Baseline Levels Research Articles

Sustained induction of autophagy enhances survival during prolonged starvation in newt cells

Salamanders demonstrate exceptional resistance to starvation, allowing them to endure extended periods without food in their natural habitats. Although autophagy, a process involving evolutionarily conserved proteins, promotes survival during food scarcity, the specific mechanism by which it contributes to the extreme starvation resistance in newt cells remains unexplored. Our study, using the newt speciesPleurodeles waltl, reveals that newt primary fibroblasts maintain constant autophagy activation during prolonged cellular starvation. Unlike normal mammalian fibroblasts, where autophagosome formation increases during acute starvation but returns to baseline levels after extended periods, newt cells maintain elevated autophagosome numbers even 4 d after autophagy initiation, surpassing levels observed in nutrient-rich conditions. UniqueP. waltlmTOR orthologs show reduced lysosomal localization compared with mammalian cells in both nutrient-rich and starved states. However, newt cells exhibit dephosphorylation of mTOR substrates under starvation conditions, similar to mammalian cells. These observations suggest that newts may have evolved a distinctive system to balance seemingly conflicting factors: high regenerative capacity and autophagy-mediated survival during starvation.

Delayed Drug-Drug Interaction Between Antiviral Drugs and Tacrolimus in a Pancreatic Islet Transplant Recipient with SARS-CoV-2 Pneumonia-A Case Study.

PAXLOVID (nirmatrelvir and ritonavir) and VEKLURY (remdesivir) are the first- and second-line antivirals administered to adult patients at risk of severe forms of SARS-CoV-2 infection (COVID-19), such as transplant recipients. As this specific population requires lifelong immunosuppressive treatments, the administration of antivirals with cytochrome P450-modulating properties exposes patients to a high risk of drug-drug interactions (DDI). A 72-year-old male patient who underwent a pancreatic islet transplant experienced DDI between antiviral treatment and tacrolimus during the management of SARS-CoV-2 pneumonia. The patient received a single dose of nirmatelvir/ritonavir followed by a single dose of remdesivir. Tacrolimus treatment was interrupted for the duration of the antiviral treatment, and the concentration of tacrolimus was within the target range for this patient. Once antiviral treatment was stopped, tacrolimus was reintroduced at the initial dose. On day 6, the patient presented with clinical and biological parameters consistent with a tacrolimus overdose. A trough concentration 18 times higher than the therapeutic target was found, prompting tacrolimus to be discontinued for 9 days and reintroduced at a lower dose, followed by a gradual increase based on therapeutic drug monitoring to the initial dose. Clinical and biological parameters gradually returned to baseline levels. Management of DDI between tacrolimus and anti-SARS-CoV-2 drugs requires a substantial therapeutic intervention and close therapeutic drug monitoring during and for several days after antiviral treatment.

6/0 PROLENE DOUBLE-FLANGED INTRAOCULAR LENS SUTURELESS SCLERAL FIXATION WITH A 27-GAUGE NEEDLE FOR INTRAOCULAR LENS SURGERY.

To report the initial experience of a modified intraocular lens (IOL) scleral fixation technique using 6/0 prolene in a double-flanged sutureless technique with a 27-gauge needle. Twenty-nine consecutive patients with IOL surgery were retrospectively reviewed between December 2021 and October 2023. Early Treatment Diabetic Retinopathy Study letters, spherical equivalent (SE), astigmatism axial degree, and intraocular pressure were evaluated at baseline and 1, 2, 3, and 6 months postoperatively. Surgery-related complications were evaluated during follow-up. Early Treatment Diabetic Retinopathy Study letters or SE at 1, 2, 3, and 6 months postoperation was significantly improved compared with baseline levels. Patients with younger (estimate [SE] = 8.011 [2.485], P = 0.006), preoperative lens drop (estimate [SE] = 8.621 [2.906], P = 0.009), idiopathic cataract (estimate [SE] = 6.021 [2.099], P = 0.048), high baseline Early Treatment Diabetic Retinopathy Study letters (estimate [SE] = 15.449 [2.352], P < 0.001), or low baseline SE (estimate [SE] = 6.357 [2.406], P = 0.018) had the greatest improvement in Early Treatment Diabetic Retinopathy Study letters during follow-up. Patients with preoperative lens or IOL dislocation had a greater postoperative SE improvement than those with preoperative lens or IOL subluxation (dislocation vs. subluxation: estimate [SE] = -189.235 [70.692], P = 0.016). There were no cases of vitreous hemorrhage, cystoid macular edema, endophthalmitis, subluxation, or dislocation were observed during the 6-month follow-up. This modified IOL scleral fixation technique is a simple, safe, and efficient method that avoids haptic manipulation and slippage, reduces postoperative complications, achieves completely sutureless surgery, and results in an achievement of surgical refractive goals.

Driving brain state transitions via Adaptive Local Energy Control Model.

The brain, as a complex system, achieves state transitions through interactions among its regions and also performs various functions. An in-depth exploration of brain state transitions is crucial for revealing functional changes in both health and pathological states and realizing precise brain function intervention. Network control theory offers a novel framework for investigating the dynamic characteristics of brain state transitions. Existing studies have primarily focused on analyzing the energy required for brain state transitions, which are driven either by the single brain region or by all brain regions. However, they often neglect the critical question of how the whole brain responds to external control inputs that are driven by control energy from multiple brain regions, which limits their application value in guiding clinical neurostimulation. In this paper, we proposed the Adaptive Local Energy Control Model (ALECM) to explore brain state transitions, which considers the complex interactions of the whole brain along the white matter network when external control inputs are applied to multiple regions. It not only quantifies the energy required for state transitions but also predicts their outcomes based on local control. Our results indicated that patients with Schizophrenia (SZ) and Bipolar Disorder (BD) required more energy to drive the brain state transitions from the pathological state to the healthy baseline state, which is defined as Hetero-state transition. Importantly, we successfully induced Hetero-state transition in the patients' brains by using the ALECM, with subnetworks or specific brain regions serving as local control sets. Eventually, the network similarity between patients and healthy subjects reached baseline levels. These offer evidence that the ALECM can effectively quantify the cost characteristics of brain state transitions, providing a theoretical foundation for accurately predicting the efficacy of electromagnetic perturbation therapies in the future.

Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors.

286 Background: Constitutive activation of ß-catenin, resulting in its nuclear accumulation and deregulated transcriptional activity, is a key event in colorectal cancer (CRC). Additionally, pathway mutations correlate with immune exclusion in CRC and across different tumor types. Disruption of the interaction of ß-catenin and its co-activator BCL9 is sufficient to suppress oncogenic ß-catenin transcriptional activity, without impacting its homeostatic functions in normal tissue. ST316 is a first-in-class, cell-penetrating peptide antagonist of the ß-catenin and BCL9 interaction. Preclinical evaluation revealed significant bioavailability and potent activity in CRC models with no impact on ß-catenin homeostatic functions such as intestinal stem cell survival or bone morphology. Methods: A phase 1-2 (P1-2) escalation-expansion study has enrolled patients (pts) with advanced solid tumors likely to harbor abnormalities in the Wnt/ß-catenin pathway, to assess the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a P2 dose (RP2D). Paired biopsies were collected when feasible and assessed for drug penetration and pharmacodynamic biomarkers. Peripheral blood (PB) collected pre- and post-treatment was assessed by flow cytometry for polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Results: As of Sep.24, 2024; 23 pts with CRC (N=14), NSCLC (N=4), PDAC (N=2), or Breast and Ovarian cancer (N=1, each), were treated in 6 cohorts (0.5-12mg/kg) with IV ST316, once weekly. Treatment related AEs were observed in 17/23 pts and were mostly low grade, except for 2 G3 AEs that resolved: Fatigue (1) and ALT/AST elevation (1). No dose-limiting toxicities (DLTs) were observed. Single agent ST316 showed disease stabilization in 4 pts. PK analysis showed dose-proportional increases in Cmax and AUC for doses up to 8 mg/kg. IHC analysis showed substantial tumor penetration of ST316 in all analyzed samples and evidence of a treatment-induced redistribution of β-catenin in a subset of pts. PB analysis indicated high baseline levels of the ß-catenin-driven immunosuppressive PMN-MDSCs , followed by a significant decrease after ST316 exposure (p&lt;0.005). The RP2D selected for combination cohorts in CRC is 8mg/kg; additional PD assessments are ongoing. Conclusions: Monotherapy ST316 was well-tolerated with dose-proportional PK and substantial tumor uptake. Pharmacodynamic analyses demonstrate mechanistic evidence of antagonism of ß-catenin signaling, including redistribution of ß-catenin subcellular localization and significant depletion of the ß-catenin-driven immunosuppressive PMN-MDSC population. Based on these data, ST316 advanced into P2 in CRC pts in combination with SoC in 2 nd and 3 rd line. Clinical trial information: NCT05848739 .

Identifying the optimal post-surgical timing of molecular residual disease (MRD) detection in colorectal cancer (CRC) using an ultra-sensitive assay: Interim results from the VICTORI study.

275 Background: While detection of MRD using ctDNA is prognostic for recurrence in CRC, some patients still recur prior to MRD detection. VICTORI is prospectively investigating NeXT Personal, an ultra-sensitive NGS-based MRD assay, to profile patients with resected CRC. Methods: Patients with CRC treated with curative intent (all stages) are tested for MRD using NeXT Personal, a bespoke assay with up to ~1,800 tumor-informed single nucleotide variants (SNVs) identified from whole-genome sequencing. Plasma is collected prior to surgery, every 2 weeks post-surgery up to week 8 (MRD landmark window), and every 3 months for up to 3 years (surveillance). We present preliminary results on 397 samples from the first 62 patients. Results: A total of 62 patients (N=36 rectal [58%], N=26 colon [42%]; N=46 stage I-III [74%], N=16 stage IV [26%]) were included in our analysis. Baseline pre-surgical sensitivity (treatment naive) was 93.5% [N=29/31]. Pre-surgical positivity rate in patients who had received neoadjuvant therapy and had residual cancer at the time of surgery was 67% [N=16/24]. 60 patients were evaluable for clinical outcomes. At a median follow-up of 355 days, 15 patients (25%) had a recurrence. Of these, all patients were ctDNA-positive prior to recurrence (100%, 14/14; 1 pt excluded due to lack of samples prior to recurrence). ctDNA detection preceded clinical relapse by a median of 194 days [range: 5-397]); ctDNA for 78.6% (N=11/14) were first detected in the MRD landmark window. All landmark-positive recurrences occurred within one year of surgery. The 14 recurrent cancers with samples were first detected at a median ctDNA concentration of 28.7 parts per million (PPM) (range 2.4-111,120), with 64.3% (9/14) of those detections in the ultra-low range of &lt;100 PPM. MRD detection at week 4 and week 8 had the greatest reduction in RFS (HR 12.86 [2.74-60.28], p=0.0012 week 4; HR 16.14 [3.52-74.09], p=0.0004 week 8), with weeks 4, 6 and 8 having similar higher prevalence of ctDNA detection (36.0% [18/50], 35.3% [18/51], 38.5% [20/52] respectively). Week 2 detection rate was 17.0% (8/46). cfDNA concentration was highest at week 2 (4.63ng/ml vs. 2.22 at baseline, p=0.00028) and 4 (3.68 vs. 2.22, p=0.0081), returning to baseline levels at week 6 (2.28 vs. 2.22, p=0.67) and 8 (2.48 vs. 2.22, p=0.64). Conclusions: In this interim report after a median ~1 year follow-up, NeXT Personal detected MRD for all patients prior to disease recurrence. Most initial MRD detection was in the ultra-sensitive range &lt;100ppm and detection at 4-8 weeks after surgery was highly prognostic for recurrence.

Supervisor resilience promotes employee well-being: The role of resource crossover

Drawing on Conservation of Resources theory and Crossover theory, we investigated the potential for crossover of a personal resource, resilience, from supervisors to employees. Specifically, the present study examined whether supervisor resilience influences employee well-being via a top-down resilience crossover process. The present study utilized a time-lagged design with three data points over a 9-month period. The sample consisted of 178 supervisors and 741 employees from the United States National Guard. Multi-level models controlling for baseline levels of the outcome variables demonstrated support for time-lagged resilience crossover from supervisor to employee. Moreover, results demonstrated support for the subsequent indirect effects on improved employee well-being outcomes including lower burnout and psychological distress, and greater life satisfaction. As such, our research contributes to our understanding of promoting employee resilience, crossover effects, and promoting employee well-being. In doing so, we integrate COR theory and Crossover theory to elucidate personal resource crossover as it pertains to supervisor and employee resilience. Additionally, we expand on understanding of how supervisor resilience can have indirect positive effects on employee well-being. Implications for theory and practice, as well as future research directions are also discussed in light of our findings.

A phase 2 study of intravenous pembrolizumab and intratumorally injected autologous dendritic cells (DCs) in refractory colorectal cancer (CRC).

TPS319 Background: Immune checkpoint inhibitors (ICIs) have shown limited benefit in CRC outside the microsatellite instability high (MSI-H) population. Deficient cytotoxic T lymphocyte (CTL) trafficking to the tumor microenvironment (TME) and excess pro-tumorigenic cytokines and immunosuppressive cells may contribute to primary ICI resistance in microsatellite stable (MSS) CRC. Selective enrichment of T cells with specific chemokine receptors may enhance antitumor immunity. Studies highlight the role of IL-12 in improving progression-free survival (PFS) and overall survival (OS) in patients on DC therapies. Our group developed ST-aDC1s, optimized for high production of high levels of IL-12 and CTL-attracting chemokines when injected intratumorally. In preclinical models, ST-aDC1s combined with anti-PD-1/PD-L1 therapy showed therapeutic synergy, suggesting ST-aDC1s as a promising alternative to traditional DC vaccines for inducing CTL entry into tumors. Methods: We designed an open-label, non-randomized, phase 2 study of intratumoral autologous ST-αDC1 combined with pembrolizumab in recurrent/metastatic unresectable MSS CRC. Eligible patients must have prior treatment with, or contraindication to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (if RAS wild type), be anti-PD-1/PD-L1 therapy naïve, have ECOG PS ≤1, and have at least two target lesions, one amendable to biopsy and injection. Leukapheresis will collect monocytes for ST-αDC1 generation. Patients will receive intratumoral ST-αDC1s (6 million) on days 1 and 8 with biopsies, and an optional dose on day 50 before a third pembrolizumab dose. Pembrolizumab 200 mg IV will start on day 8, given every 3 weeks for 4 doses during the study period. Pembrolizumab will continue as conventional care afterwards. CT scans will occur after 2 and 4 doses of pembrolizumab. A safety lead-in cohort will include six patients, with up to 17 patients enrolled. The primary endpoint is objective response rate (ORR) at 12 weeks per RECIST 1.1. Secondary endpoints are safety, PFS, OS, and ORR per iRECIST. Correlative analysis will assess baseline levels and post-treatment changes in infiltrating T cells, CD4/CD8 ratios, FoxP3+ Tregs, and Teff-attracting and Treg-favoring chemokines from biopsy specimens, and immune cell subsets and cytokine levels from peripheral blood. With an expected ORR under 5% for standard treatment, 17 patients are required to show at least a 25% ORR with 81.2% power and a one-sided type I error rate of 0.05. A Simon two-stage Optimal design will enroll 9 patients in stage 1, and if ≥1 response occurs, 8 more patients will be added in stage 2. If ≥3 responses are observed, the treatment will be deemed promising for further study. Clinical trial information: NCT05518032 .

Phase Ib study of gevokizumab (GEVO) in combination with standard-of-care (SoC) anticancer therapies in patients (pts) with metastatic colorectal cancer (mCRC), metastatic gastroesophageal cancer (mGEC), and metastatic renal cell cancer (mRCC).

135 Background: GEVO, a humanized monoclonal antibody, binds to interleukin-1β (IL-1β) and inhibits its activity. We report results from a phase Ib study of GEVO + SoC anticancer therapies in pts with mCRC/mGEC/mRCC. Methods: This open-label study enrolled pts aged ≥18 years in cohorts A (first line mCRC, [A]), B (second line [2L] mCRC, [B]), C (2L mGEC, [C]) and D (2L/third line mRCC, [D]). The primary objectives were to determine the pharmacodynamically-active dose (PAD) of GEVO monotherapy in A/B, the safety and tolerability, and the recommended dose for expansion (RDE) of GEVO + SoC in A/B/C/D, and the efficacy of GEVO + SoC at RDE in A/B/C measured by the progression-free survival (PFS) rate. The proof of concept (PoC) criteria for PFS rates were ≥42% at 15 months (m) (lower 80% CI limit ≥29%) in A, ≥48% at ~9 m (lower 80% CI limit ≥37%) in B, ≥51% at 6 m (lower 60% CI limit ≥38%) in C. The relationship between baseline levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and IL-1β, and on-treatment decrease of circulating tumor DNA (ctDNA) levels with clinical response was explored. Results: As of March 1, 2023, 71 (A), 62 (B), 26 (C) and 7 pts (D) were treated. The PAD was established as 120 mg GEVO intravenous (IV) every 4 weeks (Q4W) and the RDE as 120 mg GEVO IV Q4W + SoC. There were 2 dose-limiting toxicities: grade 4 decreased neutrophil count (1 pt in C) and grade 3 hyponatremia (1 pt in D). The most frequent grade ≥3 treatment-related adverse events (≥15% of all pts) were neutropenia (A/B: 21.1%/22.6%), decreased neutrophil count (A/B/C: 18.3%/17.7%/15.4%) and hyponatremia (D: 28.6%). The PFS rates were 29.0% (80% CI: 20.4, 38.2), 39.4% (80% CI: 29.8, 48.9), 20.0% (60% CI: 13.3, 27.6) in A/B/C, respectively. In B, median PFS and overall survival (OS) were significantly longer in pts with baseline hs-CRP &lt;10 mg/L (low [L]) than ≥10 mg/L (high [H]), IL-6 &lt;9.58 pg/mL (L) than ≥9.58 pg/mL (H), and IL-1β &lt;0.12 pg/mL (L) than ≥0.12 pg/mL (H). In A + B, a median on-treatment decrease of ctDNA fraction by &gt;72% (H) was associated with significantly longer OS. Conclusions: The safety and tolerability of GEVO combinations was acceptable. The primary PFS rates did not meet the PoC criteria. Baseline levels of hs-CRP, IL-6 and IL-1β in pts with 2L mCRC, and on-treatment reduction of ctDNA in pts with 1L + 2L mCRC may have prognostic value. Clinical trial information: NCT03798626 . Variables PFS HR (95% CI) p-value OS HR (95% CI) p-value Ahs-CRP L / HIL-6 L / HIL-1β L / H 1.74 (0.81, 3.73)1.38 (0.70, 2.72)1.50 (0.74, 3.01) 0.1550.3520.259 1.99 (0.66, 5.98)1.73 (0.71, 4.20)0.98 (0.38, 2.52) 0.2210.2250.973 Bhs-CRP L / HIL-6 L / HIL-1β L / H 2.56 (1.27, 5.18)2.92 (1.33, 6.40)2.41 (1.13, 5.13) 0.0090.0070.022 3.04 (1.40, 6.60)3.25 (1.43, 7.36)3.60 (1.54, 8.44) 0.0050.0050.003 A + BctDNA decrease L / H 0.65 (0.39, 1.10) 0.108 0.45 (0.24, 0.83) 0.011

Immunotherapy Using HBV Vaccine Pulsed DCs and Induced T-Cells Combined Antiviral Drugs in Treatment Naive CHB Patients-A Multi-Centre Phase II Study.

Dendritic cells are the most potent antigen-presenting cells in immune therapeutic approaches for chronic hepatitis B (CHB) infection. Here, we developed a clinical trial to evaluate the efficacy and safety of autologous HBV vaccine-pulsed DCs and their induced T cells (HPDCT) in CHB patients. This was a randomised, prospective, open-label, multicentre, superiority study and 309 treatment-naive CHB patients were divided into HPDCT plus nucleos(t)ide analogues (NAs) group (n = 84), NAs mono-therapy group (n = 82), HPDCT plus Peg-interferon (Peg-IFN) group (n = 69), Peg-IFN mono-therapy group (n = 74). Twelve times of HPDCT vaccinations were given intravenously, and all the patients were followed up for 72 weeks. In total, 1836 HPDCT infusions were administered with no obvious toxicity and side effect although few patients had self-limited low fever. More patients got HBsAg loss in those receiving HPDCT therapy. Patients of HPDCT plus Peg-IFN group with HBV DNA < 1 × 107 IU/mL at baseline exhibited earlier, stronger and longer lasting of viral response, especially HBV DNA < 20 IU/mL, than those patients of Peg-IFN mono-therapy group, from week 24 till week 72 (p < 0.05). Comparable efficacy was observed between the patients of HPDCT plus NAs group and NAs mono-therapy groups. In addition, CD25 on CD8+ T cells and HBV-specific CD8+ T cell increased significantly in patients of HPDCT combined antiviral drugs therapy. HPDCT combined with antiviral drugs was safe and able to enhance T cell immunity. Furthermore, HPDCT combined with Peg-IFN could provide an incremental benefit to patients with baseline levels of lower HBV DNA. Trial Registration: ClinicalTrials.gov identifier: NCT01935635.

Recovery trajectories after major abdominal surgery: A retrospective pooled cohort study.

Recovery from major surgery can be difficult to predict given the many factors involved in treating disease and restoring preoperative function. Postoperative recovery metrics such as length of stay, complications, and mortality are typically described. However, large data quantities for patient-reported recovery are scarce. In this retrospective study, we aimed to describe the multidimensional recovery trajectory of patients undergoing major abdominal surgery 4-8 weeks after surgery and explore factors related to incomplete overall recovery. We retrospectively analysed pooled cohort data of adults undergoing elective major abdominal surgery between 2018 and 2024 across three tertiary-level hospitals. Recovery was measured at postoperative days 1, 3, 7, 14, weeks 4-8, and 3 months using the Postoperative Quality of Recovery Scale (PostopQRS). Physiological, nociceptive, emotive, activities of daily living (ADL), and cognitive domains were assessed, with recovery defined as a return to, or improvement of, preoperative baseline levels. Overall recovery was defined as recovery in all domains. Length of stay was assessed for patients who recovered overall, or did not recover, at postoperative weeks 4-8. Six hundred and fifty-three patients were included, with mean (SD) age of 57.8 (14.4) years. Of these, 36% were aged ≥65 years and 58% were male. The incidence of overall recovery at postoperative week 4-8 was 42%. Domain-level recovery at postoperative weeks 4-8 was 63% for nociception, 81% for emotion, 82% for ADLs, and 83% for cognition. Patients failing to achieve overall recovery at weeks 4-8 had longer mean (SD) lengths of stay compared to those who recovered (11.3 (10.3) vs. 7.3 (7.1) days, p < .001). The incidence of overall recovery at postoperative week 4-8 was 42%. Patients with incomplete overall recovery had longer lengths of stay. Multidimensional strategies to improve the recovery trajectory warrant further investigation. Major surgical procedures are often followed by a lengthy and difficult recovery period. Traditional measures such as mortality and complications are usually analysed, but this 653-patient study investigated patient-reported recovery scores after major abdominal surgery. Novel findings include that only 42% of patients have recovered fully in all recovery domains at weeks 4-8, and these patients also had longer hospital stays. Preoperative risk factors were analysed for associations with recovery trajectories.

Inter-Reader Agreement in LR-TRA Application and NLR Association in HCC Patients Treated with Endovascular vs. Ablative Procedures

Objectives: This study aimed to assess the performance of the LI-RADS tumor response algorithm in analyzing inter-reader agreement in patients with hepatocellular carcinoma (HCC) treated with Microwave Ablation (MWA) and Transarterial Embolization (TAE) and the relationship between inter-reader agreement and Neutrophils to Lymphocytes ratio dynamic variations at different time points to explore how inflammation influences tumor response and its interpretation on imaging. Methods: A retrospective analysis was conducted on 78 HCC patients treated with MWA or TAE. Two independent radiologists evaluated pre- and post-treatment imaging and assigned categories according to the LR-TRA. Inter-reader agreement was assessed with a focus on subgroup analysis considering the different locoregional treatments. NLR values, measured at baseline (T0), 72 h (T1), and 30 days post-procedure (T2), were compared with patients with concordant and discordant LR-TRA assessments. This analysis aimed to identify any association between NLR dynamics and inter-reader agreement on treatment response. Results: The inter-reader agreement in the LR-TRA application was “substantial” in the cases of MWA treatment evaluation (κ = 0.65), and “moderate” in the cases of TAE treatment evaluation (κ = 0.51). The differences in inter-reader agreement were found to be expressions of different levels of NLR mean values in the different time frames evaluated. Three days after treatment, NLR increased significantly in TAE groups. At 30 days, NLR had returned close to baseline levels but with NLR persisting higher in the TAE group. There was a statistically significant difference in NLR between the “mismatch” group (those with discrepant LR-TRA readings) and the “match” group at 3 days (p = 0.004) and late evaluation (30+ days). Conclusions: This study has shown that NLR levels can predict inter-reader discrepancies in LR-TRA assessment and may be translated into different levels of difficult imaging interpretation. Combining LR-TRA and NLR is promising for a more comprehensive assessment of tumor response and inflammatory dynamics.

Dynamic changes of excitatory and inhibitory synapses in layer II/III of the primary motor cortex after peripheral nerve repair.

Peripheral nerve injury disrupts communication between the primary motor cortex (M1) and the target muscle, leading to alterations in synaptic plasticity within the lesion projection zone (LPZ). While nerve repair holds the potential to restore this pathway and further modulate synaptic plasticity within the LPZ, the underlying mechanisms remain incompletely understood. In this study, we established a rat model with immediate repair following unilateral median nerve transection and categorized the functional recovery of the affected limb into three phases: the injury phase, recovery phase, and rehabilitation phase, corresponding to stages of muscle non-reinnervation, gradual reinnervation, and completed reinnervation, respectively. Our findings revealed that during these phases, excitatory synaptic transmission in M1 layer II/III pyramidal neurons initially decreases, then increases, and ultimately returns to baseline levels. Conversely, inhibitory synaptic transmission initially increases, then decreases, and remains reduced even after full peripheral recovery, accompanied by upregulation of inhibitory synaptic receptors. These findings suggest that excitatory and inhibitory synaptic plasticity play opposing roles in the nerve repair process, with excitatory plasticity primarily involved in short-term responses and inhibitory plasticity contributing to both short-term and long-term modulation.

Factors Influencing Liver Cirrhosis Progression in Wilson's Disease Patients: A Retrospective Cohort Study Over 5 Years.

Wilson's disease (WD) is a rare autosomal recessive inherited disorder characterized by dysregulated copper metabolism, amenable to treatment with chelating agents. It manifests with hepatic and neurological symptoms, often precipitating the development of liver cirrhosis as a prominent complication. This study aims to elucidate the factors, biomarker alterations, and therapeutic modalities influencing the progression of cirrhosis in WD patients. This retrospective cohort study utilized WD patient data from West China Fourth Hospital (May 2018-September 2023). The primary outcome was the development of cirrhosis in initially cirrhosis-free WD patients. LASSO-COX regression identified predictive factors. The 1:1 propensity score matching generated a matched subgroup for robust Cox regression validation. Among 133 initially cirrhosis-free WD patients, 47 developed cirrhosis during 35.98 (22.04-49.21) months. Significant differences were observed between the cirrhosis and non-cirrhosis groups in age at enrollment, age at WD diagnosis, clinical symptoms, educational levels, and administration of dimercaptosuccinic acid, compound glycyrrhizin polyene, and phosphatidylcholine. Multivariate Cox regression identified age at enrollment (hazard ratio [HR]: 1.038, 95% CI: 1.002-1.075), the use of glycyrrhizin (HR: 0.421, 95% CI: 0.192-0.926), erythrocyte (HR: 0.748, 95% CI: 0.626-0.895), and platelet counts (HR: 0.993, 95% CI: 0.988-0.998) associated with cirrhosis. Robust Cox analysis on the matched subgroup confirmed these findings. Glycyrrhizic acid emerges as a potential hepatoprotective agent for WD patients. Furthermore, the progression of cirrhosis in WD patients is characterized by advanced age and decreased baseline levels of erythrocytes and platelets, suggesting their potential utility as prognostic indicators.

Effects of critical thinking instruction on Chinese college students with varying baseline critical thinking abilities: A quasi‐experimental study

AbstractThis study aimed to contribute to the substantial body of research on critical thinking (CT) interventions by determining whether the effectiveness of two CT interventions (generic and infusion) varied according to students' baseline CT levels. Using a quasi‐experimental design, we collected data from two universities, with 167 participants from University A and 76 from University B. Students' CT skills were measured before and after the interventions using the National Assessment of Collegiate Capacity (NACC) CT assessment. The analysis employed paired t‐tests to evaluate within‐group changes and independent t‐tests with moderation analysis to compare CT gains between experimental and control groups across different baseline CT performance levels. Results showed that infusion CT interventions, rather than generic CT interventions, had a beneficial effect on these students' CT. Notably, the effectiveness of these interventions depended on students' baseline level of CT skills, suggesting that, while CT interventions may not result in substantial improvements for students with high and low baseline levels of CT skills, those with moderate levels can benefit significantly from these interventions. This study contributes to research on the effectiveness of embedding CT within course contents and differentiation based on baseline skills in maximising the impact of CT interventions within an educational context.

Werden Serum-Biomarker bald eine Rolle in der Behandlung systemischer Sklerose-assoziierter interstitieller Lungenerkrankung spielen?

Objective: Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). Methods: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. Results: Serum levels of KL-6 [MD 35.67 (95% CI 22.44–48.89, P &lt; 0.01)], SP-D [81.13 (28.46–133.79, P &lt; 0.01)], CCL18 [17.07 (6.36–27.77, P &lt; 0.01)], YKL-40 [22.81 (7.19–38.44, P &lt; 0.01)] and MMP-7 [2.84 (0.88–4.80, P &lt; 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53–1.00, P’ &lt;0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01–1.61, P’ =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52–9.03, P &lt; 0.01)] or SP-D [OR 2.00 (1.06–3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665–1.554, P &lt; 0.01)] showed improved performance compared with KL-6 and SP-D alone.

Subjective sleep quality, but not objective sleep measures, mediates the relationship between pre-sleep worrying and affective wellbeing.

Pre-sleep worrying is associated with sleep disturbance, which in turn is associated with impaired affective wellbeing. However, studies examining the fine-grained temporal order of these variables are still lacking. In particular, within-person mediation of the association between pre-sleep worrying and the following day's affective wellbeing by subjective and objective indicators of sleep has not been tested yet. This study investigates the extent to which pre-sleep worrying predicts positive/negative affect the following day, and whether subjective/objective sleep disturbances are possible mediators for this relationship. Data from two experience sampling studies were pooled for the analyses, resulting in a total sample of 220 participants aged between 18 and 30 years (M = 23.2 years, SD = 2.8). The hypotheses were tested at both the between- and within-subject level using causal mediation analysis. The within-subject analyses revealed partial mediation of the relationship between pre-sleep worrying and positive as well as negative affect the next day by subjective sleep quality. By contrast, sleep as measured by actigraphy appears not to be relevant for the link between pre-sleep worrying and affective wellbeing the following day. Baseline levels of depressive symptoms and sleep disturbances did not moderate the associations between pre-sleep worrying, sleep indices and affective states the following day. Improving perceived sleep quality by addressing pre-sleep worrying could be a potential avenue to enhance affective wellbeing and promote better mental health in young adults.

Early release of circulating tumor cells after transarterial chemoembolization hinders therapeutic response in patients with hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the first-line therapeutic option for patients with intermediate-stage hepatocellular carcinoma (HCC). Tumor neovascularization allows tumor growth and may facilitate the release of circulating tumor cells (CTCs) to the bloodstream after TACE. We investigated the relationship between early release of CTCs and radiological response after TACE. Prospective, single-center study including patients with HCC undergoing a first TACE from January 2019 to June 2023. The IsoFlux® system was used to evaluate EpCAM+ CTC counts before TACE, at day 1 (D1), and at day 30 after TACE. Radiological response to TACE was assessed according to the mRECIST criteria one month after the procedure. Tumor vascularity was assessed by an interventional radiologist. In all, 48 patients with HCC undergoing TACE were included (age 64.2 ± 7.6 years, 14.6% women). CTC levels increased at D1 (114.0% [IQR 76.5%-178.0%], p = 0.019) and normalized to baseline levels in the first month after TACE (76.5% [IQR 41.3%-131.8%], p = 0.263). Higher CTC counts at baseline (p = 0.009) and at D1 (p = 0.026) were associated with tumor hypervascularity. Larger tumor size [OR: 1.9 (95% CI: 1.1-3.3), p = 0.020] and CTC increase at D1 [OR: 5.3 (95% CI: 1.3-21.0), p = 0.017] were independent predictors of non-response to TACE, especially for those patients with hypervascular lesions. A meaningful release of CTCs 24 h after TACE was associated with suboptimal tumor response one month after the procedure. Future studies should evaluate the role of CTC dynamics to select candidates for adjuvant therapy after TACE and to analyze their impact on long-term outcomes.

Biomimetic Silk Nanoparticle Manufacture: Calcium Ion-Mediated Assembly.

Silk has emerged as an interesting candidate among protein-based nanocarriers due to its favorable properties, including biocompatibility and a broad spectrum of processing options to tune particle critical quality attributes. The silk protein conformation during storage in the middle silk gland of the silkworm is modulated by various factors, including the most abundant metallic ion, calcium ion (Ca2+). Here, we report spiking of liquid silk with calcium ions to modulate the silk nanoparticle size. Conformational and structural analyses of silk demonstrated Ca2+-induced silk assemblies that resulted in a liquid crystalline-like state, with the subsequent generation of β-sheet-enriched silk nanoparticles. Thioflavin T studies demonstrated that Ca2+ effectively induces self-assembly and conformation changes that also increased model drug loading. Ca2+ incorporation in the biopolymer feed significantly increased the nanoparticle production yield from 16 to 89%, while simultaneously enabling Ca2+ concentration-dependent particle-size tuning with a narrow polydispersity index and altered zeta potential. The resulting silk nanoparticles displayed high biocompatibility in macrophages with baseline levels of cytotoxicity and cellular inflammation. Our strategy for manufacturing biomimetic silk nanoparticles enabled overall tuning of particle size and improved yields─features that are critical for particle-based nanomedicines.

P-441. Gut Permeability Response to Inulin Supplementation in Well-Controlled HIV Patients with Metabolic Syndrome

Abstract Background HIV infection is known to cause abnormally increased gut permeability resulting in chronic inflammation. Serum levels of Zonulin protein are elevated in persons with increased gut permeability. The objective of this study is to assess whether Inulin (fiber) supplementation will result in a decrease in gut permeability in well-controlled HIV patients with metabolic disorder as measured by baseline and post-intervention Zonulin levels. Statistical Results There was a statistically significant increase in median Zonulin levels from baseline to post-intervention (p=0.002) Methods 10 subjects were selected from patients enrolled in care at the Center for AIDS Research and Treatment (CART) based at North Shore University Hospital. Eligibility criteria included well-controlled HIV patients with evidence of metabolic syndrome. The duration of the study was 6 weeks and the intervention was Inulin supplement use. Bloodwork drawn pre- and post-intervention included Zonulin levels, A1c, Fructosamine, Cholesterol, Triglycerides, HDL, LDL, and non-HDL levels. BMI was also checked. Patients were provided with organic Inulin powder and instructed to take 1 tablespoon once a day for the first week and advance to twice a day for the rest of the study. Every week patients were contacted via telephone to assess compliance and side effects. The primary endpoint was the assessment of baseline and post-intervention Zonulin levels, with the secondary endpoint including baseline and post-intervention BMI, A1c, Fructosamine and Lipids. Descriptive statistics were computed and significance was determined via Wilcoxon signed-rank test. Pre and Post Intervention Zonulin levels in all 10 subjects Results Among the patients enrolled 80% were male, 60% were White, 80% were not Hispanic or Latino, and the median age was 60.5. Flatulence and bloating were the most frequent side effects of inulin reported. The median Zonulin levels at baseline were 177.9µg/mL, and post-intervention were 532.4µg/mL. There was a statistically significant increase in Zonulin levels from baseline to post-intervention (p=0.002). There was no significant difference between baseline and post-intervention for any of the other parameters in the dataset. Conclusion Inulin supplementation resulted in a statistically significant increase in Zonulin levels, which goes against our hypothesis. Whether this is due to underlying worsening of pre-existing gut dysbiosis or other factors needs further study. Disclosures All Authors: No reported disclosures