One-tailed Research Articles

A Retrospective Analysis of the Long-Term Safety and Efficacy of A1-UV Intraocular Lens Combined with Capsular Tension Ring in the Treatment of Patients with Cataract and Suspensory Ligament Abnormalities

Objective: To evaluate the long-term safety and efficacy of the combination therapy of A1-UV Intraocular Lens (IOL) and Capsular Tension Ring (CTR) for cataract patients with abnormal suspensory ligaments. Method: Retrospective data analysis. Extract all patient information related to A1-UV IOL and 920H IOL from the existing Clinical Trial Database of CTR to form a new dataset. The new dataset focuses on IOL and the clinical safety and efficacy of A1-UV IOL and 920H IOL combined with CTR was compared and analyzed based on it. The follow-up time points include 1-2 days, 1 week, 1 month, 3 months, 6 months and 1 year. Evaluation indicators include Best-Corrected Distance Visual Acuity (BCDVA), Uncorrected Distance Visual Acuity (UCDVA), spherical power, cylindrical power, Equivalent Spherical power (SE), Intraocular Pressure (IOP), corneal endothelial cell density, inflammatory response, Adverse Events (AE) and Serious Adverse Events (SAE). Statistical analysis was conducted using SPSS 22.0 software. All statistical tests are conducted using a two-sided test, and a P-value less than 0.05 is considered statistically significant for the difference being tested. Compare the quantitative data using t-test or Wilcoxon rank-sum test. Compare count data using chi-square test or Fisher's exact probability. Results: The number of cases in the A1-UV group and 920H group were both 27 (monocular), with an average age of 68.46 ± 6.93 years old and 70.27 ± 10.95 years old, respectively. The sample sizes at 6 months and 1 year after surgery were 26 cases (96.30%) and 21 cases (77.77%) in the A1-UV group, respectively, while the 920H group consisted of 26 cases (96.30%) and 22 cases (81.48%), respectively. The use of two types of IOLs combined with CTRs can significantly improve BCDVA and UCDVA (both P<0.05). The differences between the groups during each follow-up period were not statistically significant (all P>0.05). The average residual spherical power, residual cylindrical power, and residual SE of both groups of patients after surgery were close to emmetropic eye. There was no statistically significant difference (P>0.05) in the comparison of other refraction indicators between the groups during each follow-up period, except for the cylindrical power at 3 months and 1 year after surgery. In the A1-UV group, a total of 2 patients experienced 3 episodes of mild IOP elevation, which was judged by the investigator to be unrelated to IOL, and no drug treatment was used, and it recovered spontaneously. 3 patients in the 920H group experienced three episodes of high IOP, including two mild cases (one possibly related to the IOL) and one moderate case (possibly related to the IOL), all of which were controlled by medication and recovered. In addition, the IOP of the remaining patients during each follow-up period after surgery was within the normal range. There was no AE or SAE related to implanted products in the A1-UV group. Conclusion: The combination of A1-UV IOL and CTR has long-term good safety and efficacy in the treatment of complex cataract patients with suspensory ligament abnormalities.

Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer.

NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non-small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428), a randomized phase II trial, studied whether midtreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease. Patients fit for concurrent chemoradiation were randomly assigned (1:2) to standard (60 Gy/30 fractions) or FDG-PET-guided adaptive treatment, stratified by substage, primary tumor size, and histology. All patients had midtreatment FDG-PET/CT; adaptive arm patients had an individualized, intensified boost RT dose to residual metabolically active areas. The primary therapeutic end point was 2-year centrally reviewed freedom from local-regional progression (FFLP), defined as no progression in or near the planning target volume and/or regional nodes. FFLP was analyzed on a modified intent-to-treat population at a one-sided Z-test significance level of 0.15. The primary imaging end point was centrally reviewed change in SUVpeak from baseline to midtreatment; its association with FFLP was assessed using the two-sided Wald test on the basis of Cox regression. Of 138 patients enrolled, 127 were eligible. Adaptive-arm patients received a mean 71 Gy in 30 fractions, with mean lung dose 17.9 Gy. There was no significant difference in centrally reviewed 2-year FFLP (59.5% and 54.6% in standard and adaptive arms; P = .66). There were no significant differences in protocol-specified grade 3 toxicities, survival, or progression-free survival (P > .4). Median SUVpeak and metabolic tumor volume (MTV) in the adaptive arm decreased 49% and 54%, from pre-RT to mid-RT PET. However, ΔSUVpeak and ΔMTV were not associated with FFLP (hazard ratios, 0.997; P = .395 and .461). Midtreatment PET-adapted RT dose escalation as given in this study was safe and feasible but did not improve efficacy outcomes.

Palliative Homecare in Chronic Liver Disease: A Cohort Analysis of Factors and Outcomes Associated with Home Palliative Care in Patients with End-Stage Liver Disease.

Objective: The prevalence and mortality of chronic liver disease has risen significantly. In end-stage liver disease (ESLD), the survival of patients is approximately 2 years. Despite the poor prognosis and high symptom burden, integration of palliative care in ESLD is reduced, and the majority of patients continue to die in inpatient care. We aim to assess predictors and outcomes of home palliative care, as well as factors associated with death at home in patients with ESLD. Methods: Retrospective cohort study of patients with ESLD, followed by a palliative care team between 2017 and 2022. Information regarding patient demographics, ESLD etiology, decompensations, and interventions was collected. Two-sided tests were used to identify factors associated with home palliative care. Results: We analyzed 75 patients: 44% had home palliative care and 33% died at home. ESLD patients with home palliative care were older (72.52 vs 64.45; p = 0.002), had a longer palliative care intervention time (149.97 ± 196.23 vs 43.69 ± 100.60 days; p = 0.007), higher rates of ascites or hepatic encephalopathy (χ2 = 11.024; p = 0.029), and hepatocarcinoma (90.9% vs 64.3%; p = 0.007). Patients with home palliative care had a reduction in-hospital admissions (2.61 vs 1.06; p = 0.000) and a greater probability of death at home (66.7% vs 33.3%; p = 0.000). Patients who died at home (33.3%) were older (72.20 vs 64.40; p = 0.000) and had longer palliative care intervention time (178.80 ± 211.78 vs 46.28 ± 99.67 days; p = 0.006). Conclusion: Home palliative care in ESLD differs based on demographics and disease complications, with a positive impact of homecare translated into a reduction in hospital admissions and an increased probability of death at home.

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.

Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing. We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

Predisposing factors for incomplete spontaneous recovery after Parsonage-Turner Syndrome.

Parsonage-Turner Syndrome (PTS) is a rare idiopathic brachial neuritis that classically presents with sudden onset upper extremity pain followed by upper limb weakness, sensory disruption, and muscle atrophy. We hypothesized that the type of antecedent event before symptom onset would determine the degree of spontaneous recovery after PTS. We retrospectively reviewed all patients who presented with PTS to a single tertiary referral center from January 2002 to December 2021. Each medical record was reviewed to exclude patients with any other identifiable neurologic etiology. The primary outcome was improved muscle strength measured by a modified British Medical Research Council (mBMRC) grading system. The spontaneous recovery cohort included patients with appreciable or full recovery (mBMRC 4 and 5). In contrast, patients with little to no recovery (mBMRC 0 to 3) were included in the incomplete recovery group. Antecedent events, demographic variables, affected upper extremity region, time between symptom onset and final visit, and presence of nerve surgery were analyzed. Two-tailed T-test and Fisher exact tests were used to compare continuous and categorical variables. Multivariable logistic regression was modeled to identify variables associated with spontaneous recovery. 100 patients with 144 extremities met the inclusion criteria. The average time from symptom onset to the final clinic visit was 3.5 years. 65 extremities (57.0%) spontaneously recovered without surgical intervention, whereas 49 extremities (43.0%) incompletely recovered. The spontaneous recovery cohort was younger (mean [SD] age, 47.4 [18.1] vs. 56.5 [18.7]; p = 0.02) and had fewer bilateral cases (count[%], 4 [6.5%] vs. 10 [26.3%]; p = 0.008). Multivariable logistic regression revealed that each year of increased age was associated with a 3% decreased chance of spontaneous recovery (OR[95%CI] 0.97[0.95, 0.99], p = 0.046). Bilateral involvement was associated with 93% decreased chance of recovery (OR[95%CI] 0.07[0.01, 0.39], p = 0.002), each additional muscle affected was associated with 10% decreased chance of recovery (OR[95%CI] 0.90[0.83, 0.97], p = 0.01), and traumatic antecedent events were associated with increased chance of recovery (OR[95%CI] 27.3[2.59, 287.5], p = 0.006). Younger patients with unilateral symptoms and fewer muscle involvement have a greater chance of spontaneous recovery after PTS. PTS precipitated by trauma may have better spontaneous recovery than those precipitated by other causes.

Abstract Su202: Physiological response to vasopressor administration during hemodynamic-directed CPR

Background: The hemodynamic response to successive vasopressor doses during CPR and its association with survival is poorly defined. Understanding these relationships can facilitate identification of alternative vasopressor strategies. Hypothesis: Non-survival is associated with lower responsivity to successive vasopressors. Methods: We performed retrospective analysis of hemodynamic data acquired in pediatric swine models (sus scrofa, 9-12kg) of asphyxia-associated ventricular fibrillation cardiac arrest with use of hemodynamic-directed CPR (n=175). Starting 2m into CPR, if hemodynamic targets were not met, vasopressors were given in cycles comprising two doses of 0.02mg/kg epinephrine (Epi) followed by vasopressin (Vaso, 0.4U/kg), separated by a minimum of 1m. After a minimum of 2m, the cycle was repeated. Hemodynamic response was evaluated using the peak diastolic blood pressure (DBP) within 1m for Epi, 2m for Vaso administration and the difference between the initial and peak DBP (delta DBP). Subjects were classified as “responder” if either a delta DBP > 5 mmHg or a peak DBP > 25 mmHg was achieved, and a “non-responder” otherwise. Animals were deemed “survivors” if ROSC was achieved following initial defibrillation. The change in delta DBP for successive vasopressors was compared in survivors versus non-survivors using two-sided Wilcoxon rank-sum tests. Continuous variables are summarized using the median with interquartile ranges. The burden of “non-response” was used to a construct confusion matrix and calculate performance. Results: Non-survivors (n=30) had lower delta DBP than survivors (n=145) following successive vasopressor administration at the first cycle (first Epi dose: 7.8 [2.4, 14] vs 16 [7.5, 24], p< 0.01; second Epi: 2.0 [0, 4.7] vs 7.1 [2.0, 12], p< 0.01; Vaso : 1.1 [0, 2.3] vs 7.1 [2.0, 12], p< 0.01). Classification as a “non-responder” at the first cycle (Epi-Epi-Vaso) was significantly predictive of non-survival (Sensitivity 32%, Specificity 92%). Animals that failed to respond to all vasopressors at the first cycle had a significantly increased rate of mortality (86%; 6 non-survivors, 1 survivors) compared to animals that responded to all 3 vasopressors (13%; 16 non-survivors, 111 survivors). Conclusion: Mortality was significantly associated with lower DBP response to successive vasopressors during hemodynamic-directed CPR in pediatric swine models of cardiac arrest, which may suggest a critical timepoint to activate ECPR.

Abstract Su503: Relationships Between Quantitative ECG Measures and Defibrillation Success in Early Ventricular Fibrillation

Introduction: Rapid termination of ventricular fibrillation (VF) has long been recognized as the cornerstone of effective cardiac arrest resuscitation. In recent years, amplitude spectral area (AMSA) has been shown to be highly associated with defibrillation success, and AMSA has been experimentally used to personalize defibrillation timing and strategy. However, questions remain about whether the interpretation of AMSA holds uniformly in varied conditions, such as ultra-early or prolonged cardiac arrest or after anti-arrhythmic administration. Hypothesis: AMSA is greater after 20 seconds of untreated VF compared to 50 seconds of untreated VF; a higher AMSA predicts greater first-defibrillation success. Methods: VF was induced in adult swine (n = 3) with a bipolar pacing catheter placed in the right ventricle. Animals were randomized to 20- or 50-second-long episodes of VF (n = 123), followed by standard 150 J biphasic defibrillation. In MATLAB, AMSA was calculated as the summed product of frequency and square root of power after Fast Fourier Transform for the four second period of VF immediately prior to defibrillation. Results were analyzed by a two-sided Chi-squared test or ANOVA with Tukey’s HSD in R; a p-value < 0.05 was considered significant. Results: First shock success was lower in the 20-second-VF group compared to the 50 second group (31/78 (39.7%) vs 31/45 (68.8%), p = 0.003). The AMSA at 20 seconds was significantly higher for successful compared to unsuccessful first defibrillation (8.20 vs. 7.31 mV-Hz, p = 0.034). The AMSA at 50 seconds was not statistically different between successful and unsuccessful defibrillations (6.32 vs. 5.67 mV-Hz, p = 0.470). Evaluating the AMSA after a duration of VF irrespective of shock success, AMSA was higher at 20 seconds compared to 50 seconds (7.66 vs 6.12 mV-Hz, p < 0.001). Conclusion(s): AMSA decreases from 20 to 50 seconds of untreated VF, and higher AMSA at a given time point is associated with greater first defibrillation success. However, first defibrillation success was higher after 50 seconds of untreated VF compared to 20 seconds, raising questions about special cases, such as edge effects, that may influence AMSA interpretation.

NIMG-50. MULTIPARAMETRIC MRI DISTINGUISHES NEURONAL AND IMMUNE SIGNATURES IN INVASIVE HIGH-GRADE GLIOMA RIM THROUGH GRAPH NETWORK ANALYSIS

Abstract BACKGROUND Standard of care surgery for high grade glioma (HGG) employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. Multi-parametric MRI (mpMRI) has recently been used to map regional biological heterogeneity of neuronal and immune signatures in HGG, and continues to offer a promising strategy for non-invasive surveillance of tumor progression. Here, we present a graph network analysis relating mpMRI to biological signatures in the NE tumor rim and show the utility of communities of imaging features for discriminating tumor phenotypes. METHODS 53 mpMRI features across 101 spatially-localized RNA-sequenced biopsy samples from 64 patients with IDH-wt HGG were represented as nodes within a Neo4j graph network. Modularity optimization was used to identify communities of densely connected nodes. Communities of nodes representing high proportions of NE samples (one-tailed test) were kept for further analysis. Gene set enrichment analysis (GSEA) on samples within selected imaging communities was analyzed for biological process enrichment using clusterProfiler. Single sample GSEA (ssGSEA) using ssGSEA2 was used to annotate neuronal and immune cell states across samples within selected communities. mpMRI feature selection within each community identified the most relevant imaging features for isolating samples classified into neuronal and immune cell states. RESULTS 11 imaging communities gathered a high proportion of NE samples. Three NE communities showed significant enrichment of neuronal signatures, while one showed significant enrichment of immune pathways. One neuronal-predominant community showed unique upregulation of 14 pathways related to neuronal migration/astrocyte projection. CONCLUSION Network imaging communities can identify clusters of NE glioma samples showing contrasting neuronal and immune signatures, including distinct upregulation of migration and projection pathways. Mapping these imaging feature communities to specific biological processes implicated in glioma progression may aid treatment planning and prognostication for glioma patients.

ANGI-10. NETWORK ANALYSIS ESTABLISHES CSF2RA’S REGIONAL INFLUENCE ON HYPOXIA RESPONSE IN THE INVASIVE RIM OF HIGH GRADE GLIOMA

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer. Standard of care surgery employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. The hypoxic tumor microenvironment is thought to drive invasion into healthy brain, and understanding cellular responses to hypoxia may provide insight into combatting recurrence. Here, we apply a graph network to integrate regionally heterogeneous data from a unique dataset of spatially-localized CE and NE biopsies from a large cohort of patients with HGG to identify gene networks regulating hypoxia response and invasion. METHODS RNA-sequencing of 1159 differentially expressed genes across 159 IDH-wt biopsies (74 patients) from NE/CE regions were represented as nodes in a Neo4j graph network. Candidate genes for network random walks occurred exclusively within NE communities detected by modularity optimization and were localized by cell-type using single-cell RNA-sequencing (scRNAseq). CSF2RA was selected as source (walk length = 5; 10,000 walks/source node). Frequently occurring genes (one-tailed test) in walks were ranked by correlation with CSF2RA expression in NE samples and analyzed by gene set enrichment analysis for biological processes (clusterProfiler). CSF2RA and hypoxia gene expression were visualized with DoHeatmap in composite NE/CE scRNAseq profiles. RESULTS CSF2RA, an immune receptor, was upregulated (logFC = 0.789) in NE samples, scRNAseq myeloid populations, and Glycolytic/Plurimetabolic glioma subtype. CSF2RA random walk genes (n=46) enriched metabolic/proliferative signatures. CSF2RA expression correlated negatively with hypoxia genes globally and regionally (NE/CE), while NE/CE scRNAseq revealed distinct cellular expression patterns of CSF2RA and hypoxia response genes. CONCLUSION CSF2RA expression may prime NE glioma cells for invasion by altering hypoxia response. The genetic network bridging CSF2RA and hypoxia response may be a targetable mechanism of tumor recurrence.

ANGI-09. GRAPH NETWORK ANALYSIS IDENTIFIES GENETIC COMMUNITIES OF CSF2RA AND RBFOX1 AS REGULATORS OF INVASIVE HIGH-GRADE GLIOMA BIOLOGY

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer. Standard of care surgery employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. Recent multi-omics analyses identified predominant neuronal and immune signatures within NE tumor. Here, we apply a graph network to integrate regionally heterogeneous data from a unique dataset of spatially-localized CE and NE biopsies from a large cohort of patients with HGG. METHODS RNA-sequencing of 1159 differentially expressed genes across 159 IDH-wt biopsies (74 patients) from NE/CE regions were represented as nodes in a Neo4j network. Candidate genes for network random walks occurred exclusively within NE communities detected by modularity optimization and localized by cell-type using single-cell RNA-sequencing (scRNAseq). CSF2RA and RBFOX1 were selected as sources (walk length = 5; 10,000 walks/source node). Frequently occurring genes (one-tailed test) in walks were ranked by correlation with CSF2RA/RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis for biological processes (clusterProfiler). Random walk genes were visualized (DoHeatmap) against composite NE/CE scRNAseq profiles. RESULTS CSF2RA and RBFOX1 were upregulated in NE samples (logFC = 0.789, 1.85). Upregulation of CSF2RA, an immune receptor, in the Glycolytic/Plurimetabolic and RBFOX1, a neurodevelopmental regulator, in the Neuronal glioma subtypes were observed in NE samples (ANOVA p < 0.05). CSF2RA walk genes (n=46) enriched metabolic/proliferative signatures, while RBFOX1 walk genes (n=201) showed neurodevelopmental upregulation. scRNAseq localized CSF2RA to monocytes/macrophages while RBFOX1 was expressed in distinct astrocyte/neuroepithelial populations. CONCLUSION CSF2RA and RBFOX1’s gene networks modulate immune and neurodevelopmental processes influencing glioma progression in NE tumor. Understanding the region-specific roles of these networks may offer strategies for targeting cells in the invasive glioma rim.

RTID-03. A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)

Abstract BACKGROUND Systemic therapy for brain metastases (BM) is hindered by blood-brain barrier (BBB). Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive BBB disruption, which could enhance intracranial delivery of systemic immune checkpoint inhibitors. This randomized controlled trial (RCT) aims to evaluate safety and efficacy of LIFU-mediated BBB disruption plus systemic pembrolizumab for NSCLC BM. METHODS LIMITLESS (NCT05317858) is an ongoing, multicenter, parallel-arm, open-label RCT that randomizes NSCLC BM patients on standard-of-care pembrolizumab monotherapy to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting RANO-BM measurable disease criteria. All patients receive standard-of-care therapy, while those on arm 1 undergo LIFU before each pembrolizumab dose (200mg IV q3weeks). Patients undergo pre-treatment brain MRI, followed by IV microbubbles for enhanced sonication effects. MR-guided BBB disruption is performed using transcranial 220kHz LIFU device with real-time acoustic-feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after sonication, and repeat MRI is done 24-48 hours later to assess treatment effects. Primary study outcome is overall objective response rate (ORR) at 6 months as assessed using RANO-BM. Using Bayesian design for power analysis, a superior ORR of 60% is assumed for LIFU arm versus 30% for control arm for total sample size of N=96 (64 participants in LIFU and 32 in control arm), for 80% power using two-sided chi-square test with alpha=0.05. For upper-bound estimate, ORR of 45% in LIFU arm and 30% in control arm, the study needs N=369 participants (246 in LIFU arm and 123 in control arm). Secondary outcomes are best ORR and median time-to-response. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. Patient enrollment commenced in 2022 and remains ongoing.

Intrathecal enalapril reduces adhesion formation in experimentally induced digital flexor tendon sheath injuries in horses.

The objectives of the study were to describe a standing percutaneous adhesion induction model in the digital flexor tendon sheath (DFTS) of horses and to evaluate the effect of intrathecal administration of the angiotensin-converting enzyme (ACE) inhibitor enalapril on tendon healing and adhesion formation. Randomized, blinded, controlled experimental study. Eight healthy horses. A collagenase-induced adhesion model was implemented in the deep digital flexor tendon (DDFT) of both forelimbs under standing ultrasonographic guidance. Daily intrathecal injections of 5 mg enalapril (the treatment condition) were administered to a randomly assigned forelimb for 5 days, with the contralateral limb receiving an equivalent volume of 0.9% NaCl (the control). Lameness and limb circumference were recorded weekly. Horses were euthanized after 8 weeks and evaluated for gross digital flexor tendon sheath (DFTS) adhesions. Tendons were collected for histopathologic scoring of DDFT healing. Paired data were analyzed using a one-sided alternative sign test and longitudinal regression. Multiple DFTS adhesions were formed in control limbs of all horses. The median number of gross DFTS adhesions in treated limbs was less than in control limbs (p = .0039). The average reduction in limb circumference and lameness scores over time occurred faster in treated versus control limbs (p < .025). There were no differences in DDFT histopathologic scores between groups. The standing percutaneous DFTS adhesion induction model demonstrated that intrathecal enalapril reduced DFTS adhesion formation, lameness scores, and limb circumference over time. Intrathecal enalapril administration may reduce morbidity in horses with naturally occurring tendon injuries.

Sleep quality and hypertension in an indigenous African population: a cross-sectional investigation from the COMBAT-CVDs study.

Hypertension is a major risk factor for cardiovascular events worldwide, and little is known about its association with sleep quality (SQ) among Africans. We evaluated the association of SQ with hypertension among adults in Ibadan, Nigeria. In Ibadan and its suburbs, we identified 3635 participants in the door-to-door Community-based Investigation of the Risk Factors for Cardiovascular Diseases (COMBAT-CVDs) study. SQ was self-reported, and SQ scores were classified by the tertile distribution in this sample as good(<9), moderate(10-18), and poor(≥19), and hypertension was defined as one of the following conditions: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or prior diagnosis by a certified health professional or current use of blood pressure-lowering drugs. Using good SQ as a reference, logistic regression models were used to estimate the multivariable-adjusted odds ratio and 95% confidence interval (CI) for odds of hypertension by tertiles of SQscores in a two-sided test at p < 0.05. In all, 1182 (32.5%) had poor SQ, 903 (24.8%) had hypertension, and the mean(±SD) age was 35.3 ± 15.2 years in this sample. The multivariable-adjusted odds of hypertension by tertiles of SQ scores (using good SQ as reference) were OR: 1.13 (95% CI: 0.92, 1.38) for moderate SQ, and OR: 1.29 (95% CI: 1.05, 1.59) for poor SQ; P for trend = 0.06 after adjusting for relevant covariates. Poor SQ is associated with higher odds of hypertension in this sample. The imperative of culturally sensitive interventions to improve SQ would be promising in managing poor sleep-associated hypertension burdenin this population.

Thyroid-stimulating hormone suppression in low-risk papillary thyroid cancer: a large-scale retrospective analysis of real-world data

Over 500,000 new cases are diagnosed with papillary thyroid cancer (PTC) globally per year, of whom the vast majority are in the low-risk stratification. Although thyroid-stimulating hormone (TSH) suppression is traditionally recommended for all postoperative PTCs in current guidelines, its necessity remains highly controversial in low-risk patients. Since relevant recommendations in current guidelines are still empirical, we aim to provide a direct, large-scale, real-world evidence. This large-scale real-world retrospective study included 11,140 low-risk PTC patients from two Chinese large-volume centers (Fudan University Shanghai Cancer Center [FUSCC] and Cancer Hospital of Chinese Academy of Medical Sciences [CH-CAMS]) treated from January 1, 2000 to June 30, 2022. The mean TSH level was calculated based on postoperative serum TSH values during follow-up. The primary outcome was the association between postoperative TSH level and structural recurrence assessed by Kaplan-Meier, log-rank, multivariate Cox regression analyses and equivalence testing by Two One-Sided Tests (TOST) procedure. Propensity score matching (PSM) was used to adjust for confounders among groups. A total of 11,140 patients with low-risk PTC were included with a median follow-up of 70 months. Based on the mean TSH level, we classified these patients into ≤0.5 (n=1,504, 13.5%), (0.5-1] (n=4,336, 38.9%), (1-2] (n=4,285, 38.5%), (2-3] (n=704, 6.3%) and >3 (n=311, 2.8%) mU/L groups. After PSM adjusting for age, sex, T and N stage, 8991 patients were included in further analysis, for whom the log-rank analyses showed no significant differences between any two groups (all P>0.05) in recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS), and suppressed TSH was not associated with tumor recurrence in the multivariate Cox analysis (TSH > 2 group vs TSH ≤ 2 group: HR=1.30, 95% CI=0.85-2.01, P=0.23). Furthermore, the TOST equivalence tests showed that tumor recurrence status of any two TSH groups were statistically comparable (all Bonferroni-corrected P values<0.005). Subgroup multivariate analyses showed that TSH level did not impact tumor recurrence regardless of age, tumor size, lymph node metastasis, multifocality, surgical extent, biochemical evidence. Our results suggested that postoperative TSH level was not associated with tumor recurrence in patients with low-risk PTC, for whom deliberate TSH suppression may be exempted to avoid potential secondary complications. Maintaining a TSH level within the normal range may be safe for these patients. The study was supported by the National Natural Science Foundation of China (82072951 to Y.W.; 82373008 to X.S.), Shanghai Hospital Development Center (SHDC2020CR6003-001 to Y.W., SHDC2024CRI087 to Y.-J.W.), the Science and Technology Commission of Shanghai Municipality (22Y21900100/23DZ2305600 to Y.W.; 23ZR1412000 to X.S.), the Shanghai Anticancer Association Foundation (SACA-AX202213 to Yu Wang), Shanghai Municipal Health Commission and Shanghai Medicine and Health Development Foundation (WJWRC202302 to X.S.).

The Replication of Equivalence Studies.

Replication studies are increasingly conducted to assess the credibility of scientific findings. Most of these replication attempts target studies with a superiority design, but there is a lack of methodology regarding the analysis of replication studies with alternative types of designs, such as equivalence. In order to fill this gap, we propose two approaches, the two-trials rule and the sceptical two one-sided tests (TOST) procedure, adapted from methods used in superiority settings. Both methods have the same overall Type-I error rate, but the sceptical TOST procedure allows replication success even for nonsignificant original or replication studies. This leads to a larger project power and other differences in relevant operating characteristics. Both methods can be used for sample size calculation of the replication study, based on the results from the original one. The two methods are applied to data from the Reproducibility Project: CancerBiology.

A systematic review and meta-analysis of health-related quality of life (HRQoL) outcomes in randomised controlled trials for pulmonary arterial hypertension (PAH)

Abstract Introduction ESC guidelines recognise the under use of disease-specific health-related quality of life (HRQoL) instruments. These include CAMPHOR, PAH-SYMPACT, Emphasis-10 and Living with Pulmonary Hypertension (LPH). Patients highly value HRQoL as a treatment outcome in PAH. This is the first meta-analysis to evaluate HRQoL instruments and outcomes in RCTs in pulmonary arterial hypertension (PAH). Purpose To evaluate which PAH-RCT interventions improve HRQoL outcomes and compare the suitability of HRQoL instruments used. Method We searched MEDLINE (Jan 1970 to Dec 2023) and Cochrane Library from Jan 1990 to Dec 2023 (EMBASE, CT.gov, ICTRP, CINAHL) for RCTs in PAH. Abstracts and unpublished studies were excluded and PRISMA reporting structure followed. Trials meeting final selection criteria included HRQoL instruments sufficiently powered to detect a minimal clinically important difference (MCID). Effective sample sizes were calculated in GPower3.1 from a two independent means model for 80% power, 5% significance, one-tailed test. Meta-analysis was performed in SPSSv28.1. Full search criteria are registered on PROSPERO (ID: CRD42024484021). Results After removal of duplicates, 896 records were screened, 43 studies included a HRQoL endpoint. 8 studies were included in the meta-analysis after exclusion for insufficient data (n=10) or power (n=25). 3 of these did not meet the MCID (&amp;gt;33m) for six-minute walk distance (6MWD) and evaluated separately to discriminate accuracy of HRQoL instrument. Instruments available for comparison were Short Form-36(SF-36), EuroQol (EQ-5D-5L) and Living with Pulmonary Hypertension (LPH). Studies not reaching MCID for 6MWD also showed no change in HRQoL (figure 1). Ambrisentan and exercise training demonstrate a significant improvement (p&amp;lt;0.05) in SF-36 physical(P) component (figure 2). This component was anchored to determine 6MWD MCID; other HRQoL values responded variably. Utility weighting to account for geographical variation was not reported with EQ-5D-5L and SF-36 in multicentre studies however AIR 2002 (Iloprost) was significant for both EQ-5D-5L instruments. The total component score of the disease-specific LPH was more sensitive to functional improvements and overall change in HRQoL compared to EQ-5D-5L (p&amp;lt;0.05). Conclusion Fewer than 10% of all RCTs in PAH have adequately considered a HRQoL outcome measure. 8 RCTs were powered to assess HRQoL. Iloprost, ambrisentan, riociguat and exercise training interventions demonstrate significant improvement in HRQoL. LPH was the only PAH-instrument powered to detect change. LPH was more sensitive to HRQoL than generic instruments and is multidimensional. Geographical indexing should be considered for generic instruments such as EQ-5D-5L and SF-36 in multicentre trials. As a highly valued outcome for patients, future studies should prioritise HRQoL as an endpoint.Figure 1Figure 2

Mental health and resilience of students with a refugee background in Greece.RaRE project findings

Abstract Background Research highlights the mental health challenges faced by children and adolescents from refugee backgrounds due to various risk factors encountered during migration, including exposure to violence, family disruptions, insecure legal status, and educational interruptions. These factors increase the risk of psychological issues and academic difficulties. This study investigates the relationship between mental health and resilience in refugee adolescents in Greece. Methods The study focuses on refugee adolescents aged 12-18 from Syria, Iraq, Afghanistan, Somalia, and Ukraine, the countries with the highest numbers of school-age refugees in Greece. Data were collected from 37 refugee children, 37 teachers, 4 parents, and 19 guardians using Poisson sampling. Results are based on responses to the Strengths and Difficulties Questionnaire (SDQ) and the Child Youth Resilience Measure (CYRM), with triangulation of self-completed questionnaires from students, parents/legal guardians, and teachers. Pearson correlation coefficient was employed for analysis. Results We present the pairwise Pearson correlation coefficients of students’ responses to psychometric tests in relation to those of teachers, along with the corresponding p-values for a two-tailed test of significance. Specifically, cor(SDQst,SDQt)=0.443 (p-value=0.006), cor(SDQst,CYRMt)=-0.341 (p-value=0.039), cor(CYRMst,SDQt)=-0.333, (p-value=0.006), cor(CYRMst,CYRMt)=0.323 (p-value=0.051). All p-values are below 0.05 or very close to it, so we reject (or we are close to) the null hypothesis of no association at 5% significance level for every case. On the contrary, we note that the corresponding coefficients between students and parents/legal guardians are all statistically non-different from 0 at 5% significance level. Conclusions Educators exhibit a solid understanding of students’ challenges and resilience compared to parents and guardians. These promising findings support further research.

AI-enabled automated cardiac chambers volumetry in non-contrast ECG-gated cardiac scans vs. non-contrast non-gated lung scans

Abstract Introduction We have developed an AI-enabled automated volume measurement of cardiac chambers (AutoChamber) that works on ECG-gated coronary artery calcium scans and correlates well with contrast enhanced coronary CT angiography scans. We have recently reported that increased left atrial volume measured by AutoChamber is a strong predictor of new onset atrial fibrillation (AF) in asymptomatic individuals of Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we compare the volumetry results in ECG- gated CAC scans with those of non-gated full-chest lung cancer screening scans in the same individuals. Methods We have studied 169 cases of paired ECG-gated cardiac CT scans and non-gated lung scans obtained from Harbor UCLA. Mean±SD for age was 62.1±10.0 years with 52% female participants. All cases were asymptomatic and were scanned for preventive health assessment. AutoChamber was run on all cases by an independent operator who was not involved in data analysis. P value was calculated using a two-tailed test of significance with α=0.05. Results AutoChamber in cardiac scans vs lung scans reported volume (Mean±SD) for left atrium (LA) was 63.8 ± 18.5 vs. 65.5 ± 19.4, left ventricle (LV) 102.8 ± 25.3 vs. 105.5 ± 25.2, right atrium (RA) 81.9 ± 20.5 vs. 85.7 ± 21.9 right ventricle (RV), 140.7 ± 34.2 vs. 134.2 ± 33.7, left ventricle wall (LVW) 113.0 ± 26.6 vs. 109.7 ± 27.0 respectively (P &amp;lt; 0.0001). Strong correlation was shown between cardiac and lung scans for each cardiac chamber: LA (R = 0.92), LV (R = 0.93), RA (R = 0.91), RV (R = 0.92), and left ventricular wall (LVW) R = 0.95. Conclusions AutoChamber volumetry results are similar in ECG-gated cardiac scans vs non-gated full-chest lung scans. This AI-enabled automated tool is promising as it can provide added value to patients undergoing coronary calcium and lung cancer screening scans flagging enlarged cardiac chambers at risk of AF and heart failure.

Assessment of inverse publication bias in safety outcomes: an empirical analysis

BackgroundThe aims of this study were to assess the presence of inverse publication bias (IPB) in adverse events, evaluate the performance of visual examination, and explore the impact of considering effect direction in statistical tests for such assessments.MethodsWe conducted a cross-sectional study using the SMART Safety, the largest dataset for evidence synthesis of adverse events. The visual assessment was performed using contour-enhanced funnel plots, trim-and-fill funnel plots, and sample-size-based funnel plots. Two authors conducted visual assessments of these plots independently, and their agreements were quantified by the kappa statistics. Additionally, IPB was quantitatively assessed using both the one- and two-sided Egger’s and Peters’ tests.ResultsIn the SMART Safety dataset, we identified 277 main meta-analyses of safety outcomes with at least 10 individual estimates after dropping missing data. We found that about 13.7–16.2% of meta-analyses exhibited IPB according to the one-sided test results. The kappa statistics for the visual assessments roughly ranged from 0.3 to 0.5, indicating fair to moderate agreement. Using the one-sided Egger’s test, 57 out of 72 (79.2%) meta-analyses that initially showed significant IPB in the two-sided test changed to non-significant, while the remaining 15 (20.8%) meta-analyses changed from non-significant to significant.ConclusionsOur findings provide supporting evidence of IPB in the SMART Safety dataset of adverse events. They also suggest the importance of researchers carefully accounting for the direction of statistical tests for IPB, as well as the challenges of assessing IPB using statistical methods, especially considering that the number of studies is typically small. Qualitative assessments may be a necessary supplement to gain a more comprehensive understanding of IPB.

The Mechanical Properties of Orthodontic Aligners of Clear Aligner After Intraoral Use in Different Time Periods.

Although the technique of orthodontic aligners has risen in popularity, their mechanical properties have not been thoroughly investigated. The aim of this study was to evaluate the mechanical properties of the orthodontic aligners Clear Aligner after intraoral use for 7, 10 and 14 days, and to compare them with as-received aligners (0 days). It was also sought to examine the properties of the unprocessed raw material (polyethylene glycol terephthalate) used to manufacture these aligners. Thirty-two aligners by four patients were evaluated and studied at 0, 7, 10, 14 days of use. Each aligner was divided into three segments (two posterior and one anterior), which resulted in 96 samples. Also, 16 samples of unprocessed material were studied. For all samples, elastic modulus, ultimate tensile stress (UTS) and yield stress were calculated by conducting tensile testing. Additionally, material hardness was tested. The two-tailed Mann-Whitney test was performed, having set the level of significance at p = 0.05. Analysis of the measurements indicated a statistically significant decrease in elastic modulus between days 0 and 14 of use, of UTS between days 0 and 7, 7 and 10, and of yield stress between days 0 and 7. For hardness, in every period, posterior segments demonstrated significantly higher values than anterior segments. All properties of the unprocessed material were statistically significantly higher than the processed samples. The unprocessed material presented significant differences in every property tested in comparison to the processed aligners. The processed material showed further deterioration over time during use. The present study provides evidence that thermoforming and ageing affect the mechanical properties of the aligners.