Long-term Disease Progression Research Articles

Prognostic value of morphology and hemodynamics in moyamoya disease for long-term outcomes and disease progression

To explore the relationship between morphological and hemodynamic parameters, baseline characteristics, and long-term outcomes in patients with moyamoya disease (MMD) using a computational fluid dynamics model. We retrospectively reviewed 129 patients at Beijing Tiantan hospital between July 2020 and December 2021. Perioperative clinical variables and Suzuki stage were recorded. Logistic regression analysis was employed to identify the risk factors for unfavorable long-term outcomes. The association between morphological, CT perfusion parameters, hemodynamic parameters and the Suzuki stage, clinical variables of MMD was also analyzed. Patients with high relative Wall Shear Stress (rWSS) were older and had more cases with higher Suzuki stage and worse follow-up mRS scores (p < 0.05). High rWSS at the terminal ICA and diabetes mellitus were identified as independent predictors of unfavorable long-term outcomes [OR = 3.039(1.191–7.754), p = 0.020; OR = 3.164(1.141–8.723), p = 0.027, respectively]. ROC analysis demonstrated that predictive models incorporating rWSS improved AUC values, with the highest AUC in Model 2 (AUC = 0.889). High rWSS was significantly associated with future TIA and stroke events (p = 0.032). We speculated that high rWSS and diabetes mellitus were independent risk factors for unfavorable long-term outcomes in patients with MMD. rWSS and morphological parameters are crucial for predicting MMD progression and understanding its pathogenesis.

Use of MM-SES-CD Endoscopic Improvement Thresholds Enhances Effect Size Differentiation between Adalimumab vs. Placebo: A Post-hoc Analysis of the EXTEND Trial.

The Modified Multiplier of the SES-CD (MM-SES-CD) refines the assessment of endoscopic Crohn's Disease (CD) severity by differentially weighting parameters in the original SES-CD. A threshold of <22.5 for MM-SES-CD suggests endoscopic remission and correlates with a low risk of long-term disease progression. This study examines whether MM-SES-CD-defined endoscopic remission (ER) and response criteria are more sensitive to treatment effects compared to conventional SES-CD definitions. This post-hoc analysis of the EXTEND trial compared various SES-CD and MM-SES-CD definitions of ER and endoscopic response in CD patients treated with adalimumab or placebo. The study included participants with moderate-severe CD and a baseline MM-SES-CD score ≥22.5. The primary outcome of ER, defined as MM-SES-CD <22.5, was evaluated at weeks 12 and 52. AUC analyses compared thresholds for predicting week 52 ER. Of the 100 participants (77.5% of the EXTEND population), 51 received adalimumab and 49 placebo. At week 12, 62% achieved MM-SES-CD ≥20% reduction from baseline, compared to 39% with SES-CD ≥50% reduction. At week 52, 56.9% of adalimumab-treated participants achieved MM-SES-CD <22.5, compared to 10.2% in the placebo group. MM-SES-CD ≥20% reduction at week 12 better predicted week 52 ER than SES-CD ≥50% reduction (AUC: 0.73 vs. 0.62, p=0.002). MM-SES-CD definitions improved discrimination between treatment and placebo and offered superior predictive accuracy for week 52 ER. Its use may enhance trial efficiency and better predict long-term disease outcomes.

IPECAD Modeling Workshop 2023 Cross-Comparison Challenge on Cost-Effectiveness Models in Alzheimer’s Disease

ObjectivesDecision-analytic models assessing the value of emerging Alzheimer’s disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. MethodsA benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. ResultsNine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating – sum of boxes, clinical dementia rating – global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from −US$66 897 to US$11 896. ConclusionsTrial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

The Association Between Distinct Delusional Ideations and Depressive Symptoms in Alzheimer's Disease: A Re-Analysis of CATIE-AD.

Delusional ideations, one of neuropsychiatric symptoms (NPSs), are frequently shown in the long-term progression of Alzheimer's disease (AD), and comorbid with other NPSs including depression or agitation. Despite various types of delusional ideations, the comorbidity between each delusional ideation and depressive symptoms has not been discussed. The present cross-sectional study is aimed at testing the hypothetical mechanism of comorbid pattern in AD. Among 421 patients with AD, we analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease to compare age, sex, racial type, Mini-Mental State Examination (MMSE) scores, and Neuropsychiatric Inventory (NPI) depression score of between the presence and absence of each delusional ideation (delusion of persecution, theft, jealousy, abandonment, phantom boarder, Capgras syndrome, misidentification of place, or television sign). Next, with the stratification based on MMSE score of < or > = 15 points, we further explored association between delusional ideation and depressive symptom that was found significances in the primary analysis. Among eight subtypes of delusional ideations, depression score was higher in those with persecution delusion or Capgras syndrome. Moreover, the Capgras syndrome was associated with presence of depression in severer global cognitive impairment status. As comorbid NPSs of delusional ideation in AD, depressive severity is associated with specific delusional subtype: persecution delusion and Capgras syndrome. Capgras syndrome may be attributable to severe cognitive impairment in addition to depressive symptom. The consideration of pathogenetic differences in the distinct delusional ideations may be helpful for clinicians to select the treatment strategy.

Multifocal motor neuropathy in Japan: A nationwide survey on prevalence, clinical profiles, and treatment.

Multifocal motor neuropathy (MMN) is a rare disease for which epidemiological and clinical data are limited. We conducted a nationwide survey to determine disease prevalence, incidence, clinical profile, and current treatment status in Japan. A nationwide survey was conducted in 2021 using an established epidemiological method. Questionnaires were sent to all neurology and pediatric neurology departments in Japan. An initial questionnaire was administered to determine the number of patients with and incidence of MMN. A second questionnaire was administered to collect detailed clinical information. The European Federation of Neurological Societies/Peripheral Nerve Society 2010 guidelines were used as diagnostic criteria. The estimated number of patients with MMN was 507. The estimated prevalence was 0.40 per 100,000 individuals. Detailed clinical profiles were available for 120 patients. The male-to-female ratio was 2.3:1 and the median onset age was 42 years. The median disease duration at diagnosis was 25 months. Most patients presented with upper limb-dominant muscle weakness. Motor nerve conduction blocks were found in 62% of patients and positive anti-GM1 IgM antibody results in 54%. A total of 117 (98%) patients received immunoglobulin therapy, and 91% of them showed improvement. At the time of the last visit (median, 82 months from treatment initiation), 89 (74%) patients were receiving maintenance immunoglobulin therapy. A slight progression of neurological deficits was observed during follow-up. Most patients with MMN in Japan received induction and maintenance immunoglobulin therapies, which appear to suppress long-term disease progression.

Longitudinal assessment of the progression of severe keratoconus based on corneal topography

We aimed to assess long-term disease progression in patients with severe keratoconus (KC). Clinical records of 125 patients (201 eyes) with severe KC followed-up for > 12 months were retrospectively analyzed. From these, 28 patients (31 eyes) were included. Corneal topography parameters evaluated included thinnest corneal thickness (TCT), maximum keratometry (Kmax), anterior and posterior mean corneal radii of 3 mm (aKM, pKM), steep keratometry, and KC screening indices. All patients wore rigid gas permeable contact lenses (RGPCLs) for an extended period. The median patient age and follow-up period were 20 (interquartile range [IQR] 17–22) years and 25 (15–38) months, respectively. Compared to baseline, the aKM, Kmax, and KC screening indices on the anterior corneal surface were reduced at the final follow-up (P < 0.05). No changes were observed in RGP-corrected visual acuity, TCT, pKM, or KC screening indices on the posterior corneal surface. The higher the baseline value, the greater the reduction in aKM and Kmax. Five patients (16%) experienced disease progression during follow-up. Patients with severe KC showed reduced anterior corneal surface curvature and no change in corneal thickness during an average follow-up period of 2–3 years while wearing RGPCLs.

Targeted therapies and conventional care for the treatment of ankylosing spondylitis in China: a cost-effectiveness analysis based on the network-meta analysis

ObjectiveThis study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system.MethodsThe York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis.ResultsCompared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows:secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used.ConclusionTargeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Association of major candidate protein biomarkers and long-term diabetic kidney disease progression among Asians with young-onset type 2 diabetes mellitus

AimsWe aim to determine the association of seven major candidate protein biomarkers and diabetic kidney disease (DKD) progression among Asians with young-onset type 2 diabetes mellitus (T2DM). Methods824 T2DM patients (onset ≤ 40 years old) were classified as DKD progressors based on yearly estimated glomerular filtration rate (eGFR) decline of >3 ml/min/1.73 m2 or >40 % from baseline. Plasma leucine-rich α-2-glycoprotein 1 (pLRG1), tumor necrosis factor-receptor 1 (pTNF-R1), pigment epithelium-derived factor (pPEDF), urinary α-1-microglobulin (uA1M), kidney injury molecular 1 (uKIM-1), haptoglobin (uHP) and uromodulin (uUMOD) were measured using enzyme-linked immunoassays. ResultsOver 5.7 years of follow-up, 25.2 % of patients were DKD progressors. Elevated levels of pLRG1, pTNF-R1, pPEDF, uA1M, uKIM-1 and uHP were associated with DKD progression. The association between pTNF-R1 levels and DKD progression persisted after adjusting for clinical covariates (OR 1.84, 95 %CI 1.44–2.34, p < 0.001). The effects of pTNF-R1 were partially mediated through hyperglycemia (8 %) and albuminuria (10 %). Inclusion of pTNF-R1 in a clinical variable-based model improved the area under the receiver operating characteristics curve for predicting DKD progression by 0.02, from 0.72 (95 %CI 0.68–0.76) to 0.74 (95 %CI 0.70–0.78), p = 0.099. ConclusionsAmong seven major candidate proteins, pTNF-R1, partially mediated through hyperglycemia and albuminuria, robustly predicted DKD progression among Asians with young-onset T2DM.

White matter hyperintensity shape is related to long-term progression of cerebrovascular disease in community-dwelling older adults.

White matter hyperintensity (WMH) shape is associated with long-term dementia risk in community-dwelling older adults, however, the underlying structural correlates of this association are unknown. We therefore aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over time in community-dwelling older adults. The association of WMH shape and cerebrovascular disease markers was investigated using linear and logistic regression models in the Age, Gene/Environment Susceptibility-Reykjavik (AGES) study (n = 2297; average time to follow-up: 5.2 years). A more irregular shape of periventricular/confluent WMH at baseline was associated with a larger increase in WMH volume, and with occurrence of new subcortical infarcts, new microbleeds, new enlarged perivascular spaces, and new cerebellar infarcts at the 5.2-year follow-up (all p < 0.05). Furthermore, less elongated and more irregularly shaped deep WMHs were associated with a larger increase in WMH volume, and new cortical infarcts at follow-up (p < 0.05). A less elongated shape of deep WMH was associated with new microbleeds at follow-up (p < 0.05). Our findings show that WMH shape may be indicative of the type of cerebrovascular disease marker progression. This underlines the significance of WMH shape to aid in the assessment of cerebrovascular disease progression.

Case–Control and Cohort Studies in Homeopathy: Part 4 of the Research Method Series

AbstractCase–control and cohort studies are fundamental epidemiological research designs utilized to investigate the relationship between exposures and outcomes in medical research. This paper provides a comparative analysis of these two study designs, focusing on their respective strengths, applications, and implications for understanding disease etiology, progression, and intervention effectiveness. Case–control studies offer a retrospective lens, enabling researchers to assess the impact of exposures on disease development by comparing individuals with a particular outcome (cases) to those without (controls). Through meticulous selection and analysis, case–control studies unveil potential risk factors and causal relationships, particularly beneficial for investigating rare diseases or long latency periods. Conversely, cohort studies adopt a prospective approach, following a group of individuals over time to evaluate the incidence of outcomes in relation to exposures. This design facilitates the assessment of cumulative exposure effects, disease progression, and intervention efficacy, providing valuable insights into the natural history of diseases. In the context of homeopathy, both the study designs may be utilized for the evaluation of long-term treatment effects, disease progression, and patient satisfaction, shedding light on the holistic nature of homeopathic care. By embracing rigorous methodologies and leveraging the strengths of both study designs, researchers in homeopathy can advance evidence-based practice, enhancing our understanding of homeopathic principles and their practical implications in clinical settings.

Prevalence and predictors of long-term progression of chronic kidney disease in people with HIV in Ghana from 2003–2018

BackgroundHIV is associated with an increased risk of progression to chronic kidney disease (CKD), and this risk is higher in people of West African descent than many other ethnicities. Our study assessed the rates of eGFR change and predictors of rapid eGFR progression in patients receiving antiretroviral therapy (ART), including tenofovir disoproxil fumarate (TDF), in central Ghana between 2003 and 2018.MethodsThis single-centre retrospective study enrolled people with HIV (PWH) initiating ART in Ghana between 2003–2018. Demographics, hepatitis B (HBsAg) status, ART regimens and estimated glomerular filtration rate (eGFR) measurements were recorded, and analyses including multi-level model linear regression were performed to determine predictors of greater levels of eGFR decline and risk of rapid eGFR decline.ResultsSix hundred and fifty-nine adult participants were included in the study with a median follow-up time of 6 years (IQR 3.6–8.9). 149 participants (22.6%) also had confirmed HBV co-infection. eGFR mean values were lowest at the point of diagnosis and highest on the second measurement taken; mean eGFR slowly decreased over subsequent measures thereafter. TDF use was associated with the highest mean rate of eGFR decline of all nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) with a statistically significant greater annual decline of -1.08 mL/min/1.73m2/year (CI: -1.92, -0.24) compared with zidovudine. Nevirapine (-0.78mL /min/173m2/year; CI: -1.39, -0.17) and protease inhibitors (-1.55mL/mil/173m2/year; CI: -2.68, -0.41) were associated with greater eGFR declines compared with efavirenz. Negative HBsAg status was associated with greater eGFR decline compared with positive HBsAg status (-1.25mL/mil/173m2/year; CI 0.29. -2.20).ConclusionsIncreased rates of eGFR decline amongst PWH in Ghana were associated with TDF, nevirapine, and protease inhibitor use as well as negative HBsAg status. Additional research using mortality outcome data is needed to closely assess long-term predictors of eGFR decline in African populations.

Which factors help to determine the long-term response to first-line tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma: A Turkish multi-centre study.

Many developing countries lack access to recommended first-line treatments for metastatic renal cell carcinoma (mRCC), such as immune checkpoint inhibitors (ICIs) or ICI-tyrosine kinase inhibitor (TKI) combinations. As a result, predictive markers are necessary to identify patients who may benefit from single-agent TKIs for long-term response. This study aims to identify such parameters. This was a multi-centre, retrospective study of patients with mRCC who were undergoing first-line treatment with sunitinib or pazopanib. Patients who had been diagnosed with mRCC and had not experienced disease progression for 36 months or more were deemed to have achieved a long-term response. Predictive clinical and pathological characteristics of patients who did not experience long-term disease progression were investigated. A total of 320 patients from four hospitals were included in the study. The median age of the patients was 60 years (range 20-89 years). According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, 109 patients were classified as having favourable risk and 211 were in the intermediate-poor risk group. The median progression-free survival (PFS) and overall survival (OS) for all patients were 12.5 months and 76.4 months, respectively. In the long-term responder's group, the median PFS was 78.4 months. Among all patients, prior nephrectomy, the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) <1, and the absence of brain metastasis were predictive factors for long-term response. For patients in the favourable risk group, the lack of brain metastasis was a predictor of long-term response. In the intermediate-poor risk group, prior nephrectomy and ECOG PS <1 were predictive factors for long-term response. Some individuals with mRCC may experience a durable response to TKIs. The likelihood of a long-term response can be determined by factors such as nephrectomy, ECOG PS < 1, and the absence of brain metastases.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.

e18003 Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Early extracorporeal photopheresis treatment is associated with better survival in patients with chronic or recurrent acute lung allograft dysfunction.

Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation.

#2679 Prediction of acute eGFR decline after first initiation of RASI inhibitors and its impact on clinical outcomes

Abstract Background and Aims The objective of this study is to investigate the correlation between acute eGFR (estimated glomerular filtration rate) decline after initiation of ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin receptor blocker) medications and clinical outcomes in a real-world setting. Additionally, we aim to establish a risk prediction model to identify high-risk individuals who are more likely to experience a rapid decline in eGFR after drug initiation. Method A total of 2026 adult new users of ACEI/ARB were selected from the China Renal Data System (CRDS). Patients in acute clinical states and those using nephrotoxic drugs were excluded, and it was required that patients had at least one creatinine measurement during the baseline period and one week to four weeks after drug initiation. Cox proportional hazards models were used to compare the relative risks of adverse long-term outcomes in patients with different degrees of acute eGFR decline. A multivariable logistic regression model was employed to analyze the factors influencing acute eGFR decline. Lasso regression was used to select predictive factors, resulting in a logistic regression model with 18 predictive factors. Results Among the 2026 patients, 1148 (57%), 473 (23%), and 405 (20%) experienced eGFR decline &amp;lt;5% or increase, 5-20% decline, and ≥20% decline, respectively, after initiation of RASI (renin-angiotensin system inhibitor). Following adjustment for multiple variables, an eGFR decline ≥20% was found to be associated with a higher risk of long-term renal disease progression, with a hazard ratio of 1.84 (95% confidence interval 1.19-2.85), but not significantly associated with an increased risk of all-cause mortality and cardiovascular events. Factors associated with an eGFR decline ≥20% after RASI initiation included higher BMI and Charlson index, more severe proteinuria, lower hemoglobin levels, presence of hypertension, diabetic nephropathy, arrhythmias, and concomitant use of thiazide diuretics or loop diuretics. The predictive model had a C-statistic of 0.75. Conclusion This study demonstrates that a short-term eGFR decline after RASI initiation is associated with a higher risk of long-term renal disease progression but not significantly associated with increased risks of all-cause mortality and cardiovascular events. We have developed a prediction model to estimate the risk of eGFR decline ≥20% after the initial use of RASI, which can aid clinicians in identifying patients with poorer renal outcomes following RASI initiation and facilitate timely intervention.

Modeling and Analysis of Central and Peripheral Autonomic Contributions to Decreased Cardiac Vagal Tone Following Myocardial Infarction

Loss of cardiac function following myocardial infarction is accompanied by neural adaptation in baroreflex systems that are compensatory in the short term but then become associated with long-term disease progression. A hallmark of these baroreflex changes is decreased vagal tone. The closed-loop feedback structure of the baroreflexes confounds the source of decreased vagal tone following myocardial infarction (MI). We recognize that in a feedback network causality is distributed in the network interactions, and so explore the effects of MI on the potential contribution to vagal withdrawal of each neural component of our previously published closed-loop baroreflex computational model. The model is composed of differential equations representing the blood flow through various body compartments and sigmoidal functions to represent the saturating firing behavior of neurons. Neuronal adaptations leading to decreased vagal activity could occur in various neuronal groups located centrally in the brainstem. Adaptations could also occur peripherally at the baroreceptors or the heart’s “little brain”, the intrinsic cardiac nervous system. We developed five alternative models to reflect these hypotheses. Of the alternative models, only the model representing adaptation in the baroreceptors predicted both physiological baroreflex function and a decrease in vagus nerve activity. These findings suggest that decreased vagal activity after myocardial ischemia may be due, at least in part, to a decrease in baroreceptor sensitivity. We also link these model predictions with experimental evidence from the literature. NIH U01-HL133360, NIH OT2-OD030534, NSF 1940700, and NSF OAC-1919839. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab

Backgroundin the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. Methodswe retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. Resultswe recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) Discussion and conclusionstarting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in locally advanced nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with a 5-year follow-up.

This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at Guizhou Cancer Hospital. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a "MELODIE" multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n=35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis

Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. To identify CSF biological measures associated with progressive MS pathobiology. This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Defining Endoscopic Remission in Crohn’s Disease: MM-SES-CD and SES-CD Thresholds Associated With Low Risk of Disease Progression

ObjectiveWe assessed Modified Multiplier Simple Endoscopic Score for Crohn’s disease (MM-SES-CD) and SES-CD thresholds that are best associated with low likelihood of long-term disease progression. DesignData from 61 patients with early CD who participated in the CALM long-term extension study were used as the derivation cohort and validated using the McMaster IBD database (n=99). The primary outcome was disease progression (new internal fistula/abscess, stricture, perianal fistula or abscess, CD-related hospitalization or surgery) since the end of the CALM trial. Optimal MM-SES-CD and SES-CD thresholds were determined using the maximum Youden index. Receiver operating characteristic curve analyses compared threshold scores of remission definitions on disease progression. ResultsIn the derivation cohort, based on the maximum Youden index, the optimal thresholds associated with a low likelihood of disease progression were MM-SES-CD <22.5 and SES-CD <4. A significantly greater proportion of patients with a MM-SES-CD ≥22.5 had disease progression as compared to patients in the derivation cohort with MM-SES-CD <22.5 [10/17 (58.8%) vs. 3/44 (6.8%), p<0.001]. Similarly, a significantly greater number of patients with SES-CD ≥ 4 had disease progression compared to those with a SES-CD <4 [11/25 (44.0%) vs. 2/36 (5.6%), p<0.001]. Compared to other clinical or endoscopic remission definitions, which demonstrated poor to fair accuracy, MM-SES-CD <22.5 performed the best for predicting disease progression [AUC: 0.81 (95%CI: 0.68-0.94), p<0.001]. These thresholds were confirmed in the validation cohort. ConclusionsAchievement of MM-SES-CD <22.5 or SES-CD <4 in patients with ileocolonic or colonic CD is associated with low risk of disease progression and may be suitable targets in clinical trials and practice for endoscopic healing.