylation with small molecule TAK-981 favorably modulates the PDAC immune microenvironment and specifically increases the expression of TIGIT binding partners CD226 on immune cells and CD155 on tumor cells. We hypothesized that inhibition of SUMOylation with small molecule TAK-981 would synergize with anti-TIGIT antibody therapy to induce anti-tumor immunity. Methods:All studies utilized a murine PDAC organoid line (KPC46) derived from a liver metastasis in a genetically engineered mouse model (KPC). KPC46 consistently metastasizes to the liver when implanted orthotopically into the tail of the pancreas in immunocompetent mice. Following tumor implantation, mice were surveilled by ultrasound until tumors reached 5-7 mm in diameter, then randomized to one of two treatment groups: TAK-981 + anti-TIGIT or vehicle control (n=10/group). Monotherapies were not included, as each drug alone did not produce significant responses in prior studies using this model. The treatment cohort received 15 mg/kg of TAK-981 and 100 micrograms of anti-TIGIT antibody via intraperitoneal injection every 48 hours starting 14 and 15 days, respectively, post-implantation, for a total of 4 weeks. Complete responders were defined as absence of disease after 2 months of observation. Complete responders and age-matched controls (n=3/group) were rechallenged with subcutaneous tumor injection and monitored for tumor development. Results:Survival of PDAC mice was significantly prolonged in the combination group when compared to the control group (median survival 81 vs 42 days, P&amp;lt;0.05). A total of 4 mice (40%) were deemed complete responders after 2 months of monitoring. The re-challenge experiment produced tumors in all three control mice but none of the treated mice by 4 weeks after implantation. Conclusion:In this study, we explored the combination of two promising immunotherapy agents for PDAC which demonstrated significant additive effects generating durable and complete responses. We were able to confirm the presence of protective immunity. These results are rarely seen in PDAC experiments. Further experiments to better understand and optimize these effects are underway. These drugs are currently in clinical trials for solid tumors and could feasibly be studied in the near future in PDAC. Citation Format: Jorge R de la Torre Medina, Utsav Joshi, Jaynath Shankara Narayanan, Herve Tiriac, Yuan Chen, Rebekah White. SUMOylation and TIGIT inhibition: a novel immunotherapy combination for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B053.

PSI-22 Evaluating colonization success of Bacteroidetes from different host origin in broiler chickens

Abstract Current broiler production practices that aim to maximize biosecurity have limited chick exposure to beneficial microbes. Previous research highlights a notable disparity in Bacteroidetes abundance and taxonomy between birds reared under intensive and extensive systems. Building upon this, we hypothesized that Bacteroidetes strains populating intensively raised birds may originate from human sources, potentially leading to varied colonization efficiencies. The objective of this study was to evaluate the colonization patterns of diverse Bacteroidetes strains within the chicken gastrointestinal tract. One day-old broiler birds (n = 63) were raised in individually ventilated isolators accommodating 3 birds per cage. The chicks were subjected to inoculation either via oral gavage with 150 µL of glycerol stock containing 1x104 colony forming units (CFU)/mL; or spray method (2 mL per cage) using chicken-derived, human-derived, and a combination of Bacteroidetes strains. Notably, birds administered via oral gavage displayed an increase in body weight gain by d 07 compared with their counterparts treated via spray and the control group (P &amp;lt; 0.01). Subsequent quantification of Bacteroidetes, Enterobacteriaceae, and total bacteria using qPCR revealed that oral gavage resulted in more successful Bacteroidetes colonization at d 14 (P &amp;lt; 0.01). Moreover, discernible variations were noted in total bacterial abundance across treatment cohorts. It can be concluded that the method of inoculation appears to influence the initial colonization patterns of Bacteroidetes in the chicken gut, or that inoculation in the environment requires a higher dose. Amplicon sequencing that is underway will reveal the success of the Bacteroidetes from different host origin and the most successful strains of chicken origin. Overall, enhanced growth coincided with more successful Bacteroidetes colonization, identifying them as potential targets for enhanced broiler performance. Further investigation is warranted to determine if Bacteroidetes from different sources demonstrate varying colonization efficiencies.

A - 116 A Neuropsychological Testing Protocol for Assessing Lecanemab Eligibility for Alzheimer’s Disease: the First Fifty Patients

Abstract Objective Since the FDA approved lecanemab for Alzheimer’s disease (ad) treatment in 2023, neuropsychology’s role in the treatment eligibility determination process has become increasingly important. Not only is objective evidence of cognitive impairment required for the diagnosis of mild cognitive impairment (MCI) and mild dementia, but testing can be used to measure treatment efficacy and monitor for adverse effects. Our center developed a specialized protocol to assess cognitive and behavioral functioning for assisting in the eligibility determination process. Method Fifty adults (Mean Age = 73.8 years) underwent neuropsychological testing, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), as a part of their eligibility workup. Caregiver questionnaires were used to assess behavioral functioning. Test scores and patient outcomes were explored. Results Thirteen patients (26%) were prescribed lecanemab. Another 13 patients were deemed ineligible (five due to their cognitive results), eight patients (16%) were undecided, and 16 patients (32%) had not yet completed their workup. Of those who initiated lecanemab, eight patients (62%) had a diagnosis of MCI and six were diagnosed with mild dementia. Of these patients, eight (82%) showed an amnestic pattern on testing (RBANS Delayed Recall Standard Score Mean = 46.8). Additional analyses involving ad biomarkers, neuroimaging, and APOE status, were conducted. Conclusion Over one quarter of patients referred for neuropsychological testing as a part of their eligibility determination initiated lecanemab treatment for ad. Cognitive testing was directly related to determining ineligibility in 10% of patients. This review of an initial lecanemab treatment cohort highlights the importance of neuropsychology in the eligibility determination process.

Immune-related cell death index and its application for hepatocellular carcinoma

Regulated cell death (RCD) plays a crucial role in the immune microenvironment, development, and progression of hepatocellular carcinoma (HCC). However, reliable immune-related cell death signatures have not been explored. In this study, we collected 12 RCD modes (e.g., apoptosis, ferroptosis, and cuproptosis), including 1078 regulators, to identify immune-related cell death genes based on HCC immune subgroups. Using a developed competitive machine learning framework, nine genes were screened to construct the immune-related cell death index (IRCDI), which is available for online application. Multi-omics data, along with clinical features, were analyzed to explore the HCC malignant heterogeneity. To validate the efficacy of this model, more than 18 independent cohorts, including survival and diverse treatment cohorts and datasets, were utilized. These findings were further validated using in-house samples and molecular biological experiments. Overall, the IRCDI may have a wide application in individual therapeutic decision-making and improving outcomes for HCC patients.

271. EFFICACY OF NEOADJUVANT CF OR DCF, FLOT PLUS NIVOLUMAB FOR RESECTABLE LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA (JCOG1804E: FRONTIER)

Abstract Background The standard neoadjuvant therapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC) in Japan is DCF (docetaxel [DTX] + cisplatin [CDDP] + 5-fluorouracil [5-FU]). In addition, neoadjuvant immune checkpoint inhibitors have shown a survival benefit for metastatic ESCC and several other cancers. We previously reported that neoadjuvant CF (CDDP + 5-FU) + nivolumab (Nivo), DCF + Nivo, and FLOT (5-FU + l-leucovorin [l-LV] + oxaliplatin [L-OHP] + DTX) + Nivo are tolerable and show promising short-term efficacy for resectable locally advanced ESCC. However, the long-term efficacy of these neoadjuvant treatments remains unclear. Methods JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant CF (cohorts A and B [adding run-in Nivo]) or DCF (cohorts C and D [adding run-in Nivo]) or neoadjuvant FLOT (cohort E) for resectable locally advanced ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer treatment. Secondary efficacy endpoints were pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS) for each treatment. Results Thirty-seven patients were enrolled (median age [range]: 62 [31-75] years; PS 0/1: 32/5; clinical stage I/II/III/IVA: 7/9/20/1; PD-L1 TPS &amp;lt;1%/≥1%/unknown: 10/26/1). In CF-based treatment cohorts (n=13), median follow-up time (range), pCR, and 3-year PFS were 42.3 (20.9-50.1) months, 7.7%, and 66.6%, respectively. The respective values for the DCF-based treatment cohorts (n=12) were 32.2 (8.0-39.8) months, 33.3%, and 83.3% and for the FLOT-based treatment cohort (n=12) were 16.2 (5.3-20.6) months, 41.7%, and 91.7%. In the overall population (n=37), median follow-up time was 31.9 (5.3-50.1) months and 3-year OS was 82.4%. Conclusion Neoadjuvant CF or DCF or neoadjuvant FLOT + Nivo followed by surgery for resectable locally advanced ESCC showed promising short- and long-term efficacy. (NCT03914443)

Predicting the risk of cardiovascular and cerebrovascular event in systemic lupus erythematosus: a Chinese SLE treatment and research group study XXVI

ObjectivePatients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular and cerebrovascular events (CCEs). Furthermore, CCE was a significant factor contributing to mortality in patients with SLE. However,...

542P Long-term outcomes of neoadjuvant toripalimab with or without celecoxib in patients with dMMR/MSI-H locally advanced colorectal cancer: 3-month treatment cohort of the randomized phase II PICC trial

542P Long-term outcomes of neoadjuvant toripalimab with or without celecoxib in patients with dMMR/MSI-H locally advanced colorectal cancer: 3-month treatment cohort of the randomized phase II PICC trial

Trends in continuity of treatment among children and adolescents living with HIV in 14 districts in South Africa from 2018-2023: A retrospective program analysis

ObjectivesUNAIDS estimates 152,984 children under 15 years living with HIV (C/ALHIV) by 2022 in South Africa. Monitoring the continuity of antiretroviral treatment remains challenging without electronic health records. We explored treatment cohort growth and interruption trends in 14-USAID-PEPFAR-supported districts. MethodsWe reviewed data from 2018 to 2023. We triangulated this data with NAOMI HIV estimates. We used Tableau version 2023.2 for analysis to understand heterogeneity in outcomes. ResultsHIV incidence halved from 4.3 per 1000 in 2017 to 2.5 per 1000 in 2022. HIV testing doubled: 188,371 in FY19Q1 to 399,708 in FY23Q4 while testing positivity declined from 3.3% to 0.7%. Linkage to treatment increased from 67% to 102%, viral suppression increased from 79% to 84%. C/ALHIV treatment cohort started at 82,897 in FY19Q1 and increased to 105,107 in FY20Q2. Subsequently, the cohort decreased to 79,288 in FY23Q4 despite 42,498 initiations and 62,256 returns. ConclusionsThe C/ALHIV treatment and viral suppression increased substantially commensurate with expected trends. Subsequent cohort decline was aligned to vertical transmission reduction, HIV incidence decline, and expected aging. We highlight the inadequacy of the information systems to quantify losses. We underscore a need for resources to enhance program monitoring and interventions to address this gap.

Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA.

Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine.

A subset of patients with postural tachycardia syndrome (POTS) are thought to have a primary hyperadrenergic cause. We assessed clinical biomarkers to identify those that would benefit from sympatholytic therapy. We measured sympathetic function (supine muscle sympathetic nerve activity, upright plasma norepinephrine, and blood pressure responses to the Valsalva maneuver) in 28 patients with POTS (phenotyping cohort) to identify clinical biomarkers that are associated with responsiveness to the central sympatholytic guanfacine in a separate uncontrolled treatment cohort of 38 patients that had received guanfacine clinically for suspected hyperadrenergic POTS (HyperPOTS). In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mm Hg during late phase 2 of the Valsalva maneuver identified patients with the highest quartile of resting muscle sympathetic nerve activity (HyperPOTS) with 71% sensitivity and 85% specificity. In the treatment cohort, patients with HyperPOTS, identified by this clinical biomarker, more often reported clinical improvement (85% versus 44% in nonhyperadrenergic; P=0.016), had better orthostatic tolerance (∆Orthostatic Hypotension Daily Activities Scale: -1.9±0.9 versus 0.1±0.5; P=0.032), and reported less chronic fatigue (∆PROMIS Fatigue Short Form 7a: -12.9±2.7 versus -2.2±2.2; P=0.005) in response to guanfacine. These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy. These results support further clinical trials to determine the safety and efficacy of guanfacine in patients with POTS enriched for the presence of this clinical biomarker.

Addition of pyloroplasty may improve glycemic control and refractory early satiety in gastroparesis at rates similar to gastric neurostimulation alone: a retrospective analysis

Objectives Gastroparesis that is refractory to standard dietary and medical management may benefit from surgical treatment with gastric electrical neurostimulation, which has shown promise in reducing symptoms of the disease. Pyloroplasty may serve an adjunctive role to a gastric stimulator, but the precise benefit remains unclear. The present study compares reported rates of symptom improvement following gastric neurostimulator implantation with and without pyloroplasty. Materials and methods A single center retrospective analysis of consecutive patients who received operative management for symptom refractory gastroparesis from 1 January 2020 to 31 December 2021 was performed. Subjects were assigned to cohorts based on treatment with gastric electrical stimulation alone (GES-only) or combined with pyloroplasty (GES + PP). A survey-based assessment was administered post-operatively that evaluated cardinal symptoms of gastroparesis (nausea, vomiting, early satiety) before and after treatment. Results In total, 42 patients (15 GES-only, 27 GES + PP) were included in the study. Both groups reported a high degree of improvement in global symptom control following surgery (93% vs 81%) with no differences between treatment cohorts (p = 0.09). Early satiety demonstrated better improvement in patients who received gastric stimulation alone (p = 0.012). Subgroup analysis of diabetic gastroparesis patients showed a 2.2% decrease in hemoglobin A1c levels in the GES + PP group (p-0.034). Conclusions Symptom reduction in refractory gastroparesis appears to improve after placement of a gastric neurostimulator with or without the addition of a pyloroplasty procedure.

Irreversible electroporation of localised prostate cancerdownregulates immune suppression andinduces systemic anti-tumour T-cell activation - IRE-IMMUNO study.

To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa). Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase(PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts. Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory Tcells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) Tcells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP. Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

Correlation of noninvasive imaging of tumour-infiltrating lymphocytes with survival and BCG immunotherapy response in patients with bladder cancer：a multicentre cohort study

Background: Tumour-infiltrating lymphocytes (TILs) are strongly correlated with the prognosis and immunotherapy response in bladder cancer. The TIL status is typically assessed through microscopy as part of tissue pathology. Here, we developed Rad-TIL model, a novel radiomics model, to predict TIL status in patients with bladder cancer. Material and Methods: We enrolled 1089 patients with bladder cancer and developed the Rad-TIL model by using a machine-learning method based on computed tomography (CT) images. We applied a radiogenomics cohort to reveal the key pathways underlying the Rad-TIL model. Finally, we used an independent treatment cohort to evaluate the predictive efficacy of the Rad-TIL model for Bacillus Calmette-Guérin (BCG) immunotherapy. Results: We developed the Rad-TIL model by integrating tumoral and peritumoral features on CT images and obtained areas under the receiver operating characteristic curves of 0.844 and 0.816 in the internal and external validation cohorts, respectively. Patients were stratified into two groups based on the predicted radiomics score of TILs (RSTIL). RSTIL exhibited prognostic significance for both overall and cancer-specific survival in each cohort (hazard ratios: 2.27 to 3.15, all P&lt;0.05). Radiogenomics analysis revealed a significant association of RSTIL with immunoregulatory pathways and immune checkpoint molecules (all P&lt;0.05). Notably, BCG immunotherapy response rates were significantly higher in high-RSTIL patients than in low-RSTIL patients (P=0.007). Conclusion: The Rad-TIL model, a noninvasive method for assessing TIL status, can predict clinical outcomes and BCG immunotherapy response in patients with bladder cancer.

Short-term efficacy of platelet-rich plasma in the treatment of persistent olfactory dysfunction: systematic review and meta-analysis.

To assess the short-term effects of topical platelet-rich plasma (PRP) injection on persistent refractory olfactory dysfunction. A comprehensive literature search of the PubMed, SCOPUS, EMBASE, Web of Science, Google Scholar, and Cochrane databases was conducted for articles up to November 2023. The search focused on studies that compared the amelioration of olfactory dysfunction between a topical PRP treatment cohort and a control group (receiving either placebo or no treatment), along with pre- and post-treatment comparisons. Subgroup analysis of the evaluation of olfactory function was also performed. The improvement in olfactory scores 1-3months post-treatment (standardized mean difference = 1.5354 [95% confidence interval: 0.7992; 2.2716], I2 = 83.8%) was greater in the treatment group than in the control group. In the treatment group, PRP increased the threshold, discrimination, and identification (TDI) score for Sniffin' Sticks by > 5.5 (minimum clinically significant difference; mean difference = 6.1789 [3.9788; 8.3789], I2 = 0.0%), indicating clinically significant improvement based on verified examinations. The rate of significant improvement among patients was 0.6683 [0.5833; 0.7436] after treatment. All TDI subdomains were significantly and similarly improved after treatment. This meta-analysis suggests that injection of PRP into the olfactory fissure or surrounding mucosal areas is an effective treatment for persistent refractory olfactory dysfunction in the short term.

Abstract Tu141: Effect of Epicardial Application of Oxygenated Hydrogel on Scar Burden in a Rat Model of Myocardial Infarction

Background: Epicardial application of a bioadhesive at the time of experimental myocardial infarction (MI) has been shown to reduce ventricular scar burden in mice. This study assessed the impact of an oxygenated hydrogel (O 2 -hydrogel) on post-infarct cardiac function and scar burden in rats. Method: Experimental MI was performed in Lewis rats (age 12-15 weeks) by permanent ligation of the anterior interventricular artery. There were 3 cohorts in this study: 1. MI followed by epicardial application of hydrogel, 2. MI followed by epicardial application of O 2 -hydrogel, and 3. MI with no treatment. Left ventricular (LV) function was evaluated by transthoracic echocardiography (TTE) at baseline, immediately post-MI, and 3 weeks post-MI. LV scar burden was evaluated with histopathology performed 3 weeks post-MI. Result: Twenty-four rats were analyzed (hydrogel, n= 8; O 2 -hydrogel, n= 9; untreated, n=7). LV fractional shortening (FS) measured by TTE 3 weeks post-MI was significantly reduced compared with baseline in untreated rats (44.6±12.4 to 22.3±4.9, P=0.043; Figure 1) and hydrogel treated rats (32.4±6.0 to 14.9±5.2, P=0.018). No significant change in FS was observed in the O 2 -hydrogel treatment cohort (39.0±13.9 to 38.1±12.6, P=0.859). LV scar burden in the O 2 -hydrogel cohort was significantly lower than in the hydrogel alone and untreated cohorts (11.9% vs 39.9% and 36.2%, respectively; Figure 2). Conclusion: In this rat model, epicardial application of O 2 -hydrogel at the time of experimental MI is associated with greater preservation of LV function and significantly lower scar burden than application of hydrogel alone or no treatment.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

Meibography signal intensity as a novel image biomarker for meibomian gland function: evidence from cross-sectional and longitudinal analyses.

Meibomian gland dysfunction (MGD), one of the most common ocular surface diseases, can induce dry eye and reduce patients' quality of life. Methodological limitations have resulted in contradictory interpretations of gland function. This study sought to investigate the correlation between meibography signal intensity (SI) and meibomian gland (MG) function and to validate an MGD classification strategy based on different levels of SI. A multicenter, cross-sectional analysis was conducted on 817 eyes from 361 patients with MGD and 52 healthy controls. Additionally, 78 eyes from 39 patients with MGD who had undergone LipiFlow treatment were recruited for longitudinal analyses. The SI value was obtained via meibography using an automated analyzer, and all participants underwent ocular surface examinations. A cross-sectional analysis was performed to determine SI distribution and its relationship to clinical characteristics via a generalized estimating equation model. Longitudinal analyses were conducted on the treatment cohort using a mixed-effects model to explore the outcome in different SI levels. Regression analysis revealed significant correlations between SI and lipid layer thickness (β=0.016), meibum expressibility (β=-0.676), meibum quality (β=-0.251), and fluorescein-stained tear-film break-up time (FBUT) (β=0.064) (all P values <0.001 for the above associations). Low-level SI MGD cases exhibited the most severe clinical signs, including the worst meibum expressibility (16% for level 3) and quality scores (19% for level 3), the shortest FBUT (3.82±0.13 s), and the thinnest lipid layer (65.68±2.58 nm), (all P values <0.05, respectively). Patients with medium SI showed the lowest ocular surface disease index (OSDI) value (26.64±1.06), the longest FBUT (4.56±0.08 s), and the thickest lipid layer (80.20±2.90 nm). After treatment, the high SI values reduced significantly at each follow-up point compared to baseline (all P values <0.05). The medium SI group demonstrated the greatest improvement in symptoms and signs, followed by the high SI group, and the low SI group. Automated measurements of SI can effectively reflect MG secretory activity. The proposed low, medium, and high SI classifications represent different functional subtypes of MGD.

Thyroid hormone receptor-beta agonist HSK31679 alleviates MASLD by modulating gut microbial sphingolipids

As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-β (THR-β) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated. We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n= 32) or placebo (n= 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B.thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GFBTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GFBTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH. Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-β agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis.

Comparison of Real-World On-Label Treatment Persistence in Patients with Psoriatic Arthritis Receiving Guselkumab Versus Subcutaneous Tumor Necrosis Factor Inhibitors.

Treatment persistence among patients with psoriatic arthritis (PsA) is essential for achieving optimal treatment outcomes. Guselkumab, a fully human interleukin-23p19-subunit inhibitor, was approved by the United States (US) Food and Drug Administration for the treatment of active PsA in July 2020, with a dosing regimen of 100 mg at week 0, week 4, then every 8 weeks. In the Phase 3 DISCOVER-1 and DISCOVER-2 studies of patients with active PsA, 94% of guselkumab-randomized patients completed treatment through 1 year and 90% did so through 2 years (DISCOVER-2). Real-world evidence is needed to compare treatment persistence while following US prescribing guidelines (i.e., on-label persistence) for guselkumab versus subcutaneous (SC) tumor necrosis factor inhibitors (TNFis). Adults with PsA receiving guselkumab or their first SC TNFi (i.e., adalimumab, certolizumab pegol, etanercept, or golimumab) between 14 July 2020 and 31 March 2022 were identified inthe IQVIA PharMetrics® Plus database (first claim defined the treatment start date [index date]). Baseline characteristics and biologic use (biologic-naïve/biologic-experienced) were assessed during the 12-month period preceding the index date. Baseline characteristics were balanced between cohorts using propensity-score weighting based on the standardized mortality ratio approach. The follow-up period spanned from the index date until the earlier of the end of continuous insurance eligibility or end of data availability. On-label persistence, defined as the absence of treatment discontinuation (based on a gap of 112 days for guselkumab or 56 days for SC TNFi) or any dose escalation/reduction during follow-up, was assessed in the weighted treatment cohorts using Kaplan-Meier (KM) curves. A Cox proportional hazards model, further adjusted for baseline biologic use, was used to compare on-label persistence between the weighted cohorts. The guselkumab cohort included 526 patients (mean age 49.8 years; 61.2% female) and the SC TNFi cohort included 1953 patients (mean age: 48.5 years; 60.2% female). After weighting, baseline characteristics were well balanced with a mean follow-up of 12.3-12.4 months across cohorts; 51.5% of patients in the guselkumab cohort and 16.7% in the SC TNFi cohort received biologics in the 12-month baseline period. Respective rates of treatment persistence at 3, 6, 9, and 12 months were 91.2%, 84.1%, 75.9%, and 71.5% for the guselkumab cohort versus 77.3%, 61.6%, 50.0%, and 43.7% for the SC TNFi cohort (all log-rank p<0.001). At 12 months, patients in the guselkumab cohort were 3.0 times more likely than patients in the SC TNFi cohort to remain persistent on treatment (p<0.001). Median time to discontinuation was not reached for the guselkumab cohort and was 8.9 months for the SC TNFi cohort. This real-world study employing US commercial health-plan claims data to assess on-label treatment persistence in PsA demonstrated that, at 12 months, guselkumab was associated with a 3 times greater likelihood of persistence compared with SC TNFi.