To explore associations between clinical endpoints, multimodal imaging, and aqueous humor (AH) biomarker patterns in patients with diabetic macular edema (DME) treated with faricimab. A phase IIb, multicenter, open-label, single-arm, 24-week exploratory study. Adults with treatment-naïve DME, best-corrected visual acuity (BCVA) of 20-75 ETDRS letters, and central subfield thickness (CST) ≥325 μm were eligible to participate. Patients received six 4-weekly intravitreal doses of faricimab 6.0 mg. Functional and multimodal imaging assessments were conducted through week 24. Aqueous humor samples were collected at baseline and week 16 for targeted proteomic analysis. Patients were monitored for safety. Prespecified exploratory endpoints included changes from baseline over time in BCVA, CST, the proportion of patients with ≥2-step ETDRS Diabetic Retinopathy Severity Scale (DRSS) improvement, intraretinal/subretinal fluid and macular leakage on multimodal imaging, and AH biomarker patterns. Ninety-nine patients were enrolled. At week 24, treatment with faricimab resulted in clinical and anatomical improvements consistent with phase III trials in DME (YOSEMITE/RHINE); the adjusted mean (95% confidence interval) change from baseline was +9.2 (7.5-10.9) letters for BCVA and -200.2 μm (-214.1 to -186.2) for CST, and 50.0% (37.2-62.8) of patients achieved ≥2-step DRSS improvement. Macular leakage area reduced from a median (interquartile range) of 28.6 mm2 (16.9-36.5) at baseline to 2.8 mm2 (0.9-15.3) at week 20. Total AH protein concentration decreased significantly from baseline to week 16 (P < 0.0001), with reductions across plasma-derived, inflammatory, and hypoxia response proteins. Notably, faricimab treatment significantly reduced the levels of key proteins associated with worse baseline DRSS scores (including angiopoietin-2, placental growth factor, and erythropoietin) and high baseline macular leakage, suggesting normalization of the AH proteomic profile. Safety was consistent with the known safety profile of faricimab. In patients with treatment-naïve DME, faricimab treatment resulted in meaningful improvements in functional and anatomical outcomes. These clinical gains were accompanied by a significant reduction in the levels of key AH proteins associated with disease severity, which underscores their potential as biomarkers for assessing disease activity and therapeutic response. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Dysnatremia is the most common electrolyte abnormality detected during hospitalizations and outpatient visits and is associated with adverse outcomes in older adults. However, data on its prevalence and incidence in community-dwelling older individuals remain limited. This study aimed to estimate the prevalence and incidence of dysnatremia in this population across 5 European countries (Austria, France, Germany, Portugal, and Switzerland). Observational analysis of DO-HEALTH, a 3-year multicenter clinical trial including 2157 community-dwelling, generally healthy adults aged 70 years and older. Sodium blood levels were collected at baseline, 12, 24, and 36 months. Dysnatremia was defined as sodium levels <135 mmol/L (hyponatremia) or >145 mmol/L (hypernatremia). Baseline prevalence and 3-year incidence were estimated overall and by predefined subgroups based on sex, age, country of residence, body mass index, prevalent chronic conditions, polypharmacy, and use of thiazide-like diuretics. At baseline, 2141 participants (99.3%) had available sodium data. The prevalence of dysnatremia was 3.4% (2.4% hyponatremia; 1.0% hypernatremia), with higher prevalence in participants aged ≥75 years (4.8%) and those using thiazide or thiazide-like diuretics (5.4%). Over 3 years, 150 participants (7.0%) experienced at least 1 episode of dysnatremia (3.8% hyponatremia; 3.2% hypernatremia). Higher incidence of dysnatremia was observed among participants living in Switzerland, using thiazide or thiazide-like diuretics, and with prevalent dysnatremia at baseline. Dysnatremia, previously linked to adverse outcomes in older adults, was observed in a non-negligible proportion of generally healthy, community-dwelling older individuals. These findings provide valuable epidemiologic data and identify subgroups that may warrant closer clinical attention.
To evaluate clinical remission rates and its individual components in patients with severe eosinophilic asthma treated with benralizumab, and to explore predictors of clinical remission using subgroup analyses by blood eosinophils, prior exacerbations, and previous biologic treatment. Data from a prospective, observational, non-interventional study (BEEPS, NCT03907137) of patients with severe eosinophilic asthma (SEA) in Switzerland were analysed post-hoc. Benralizumab 30 mg was administered at weeks 0 (baseline), 4, and 8, followed by an 8-weekly regimen until week 56. Clinical remission was defined as meeting all four of the following criteria: Asthma Control Questionnaire (ACQ-5) scores < 1.5 or ≤ 0.75, no oral corticosteroid (OCS) use, no exacerbations, and a stable lung function. Patients were categorised into three pre-planned subgroups: (1) Blood eosinophils at baseline: 300-400 cells/μL and > 400 cells/μL; (2) exacerbations in the last 12 months: <4 and ≥4 exacerbations; (3) prior biologic treatment: naïve and experienced patients. At baseline, no patients met all four criteria for clinical remission. After 56 weeks of benralizumab treatment, 58.1% of patients achieved all criteria when using ACQ-5 < 1.5, and 51.6% did so with ACQ-5 ≤ 0.75. Throughout the study, each individual remission criterion improved consistently over time. Across all subgroups, asthma symptoms and annualized exacerbation rates (AER) continuously decreased over the course of treatment. More than 50% of patients with SEA achieved clinical remission on treatment with benralizumab. Furthermore, benralizumab demonstrated consistent clinical efficacy across all patient subgroups, providing deeper insight into the characteristics and needs of these specific populations.
Pre-existing pathogen-specific antibodies shape vaccine outcomes, yet their impact on local reactogenicity and qualitative features of the immune response are not fully defined. In this prospective human cohort receiving seasonal influenza vaccination, high baseline hemagglutinin-specific IgG1 levels were associated with more pronounced local thermal responses at the vaccinated arm and greater vaccine-induced antibody levels. These IgG antibodies formed immune complexes with hemagglutinin, activated complement and enhanced Fc-receptor-dependent monocyte activation and phagocytosis in vitro, connecting pre-existing immunity to innate activation and local reactogenicity. Despite higher antibody levels and early plasmablast responses in subjects with strong thermal reactogenicity after vaccination, we observed lower avidity and hemagglutinin-inhibition capacity, suggesting extrafollicular responses. T cell responses were unaltered. These findings support a model in which pre-existing hemagglutinin-specific IgG may contribute to local thermal reactogenicity and qualitative features of the vaccine response through immune complex-mediated pathways, providing a framework for how prior immunity may shape human vaccine responsiveness.
Esophageal cancer is a global burden, and multiple international societies exist to address the issue in international collaboration. This study aims to analyze the characteristics of esophageal cancer and robot-assisted minimally invasive esophagectomy (RAMIE) across geographic areas. We performed a retrospective analysis of the Upper GI International Robotic Association (UGIRA) international database from January 2016 to April 2024. Forty centers worldwide that were known to perform RAMIE were involved in establishing this consortium. The patient characteristics, surgical techniques, and short-term outcomes of RAMIE were compared by each regional area (Europe, Asia, North America, and South America). A total of 3,916 RAMIE cases were registered in the UGIRA database (2,643 in Europe, 1,130 in Asia, 111 in North America, and 32 in South America). The median age was 66 years, and 80.5% of patients were male. Notably, Asia had a high prevalence of squamous cell carcinoma (91.2%) and predominant use of the McKeown approach (94.9%). BMI was lower in Asia, whereas comorbidities were more common in Western countries across all types. The use of neoadjuvant chemotherapy and radiation was lower in Asia (48.2% and 20.8 %, respectively). Postoperative complications also differed by region; pneumonia was most common in Europe and South America, cardiopulmonary complications in North America, and recurrent nerve injury in Asia. In conclusion, regional differences were observed in baseline characteristics, treatment approaches, and complication patterns in patients treated by RAMIE for esophageal cancer. Recognizing these variations is essential for fostering mutual understanding and advancing the field through international collaboration.
Although esthetic concerns are a primary motivation for seeking orthodontic treatment, few studies with strong protocols have evaluated its impact on facial and smile attractiveness as perceived by laypeople. This study aimed to assess the effect of orthodontic treatment on facial and smile attractiveness compared with pretreatment and untreated controls. The sample included 37 adults (aged 21-35 years): 29 treated and 8 untreated controls. A total of 132 photographs (full-face smiles and close-up smiles) were collected at pretreatment and posttreatment for treated patients and once for controls. Laypeople (n = 297) rated the images using a visual analog scale (VAS). The association between orthodontic treatment and attractiveness was analyzed through univariate regression models; confounders were controlled via analysis of covariance. Comparisons between study and control groups were performed using t tests. The effect of evaluators' demographics on attractiveness was tested using multivariate regression models. The association of the Aesthetic Component of the Index of Orthodontic Treatment Need with pretreatment attractiveness was explored with Spearman correlation. Orthodontic treatment had a significant effect on facial and smile attractiveness, with VAS scores improving by 15.6% (P <0.001) and 24.3% (P <0.001), respectively. Posttreatment ratings were higher than those of untreated controls (Pface = 0.029; Psmile = 0.010), with no significant differences at baseline. Higher Aesthetic Component of the Index of Orthodontic Treatment Need scores correlated with lower initial VAS ratings (r = 0.67; P <0.001). Age and treatment duration had no significant effect. Orthodontic treatment improves facial and smile attractiveness as perceived by laypeople. These findings support its esthetic benefits and can enhance patient communication and treatment planning.
We assessed the proportion of patients with biochemical recurrence (BCR), the occurrence of BCR in risk groups according to prostate-specific antigen doubling time (PSA-DT), and clinical outcomes in risk groups. Retrospective observational study of patients with non-metastatic prostate cancer (PC) (n = 26,755) in the US using the Optum® PC electronic medical record database. Primary outcomes were the proportion of patients with BCR in prior radical prostatectomy (RP) or radiation therapy (RT) cohorts. Secondary outcomes included association between baseline characteristics and time to BCR, BCR risk group (high-risk: PSA-DT <12 months; low-risk: PSA-DT ≥12 months), and time from BCR to metastasis and castration-resistant PC (CRPC). BCR occurred in 19.7% of patients after RP and 8.8% after RT. Among high-risk BCR patients (n = 523) in the RP cohort, 19.3% developed metastasis, 14.5% developed CRPC, and 14.1% died. In contrast, among low-risk BCR patients (n = 1,356), rates were 10.2%, 7.0%, and 6.6%, respectively. In the RT cohort, 25.9% of the high-risk BCR patients (n = 498) developed metastasis, 21.5% developed CRPC, and 19.7% died, compared with 16.4%, 9.0%, and 16.4% among low-risk patients (n = 122), respectively. PSA and PSA-DT are key predictors of BCR. Outcomes are worse among high-risk BCR patients with short PSA-DT. This study looked at medical records from men who were treated for early-stage prostate cancer with surgery or radiation therapy. After treatment, some men showed a rise in their PSA levels in blood tests. This rise can be a sign that some cancer cells may still be present. We found that about 15 in every 100 men experience a rise in PSA levels after treatment, most often within 2 years. We also found that both the PSA level and how quickly it increases over time are important. A faster rise in PSA levels was linked to a higher chance of the cancer coming back and to poorer outcomes. Measuring how quickly PSA levels double over time can help doctors choose the most appropriate treatment to slow down or prevent the cancer from getting worse.
Childhood cancer survivors (CCS) are at risk for long-term pulmonary complications from treatment-related toxicity. Nitrogen multiple-breath washout (N2MBW) may detect small airway dysfunction earlier than standard pulmonary function tests (PFTs), but its value in CCS remains uncertain. To determine the prevalence of ventilation inhomogeneity measured by N2MBW in CCS, evaluate whether it detects abnormalities beyond spirometry and diffusion capacity for carbon monoxide (DLCO), and explore associations with treatment exposures. In this prospective multicenter study (Bern, Basel, Geneva), we measured lung function in all CCS aged 6-21 years who were undergoing routine follow-up. We stratified participants into high-risk (pulmotoxic chemotherapy [busulfan, bleomycin, nitrosoureas], thoracic surgery, radiotherapy, or hematopoietic stem cell transplantation [HSCT]) and standard-risk (other systemic anticancer treatments). PFTs included N2MBW (lung clearance index [LCI], acinar [SACIN] and conductive [SCOND] inhomogeneity), spirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC]), and DLCO. Abnormal values were defined as z-score < -1.645 or > 1.645, calculated using the Global Lung Initiative references. We quantified the proportion of participants with isolated elevated LCI and analyzed associations with treatment exposures using multivariable linear regression. We included 191 CCS (median 7 years post-diagnosis). Mean LCI was 6.27 (95%CI 6.17-6.37), with 7% of participants showing abnormal values. N2MBW results did not differ between high- and standard-risk groups, but allogeneic HSCT survivors had the highest mean LCI (7.18, 95%CI 5.88-8.37), with 33% abnormal. Survivors had mildly impaired mean FEV1, FVC, and DLCO z-scores (-0.21, -0.34, 0.23), more pronounced in high-risk CCS (-0.67, -0.85, -0.05). Isolated LCI impairment, without abnormalities in spirometry or DLCO, occurred in only 3%. Among treatment exposures, only allogeneic HSCT was associated with higher LCI (1.40, 95%CI 0.57-2.33) and SACIN (1.24, 95%CI 0.20-2.28). Most pediatric CCS had normal lung function. N2MBW abnormalities were rare, occurring mainly in allogeneic HSCT survivors. Overall, N2MBW added little beyond standard PFTs, suggesting it may not be needed for routine follow-up at this stage, except after allogeneic HSCT. Larger, longitudinal studies should clarify the onset, progression, and prognostic significance of N2MBW abnormalities and their potential role in risk-adapted follow-up care.
Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by acute hepatic decompensation, multi-organ failure, and high short-term mortality in patients with liver cirrhosis. A hallmark of ACLF is profound deterioration of the immune system, which contributes to organ-specific excessive inflammation and immune dysfunction, predisposing patients to infection and multi-organ failure. This review aims to elucidate the cellular and molecular mechanisms underlying systemic immune dysfunction in ACLF, highlighting key pathophysiological pathways and their clinical significance. We provide an overview of ACLF including its global prevalence and clinical significance, against the background of the underlying immune dysfunction in its pathogenesis. The discussion focuses on innate immune alterations, such as impaired neutrophil and monocyte phagocytosis, excessive neutrophil extracellular trap (NET) formation, and monocyte/macrophage dysfunction contributing to immuneparesis and exaggerated inflammation, respectively, which evolve in an organ-specific manner. Dysregulation of natural killer (NK) cell cytotoxicity and adaptive immune dysfunction, including changes in T cell subpopulations and B cell antibody production in ACLF, are discussed. We further dissect the emerging evidence of molecular pathways driving dysfunction of immune cells and their impaired ability to control infections in ACLF, emphasizing the roles of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs), toll-like receptor (TLR) signaling, oxidative stress, mitochondrial dysfunction, epigenetic/metabolic reprogramming and immune checkpoint molecules. The review expands on immune cell communication within the immune system (innate and adaptive), with other non-parenchymal and parenchymal cells and at the inter-organ level, detailing interactions between immune cells of key organs and compartments affected during ACLF, including the liver, circulation, brain, gut and kidney. Finally, we summarize the latest preclinical and clinical findings exploring biomarkers of immune dysfunction and immunomodulatory therapeutic strategies aimed at restoring immune homeostasis in patients with ACLF.
For fever in neutropenia (FN) during chemotherapy timely start of antibiotics is recommended. We analyzed time to antibiotics (TTA) and sub-timespans between detection of fever and start of antibiotics in children undergoing chemotherapy for cancer with FN. Specifically, we aimed to assess where delays occur, which variables influence TTA, and whether the order of certain process steps affects TTA. We analyzed 349 FN episodes reported prospectively in 155 Swiss patients from April 2016 to August 2018. In outpatients, the median TTA from fever to the start of antibiotics was 165 minutes, and the median duration from fever to hospital arrival was 80 minutes. For inpatients, the median TTA from fever to the start of antibiotics was 75 minutes. The longest delays were identified for the timespans from phone call to arrival (median, 75 min) and from arrival to decision on treatment (60 min). Known blood counts at recognition of fever, decision to treat FN before arrival at the emergency department, and arrival during office hours contributed to shorter TTA. In conclusion, the time before arrival is relevant and should be considered when optimizing TTA and evaluating its influence on outcomes. Support for transportation, using time to arrive for preparations, and regular blood counts could reduce TTA.
To evaluate the carbon footprint and clinical outcomes of once-weekly subcutaneous semaglutide in patients with type 2 diabetes mellitus (T2DM) in the United Kingdom. Using the IQVIA Core Diabetes Model, environmental and clinical impacts were projected over a lifetime horizon from the National Health Services perspective. Data from the SUSTAIN-2 (patients with T2DM) and SUSTAIN-6 (patients with T2DM and established cardiovascular [CV] risk) trials were used to compare semaglutide with sitagliptin and placebo, respectively. Outcomes included life expectancy measured in life-years (LYs), and quality-adjusted life expectancy measured in quality-adjusted life-years (QALYs) gained; incidence of diabetes-related complications and adverse events; carbon emissions; and incremental carbon footprint effectiveness ratios (ICFERs). In patients with T2DM, semaglutide dominates sitagliptin, with higher discounted LYs (0.096) and QALYs (0.095) gains, a 6.9% reduction in diabetes-related complications and adverse events, and reduced lifetime carbon emissions by 9.3% (13,899 kg carbon dioxide equivalent emissions [CO2e] versus 15,319 kg CO2e). Similarly, in patients with T2DM and established CV risk, semaglutide showed higher discounted LYs (0.206) and QALYs (0.164), with reductions in all complications except heart failure-related hospitalizations versus placebo. Lifetime carbon emissions were 5.2% lower with semaglutide (14,546 kg CO2e versus 15,341 kg CO2e), again with a dominant ICFER. The reduction in CO2 was mainly driven by reduced complications and treatment needs. Sensitivity analyses supported the robustness of the results. Semaglutide offers environmental advantages over sitagliptin for patients with T2DM overall and over standard of care for those with established CV risk.
Pregnancy is generally well tolerated in patients with arrhythmogenic cardiomyopathy (AC), but there are limited data comparing right-dominant AC (ARVC) and left-dominant AC (ALVC), as well as gene-positive but phenotype-negative (G+/P-) individuals. Recent guidelines have also introduced the non-dilated left ventricular cardiomyopathy (NDLVC). This study examines disease expression in pregnant women with AC and family members with pathogenic genetic variants but a negative phenotype (G+/P-). We also included those with NDLVC. We reviewed data from 22 patients diagnosed with definite AC and 9 G+/P- patients. Four patients meeting criteria for NDLVC were also analyzed. Each underwent at least one cardiovascular evaluation during pregnancy, which included a 12-lead ECG, echocardiography, and 24-h ambulatory monitoring. Events were defined as new or worsening arrhythmias, heart failure, or thromboembolic events. All AC patients, including those with ARVC and ALVC, tolerated pregnancy well. None of the G+/P- patients was diagnosed with AC during pregnancy. One G+/P- patient had ECG changes, while three with PKP2 mutations experienced mild left ventricular dysfunction but fully recovered postdelivery. Among the four NDLVC patients, only one developed left ventricular dysfunction. There was no increase in arrhythmias, and 31% of the cases required caesarean sections. All pregnancies resulted in live births, and no major maternal complications were reported. Pregnancy is typically safe for women with AC and G+/P- individuals, provided that they are hemodynamically stable. Patients with NDLVC also manage pregnancy well. However, careful monitoring during and after pregnancy is essential, even without obvious clinical signs of the disease.
Growing evidence for reperfusion therapies in pediatric acute ischemic stroke (AIS) increases the importance of timely diagnosis within treatment windows. We therefore aimed to describe 24-year trends and associated factors of diagnostic delay. We conducted a nationwide retrospective cross-sectional study including 314 children aged 28 days to 16 years from the Swiss Neuropediatric Stroke Registry (2000-2023). The primary outcome was time from stroke onset to diagnosis (TOD). Trends for diagnoses beyond intravenous thrombolysis (≥4.5 hours) and thrombectomy (≥24 hours) windows were assessed with multivariable logistic regression, and for continuous TOD with robust linear regression. Prespecified covariates were retained in multivariable models if associated with the outcome in univariable analyses. Analyses were stratified by AIS onset location (out-of-hospital and in-hospital). Median TOD was 26.9 hours (interquartile range, 10.1-91.5) between 2000 and 2023. During this period, the proportion diagnosed beyond the thrombolysis window decreased significantly in the overall cohort from 90.9% to 77.5% (adjusted odds ratio per calendar year 0.94 [95% CI, 0.88-1.00]) and in out-of-hospital AIS from 88.1% to 74.1% (adjusted odds ratio, 0.91 [0.84-1.00]). No significant change was observed beyond the thrombectomy window diagnoses. Continuous TOD decreased significantly only in in-hospital AIS (β=-4.3 [-7.2 to -1.5]). Older age (β=-1.8 [-2.9 to -0.8]), higher pedNIHSS (β=-1.2 [-2.1 to -0.4]), and facial palsy (β=-19.4 [-30.2 to -8.5]) were associated with shorter TOD, and nonspecific symptoms (β=110.0 [72.5-147.5]) with longer TOD. Out-of-hospital TOD was shorter when patients presented to a stroke center compared with other presentation sites. Posterior-stroke symptoms were associated with diagnoses beyond the thrombolysis window. Despite decreasing proportions of beyond-thrombolysis window diagnoses in out-of-hospital AIS and decreasing TOD in in-hospital AIS, most diagnoses occur beyond reperfusion windows. Goals to decrease delay include raising awareness of posterior-stroke signs and AIS in younger children, and strengthening direct-to-stroke center pathways.
The journal retracts the article "Evaluation of a New Dental Implant Cervical Design in Comparison with a Conventional Design in an Experimental American Foxhound Model" [...].
On-surface synthesis has emerged as a powerful tool for atomically precise C─C bond formation, enabling access to low-dimensional carbon-based materials, often unattainable by conventional solution-based chemistry. This approach gave rise to a novel class of magnetic materials, namely open-shell magnetic nanographenes, whose magnetism originates primarily from unpaired electrons. Despite this progress, a fundamental understanding of selectivity and specificity of surface-confined radical chemistry remains limited. Here, we demonstrate that nonplanar hydrocarbons such as helicenes undergo highly selective intramolecular radical-driven bond formation and reorganization on an Au(111) surface, yielding nonbenzenoid nanographenes incorporating 5-, 6-, and 7-membered rings. The products are identified using time-of-flight secondary ion mass spectrometry, scanning tunneling microscopy, and non-contact atomic force microscopy, which collectively support a radical-mediated cyclization pathway. The mechanism is distinct from the Diels-Alder cycloaddition and cyclodehydrogenation reactions previously reported for helicenes on surfaces.
Bispecific antibodies (BsAbs) have emerged as a powerful therapeutic modality with the ability to simultaneously engage two distinct targets, enabling novel mechanisms of action that traditional monoclonal antibodies cannot achieve. This dual-targeting capability offers significant advantages in treating complex diseases such as cancer, autoimmune disorders, and infectious diseases by enhancing specificity, improving immune engagement, and reducing resistance mechanisms. The development of BsAbs has been driven by innovations in antibody engineering platforms, including BiTE, TriTAC, CrossMAb, XmAb, Fcab, and κλ-body technologies. These platforms allow the construction of diverse BsAb formats, ranging from compact single-chain variable fragments (scFvs) to full-length IgG-like molecules, each optimized for specific pharmacokinetic and pharmacodynamic profiles. Clinical candidates such as blinatumomab, HPN328, and XmAb14045 demonstrate the therapeutic potential and versatility of BsAbs, several of which have progressed to advanced stages of clinical trials or received regulatory approval. However, BsAb development poses unique challenges, including molecular heterogeneity, complex manufacturing processes, and the need for precise functional characterization. Emerging technologies such as high-resolution mass spectrometry, surface plasmon resonance (SPR), hydrogen‑deuterium exchange (HDX-MS), and AI-assisted modeling are increasingly being adopted to overcome these hurdles. As the field evolves, BsAbs are redefining therapeutic strategies by offering multi-functional approaches within a single molecule. Their ability to orchestrate complex biological interactions with high specificity positions them at the forefront of next-generation biologic. This article explores the technical advancements and clinical milestones that underscore the rising impact of BsAbs in modern medicine.
The journal retracts the article titled "Enhancement of the Electrical Conductivity and Interlaminar Shear Strength of CNT/GFRP Hierarchical Composite Using an Electrophoretic Deposition Technique" [...].
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