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Chun-Hao Chen,1 Ming-Chyi Huang,2 Yi-Hang Chiu,3 I-Ming Chen,1,4 Chun-Hsin Chen,3,5 Mong-Liang Lu,3,5 Tsung-Yang Wang,1 Hsi-Chung Chen,1,6 Po-Hsiu Kuo1,7 1Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan; 3Department of Psychiatry, Wan-Fang Hospital, Taipei, Taiwan; 4Institute of Health Policy and Management, National Taiwan University, Taipei, Taiwan; 5Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 6Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan; 7Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, TaiwanCorrespondence: Hsi-Chung Chen, Department of Psychiatry, National Taiwan University Hospital, No. 7 Chung San South Road, Taipei, 10002, Taiwan, Tel +886-2-2312-3456 ext. 66787, Fax +886-2-2381-3208, Email hsichungchen@ntu.edu.twObjective: This study aimed to investigate the relationship between eveningness preference and poor sleep quality and eventually examine the moderation effect of stress susceptibility.Methods: Individuals with non-acute major depressive disorder or bipolar affective disorder and healthy participants were recruited. The Composite Scale of Morningness (CSM) and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate chronotype and sleep quality, respectively. Eysenck Personality Questionnaire, Tridimensional Personality Questionnaire, Perceived Stress Scale, and Beck Anxiety Inventory were used to formulate stress susceptibility and as indicator variables for empirical clustering by latent class analysis (LCA). Linear regression models were used to examine the relationship between chronotype preference and sleep quality. The interaction terms of CSM and stress susceptibility were examined for the moderation effect.Results: A total of 887 individuals were enrolled in this study, with 68.2% female and 44.1% healthy participants. Three subgroups were derived from LCA and designated as low stresssusceptibility (40.2%), moderate stress susceptibility (40.9%), and high stress susceptibility (18.8%) groups. After controlling for covariates, the CSM scores inversely correlated with PSQI scores [b (se)=− 0.02 (0.01), p=0.01], suggesting that individuals with eveningness preferences tend to have poor sleep quality. Moreover, stress susceptibility moderated the relationship between CSM and PSQI scores (p for interaction term = 0.04). Specifically, the inverse association between CSM and PSQI was more robust in the high stress susceptibility group than that in the low stress susceptibility group.Conclusion: Eveningness preference was associated with poor sleep quality, and this relationship was moderated by stress susceptibility.Keywords: chronotype, empirical clustering, moderation effect, stress susceptibility, sleep quality

This study examined the relationship between perceived social status, COVID-19-related discrimination, and sleep quality among 158 migrant care workers in Taiwan. Data were collected via computer-assisted interviews, assessing perceived social status with the MacArthur scale and sleep quality using the Pittsburgh Sleep Quality Index. The results revealed that higher perceived social status in reference to the destination country (B = 0.31) and experience of media stigmatization (B = 0.52) were associated with higher global Pittsburgh Sleep Quality Index (PSQI) scores, whereas perceived social status in reference to the home country and others forms of pandemic-related discrimination were not associated with PSQI scores. The study concluded that social comparison and stigmatization were linked to sleep health of migrant care workers. Understanding these factors can inform the development of targeted interventions to address inequalities faced by migrants., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease., Materials and Methods: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years., Results: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5 -altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10 -8 ). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10 -10 ; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10 -5 ; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1 , and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1 -like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL., Conclusion: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Importance: Immune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur., Objective: To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs., Data Sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023., Study Selection: Two separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2., Data Extraction and Synthesis: The PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model., Main Outcomes and Measures: In study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began., Results: In study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti-programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate., Conclusions and Relevance: Immune checkpoint inhibitor-induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

Pancreatic cancer is one of the most challenging tumor sites to treat safely and effectively with radiotherapy due to the anatomical location and aggressiveness of the disease. One modality that has shown promising results, which our institution has been employing, is online adaptive stereotactic radiotherapy using a magnetic resonance-guided linear accelerator (MR-linac). However, due to unforeseen circumstances regarding our MR-linac, it was necessary for our institution to use an alternative treatment technique. In this case report, we describe our experience using our ring-gantry linac equipped with an advanced cone-beam computed tomography (CBCT) system to treat a 61-year-old patient with advanced pancreatic cancer with CBCT-guided online adaptive stereotactic radiotherapy. In a short time period of four weeks, we prepared for this case by training with the surface scanning motion management system and developing procedures for planning and adaptation. The patient was prescribed 24 Gy in three fractions, with a risk-adapted approach using strict organ-at-risk (OAR) constraints. Daily CBCT was used for online adaptation of the plan, and the superior plan (non-adapted or adapted) was selected for treatment. For this patient, the adapted plan was chosen for all three fractions, due to OAR constraints being violated in the non-adapted plan. In summary, we found that for this patient, high-quality CBCT guidance for daily re-contouring, in combination with motion management, enabled the use of daily adaptive radiotherapy to safely deliver stereotactic radiotherapy. The results from this case report are promising, and CBCT-guided online adaptive stereotactic radiotherapy for pancreatic cancer warrants further investigation in more patients., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Den Videnskabsetiske Komité issued approval H-19075387. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Laura Rechner declare(s) a grant from Varian, a Siemens Healthineers Company. Laura Rechner is partially funded through a grant from Varian for work unrelated to this case report. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rechner et al.)

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75-2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I 2 =70 %). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat., Competing Interests: Declaration of competing interest Federica Genovese, Cecilie Bager, Peder Frederiksen, Dario Vazquez, Jannie Marie Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen, Neel I Nissen and Morten Karsdal are or have been at the time of writing, full-time employees at Nordic Bioscience. Federica Genovese, Cecilie Bager, Jannie Maria Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen and Morten Karsdal hold Nordic Bioscience stocks. Nordic Bioscience holds the patent for the PROC6 assays and commercializes the assay. Peter Rossing has received research support from Astra Zeneca, Novo Nordisk and Bayer, and has received honoraria (to Steno Diabetes Center Copenhagen) from Astra Zeneca, Boehringer Ingelheim, Bayer, Novo Nordisk, Gilead, Sanofi, Abbott for consultancy or education. Louise V. Wain has received research funding or collaborative support from Orion Pharma, GSK, Genentech, AstraZeneca and Sysmex, outside of the submitted work and provided consultancy for GSK and Galapagos., (Copyright © 2024. Published by Elsevier B.V.)

Background: The effects of thoracic endovascular aneurysm repair (TEVAR) with additional distal bare metal stents (BMSs) in patients with subacute complicated type B aortic dissection (cTBAD) are unclear and are investigated in this retrospective study., Methods: The medical records of 67 patients who received TEVAR due to subacute cTBAD were reviewed. Areas of true lumen (TL) and false lumen at five levels-pulmonary artery (PA), diaphragm, renal artery (RA), middle of the infrarenal aorta, and aortic bifurcation-were measured using computed tomography before and 3, 6, and 12 months after surgery. The TL ratio (TL area/total aortic area) and total aortic area at each time point were compared between the TEVAR + BMS (n = 37) and TEVAR-only (n = 30) groups. The effects of BMS use and time were evaluated using generalized estimating equations and generalized linear regression models., Results: Baseline characteristics, remodeling types, and clinical outcomes did not differ significantly between the two groups. Postoperative TL ratios at the diaphragm and RA were significantly higher in the TEVAR + BMS group than in the TEVAR-only group ( p < 0.05). BMS use and time had significant interaction effects at the PA, diaphragm, and RA (all p < 0.05), but effects on total aortic area were not significant at any of the five parts. TL ratios at the diaphragm and RA exhibited greater improvement in the TEVAR + BMS group than in the TEVAR-only group at postoperative months 6 and 12 (all p < 0.001). Aortic diameters at all five parts were significantly smaller in the TEVAR + BMS group than in the TEVAR-only group (all p < 0.05)., Conclusion: In patients with subacute cTBAD, TEVAR with BMS implantation effectively expands the TL from the thoracic aorta to the RA but neither enhances aortic remodeling nor elicits any change in total aortic area in whole dissected aorta relative to TEVAR only., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Introduction: Antiviral treatment can reduce the burden of COVID-19. But utilisation can be suboptimal, even in a setting like Singapore where it is fully subsidized for those with selected medical conditions and older adults (≥ 50 years). We hence investigated the factors affecting awareness, acceptance, and initiative to request Paxlovid., Methods: We assessed the Paxlovid awareness, factors impacting its uptake in a survey conducted from August 2022 to September 2022 through the SOCRATES cohort. Multivariable logistic regression was used to investigate associations between sociodemographics, perceptions, and attitudes with the key study outcomes., Results: Among respondents to the Paxlovid survey, 54% were aware of Paxlovid. On being provided essential details about Paxlovid, 75% reported they would likely be receptive to taking it if prescribed, and 38% indicated the initiative to request for it if it was not suggested by their doctors. Factors associated with awareness of Paxlovid include aged 40 years old and above, higher education, citing websites as an information source, greater trust in healthcare providers (aOR: 1.65, 95% CI 1.26 - 2.15) and government communications (aOR: 0.69, 95% CI 0.55 - 0.86), and higher perceived risk of COVID-19 infection (aOR: 1.25, 95% CI 1.10 - 1.42). Factors associated with acceptance to take Paxlovid include male gender, citing trust in healthcare providers (aOR: 1.49, 95% CI 1.11 - 1.99) and government communications (aOR: 1.38, 95% CI 1.09 - 1.76), and higher perceived severity of COVID-19 (aOR: 1.23, 95% CI 1.07 - 1.42). Factors associated with initiative to request Paxlovid include male gender, having pre-existing diabetes and higher perceived severity of COVID-19 (aOR: 1.24, 95% CI 1.09 - 1.40). The most common reasons for why respondents might not take Paxlovid were concerns about side effects (64%), concerns about costs (29%), and the perception that COVID-19 is a mild (25%)., Conclusion: The majority of our respondents would take Paxlovid if it was prescribed to them, but a much smaller proportion would have the initiative to request for this. Key factors that may influence uptake are COVID-19 threat perceptions, trust in healthcare and government, and perceptions of the drug's side effects and cost., (© 2024. The Author(s).)

Purpose: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC)., Patients and Methods: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage., Results: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group., Conclusions: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC., (©2024 American Association for Cancer Research.)

Background: Current evidence of nonpharmacological intervention for patients with treatment-resistant depression (TRD) is lacking. AIMS: To examine whether an 8-week nurse-led cognitive-behavioral based group intervention would enhance resilient coping and life quality among community-based patients with TRD., Method: The participants were randomly sampled from a cohort of TRD recruited from two general teaching hospitals. The two groups were assessed with multiple outcome measures at baseline (T 0 ); 8-week post-baseline (T 1 ); and at 3, 6, and 9 months after T 1 (T 2-4 ). Psychoeducation was nested in the cognitive behavioral group intervention to facilitate discussion., Results: Of the 23 participants (mean age 56 years, 69.6% female) in the experimental group, higher resilient coping and lower mental distress levels at T 1 as well as later improved quality of life and community integration at T 2-4 were observed compared to the controls across COVID-19 (T 3 ). Overall, the scores of resilience and community integration were higher throughout the four follow-up points of observations for the experimental group., Conclusion: The findings indicated that an 8-week nurse-led cognitive-behavioral based group intervention may enhance the TRD patients' resilient coping and mental distress levels while providing the potentials for community reintegration after mental health psychoeducation engagement. It is imperative for the nurses caring for patients with TRD to extend from clinical-based intervention to community-based self-care approach, with the importance of short-term stress management and healthy lifestyle development highlighted during the community reintegration trajectory., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: No recommendations have been made regarding the puncture position during tunnelled dialysis catheter (TDC) insertion from right internal jugular vein (RIJV). We investigated the effect of puncture positioning along with other characteristics and clinical factors associated with TDCs to determine their correlation with catheter patency rate., Methods: We retrospectively reviewed TDC insertion procedures performed between January 2018 and December 2020 at a single institution. Patients were monitored for at least 1 year or until TDC removal or replacement. The distance on the post-operative chest radiography were measured to determine the height of puncture position. End points were freedom from catheter dysfunction., Results: Total 949 catheters met the eligibility criteria. Catheter dysfunction occurred in 233 patients and catheter infection in 127 patients. By multivariate analysis, female sex [hazard ratio (HR) =1.497, 95% confidence interval (CI): 1.119-2.002; P=0.007] and split-tip catheter (HR =1.453, 95% CI: 1.087-1.944; P=0.012) were associated with an increased rate of catheter dysfunction. Every 10-year increment in age (HR =1.243, 95% CI: 1.123-1.376; P<0.001) and every 1-cm increase in the height of the catheter insertion site (HR =1.270, 95% CI: 1.096-1.473; P=0.001) were also associated with an increased rate of catheter dysfunction. After classifying the height of puncture position into 3 groups, significant worse patency was observed in the catheter with puncture height more than 4 cm (P=0.025). No immediate complications were observed., Conclusions: TDC insertion at a high puncture site correlates with an increased risk of catheter dysfunction. Puncturing the RIJV close to the clavicle is safe and enhances catheter patency., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-417/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial., Materials and Methods: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included., Results: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy., Conclusions: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PI COG ) that maximized discrimination of the predictive model. Patients with higher PI COG have higher predicted relapse risk. The PI COG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PI COG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PI COG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PI COG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PI COG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure., (© 2024. The Author(s).)

Purpose: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019., Methods: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials., Results: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 10 3 /μL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005)., Conclusion: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

The Novel Metagenome Protein Families Database (NMPFamsDB) is a database of metagenome- and metatranscriptome-derived protein families, whose members have no hits to proteins of reference genomes or Pfam domains. Each protein family is accompanied by multiple sequence alignments, Hidden Markov Models, taxonomic information, ecosystem and geolocation metadata, sequence and structure predictions, as well as 3D structure models predicted with AlphaFold2. In its current version, NMPFamsDB hosts over 100 000 protein families, each with at least 100 members. The reported protein families significantly expand (more than double) the number of known protein sequence clusters from reference genomes and reveal new insights into their habitat distribution, origins, functions and taxonomy. We expect NMPFamsDB to be a valuable resource for microbial proteome-wide analyses and for further discovery and characterization of novel functions. NMPFamsDB is publicly available in http://www.nmpfamsdb.org/ or https://bib.fleming.gr/NMPFamsDB., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed for depression treatment. Animal studies have shown that antidepressants can influence gut microbiota composition and specific bacterial taxa. We aimed to investigate the association between antidepressant use and human gut microbiota composition and functional pathway., Methods: We collected information on antidepressant use, demographic, food patterns, and clinical characteristics through questionnaires and medical records. The gut microbiota profiles of 271 depressive patients were carried out through 16S rRNA gene sequencing. Patients were categorized based on different types of antidepressant use groups for gut microbiota comparisons. MaAsLin2 was performed to evaluate microbiota composition across groups. PICRUSt2 was used to predict microbiota functional pathways., Results: Patients taking SSRIs or SNRIs had a lower microbiota diversity. We found seven taxa abundances (Turicibacter, Barnesiella, Lachnospiraceae&#95;ND3007&#95;group, Romboutia, Akkermansia, Dialister, Romboutia and Fusicatenibacter) differed in patients with various types of antidepressants compared with those without antidepressant treatments (p < 0.05). Turicibacter inversely correlated with depression severity in SSRIs or SNRI users (r = -0.43, p < 0.05). Top identified pathways were related to compound fermentation and biosynthesis in microbiota function., Conclusion: Antidepressant usage, especially SSRIs and SNRIs, associates with changes in gut microbiota composition and specific taxa. Given our study's preliminary cross-sectional nature, further research is warranted to comprehend the relationship between antidepressant use, treatment response, and gut microbiota, aiming to enhance therapeutic interventions in the future., Competing Interests: Declaration of competing interest No conflicts of interest exist, according to the authors, with the publishing of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The sleep and circadian rhythm patterns associated with smartphone use, which are influenced by mental activities, might be closely linked to sleep quality and depressive symptoms, similar to the conventional actigraphy-based assessments of physical activity., Objective: The primary objective of this study was to develop app-defined circadian rhythm and sleep indicators and compare them with actigraphy-derived measures. Additionally, we aimed to explore the clinical correlations of these indicators in individuals with insomnia and healthy controls., Methods: The mobile app "Rhythm" was developed to record smartphone use time stamps and calculate circadian rhythms in 33 patients with insomnia and 33 age- and gender-matched healthy controls, totaling 2097 person-days. Simultaneously, we used standard actigraphy to quantify participants' sleep-wake cycles. Sleep indicators included sleep onset, wake time (WT), wake after sleep onset (WASO), and the number of awakenings (NAWK). Circadian rhythm metrics quantified the relative amplitude, interdaily stability, and intradaily variability based on either smartphone use or physical activity data., Results: Comparisons between app-defined and actigraphy-defined sleep onsets, WTs, total sleep times, and NAWK did not reveal any significant differences (all P>.05). Both app-defined and actigraphy-defined sleep indicators successfully captured clinical features of insomnia, indicating prolonged WASO, increased NAWK, and delayed sleep onset and WT in patients with insomnia compared with healthy controls. The Pittsburgh Sleep Quality Index scores were positively correlated with WASO and NAWK, regardless of whether they were measured by the app or actigraphy. Depressive symptom scores were positively correlated with app-defined intradaily variability (β=9.786, SD 3.756; P=.01) and negatively correlated with actigraphy-based relative amplitude (β=-21.693, SD 8.214; P=.01), indicating disrupted circadian rhythmicity in individuals with depression. However, depressive symptom scores were negatively correlated with actigraphy-based intradaily variability (β=-7.877, SD 3.110; P=.01) and not significantly correlated with app-defined relative amplitude (β=-3.859, SD 12.352; P=.76)., Conclusions: This study highlights the potential of smartphone-derived sleep and circadian rhythms as digital biomarkers, complementing standard actigraphy indicators. Although significant correlations with clinical manifestations of insomnia were observed, limitations in the evidence and the need for further research on predictive utility should be considered. Nonetheless, smartphone data hold promise for enhancing sleep monitoring and mental health assessments in digital health research., (©Chen Lin, I-Ming Chen, Hai-Hua Chuang, Zih-Wen Wang, Hsiao-Han Lin, Yu-Hsuan Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.12.2023.)

Pancreatic cancer is one of the deadliest cancer types with poor treatment options. Better detection of early symptoms and relevant disease correlations could improve pancreatic cancer prognosis. In this retrospective study, we used symptom and disease codes (ICD-10) from the Danish National Patient Registry (NPR) encompassing 6.9 million patients from 1994 to 2018,, of whom 23,592 were diagnosed with pancreatic cancer. The Danish cancer registry included 18,523 of these patients. To complement and compare the registry diagnosis codes with deeper clinical data, we used a text mining approach to extract symptoms from free text clinical notes in electronic health records (3078 pancreatic cancer patients and 30,780 controls). We used both data sources to generate and compare symptom disease trajectories to uncover temporal patterns of symptoms prior to pancreatic cancer diagnosis for the same patients. We show that the text mining of the clinical notes was able to complement the registry-based symptoms by capturing more symptoms prior to pancreatic cancer diagnosis. For example, 'Blood pressure reading without diagnosis', 'Abnormalities of heartbeat', and 'Intestinal obstruction' were not found for the registry-based analysis. Chaining symptoms together in trajectories identified two groups of patients with lower median survival (<90 days) following the trajectories 'Cough→Jaundice→Intestinal obstruction' and 'Pain→Jaundice→Abnormal results of function studies'. These results provide a comprehensive comparison of the two types of pancreatic cancer symptom trajectories, which in combination can leverage the full potential of the health data and ultimately provide a fuller picture for detection of early risk factors for pancreatic cancer., Competing Interests: JH, SN, IJ, TS, SV, DW, JJ No competing interests declared, IC I.M.C. reported receiving research funding and hotel/airfare reimbursement to attend global health meetings from Roche, BMS, Celgene, Genis, and an advisory relationship with Amgen and AstraZeneca, LJ L.J.J. reports ownerships in Amgen Inc, AstraZeneca PLC and Novo Nordisk A/S, SB SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK A/S and managing board memberships in Proscion A/S and Intomics A/S outside the submitted work, (© 2023, Hjaltelin et al.)

Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities 1,2 . Exploration of this vast sequence space has been limited to a comparative analysis against reference microbial genomes and protein families derived from those genomes. Here, to examine the scale of yet untapped functional diversity beyond what is currently possible through the lens of reference genomes, we develop a computational approach to generate reference-free protein families from the sequence space in metagenomes. We analyse 26,931 metagenomes and identify 1.17 billion protein sequences longer than 35 amino acids with no similarity to any sequences from 102,491 reference genomes or the Pfam database 3 . Using massively parallel graph-based clustering, we group these proteins into 106,198 novel sequence clusters with more than 100 members, doubling the number of protein families obtained from the reference genomes clustered using the same approach. We annotate these families on the basis of their taxonomic, habitat, geographical and gene neighbourhood distributions and, where sufficient sequence diversity is available, predict protein three-dimensional models, revealing novel structures. Overall, our results uncover an enormously diverse functional space, highlighting the importance of further exploring the microbial functional dark matter., (© 2023. The Author(s).)

Background: YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is a secreted glycoprotein produced by various cell types including stromal, immune, and cancer cells. It contributes to cancer progression through tumor-promoting inflammation and has been shown to inhibit the cytotoxicity of T and NK lymphocytes. In vivo studies have demonstrated synergistic anti-cancer effects of blocking YKL-40 in combination with immune checkpoint inhibitors (ICIs). Biomarkers for the prediction of the response to ICIs are highly needed. We investigated the association between plasma YKL-40 and clinical benefit and survival in patients with metastatic pancreatic cancer (mPC) receiving ICIs and stereotactic body radiotherapy (SBRT)., Methods: Blood samples were collected from 84 patients with mPC who participated in the randomized phase II CheckPAC study, in which patients received nivolumab with or without ipilimumab combined with a single fraction of SBRT. Plasma YKL-40 was measured using a commercial ELISA kit., Results: Elevated baseline plasma YKL-40 was an independent predictor of shorter overall survival (OS) (HR 2.19, 95% CI 1.21-3.95). A ≥ 40% decrease in plasma YKL-40 during treatment was associated with longer progression-free survival ( p = 0.009) and OS ( p = 0.0028). There was no correlation between plasma YKL-40 and the tumor burden marker CA19-9 at baseline or during treatment., Conclusion: This study contributes new knowledge regarding YKL-40 as a predictor of clinical benefit from ICIs and radiotherapy. These exploratory results warrant further investigation of YKL-40 as a biomarker for patients treated with immunotherapies., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT02866383., Competing Interests: IC: Research Funding: Roche Inst, Bristol Myers Squibb Inst, Celgene Inst, Genis Inst, and Varian Medical Systems Inst; Travel, Accommodation Expenses: Roche, Bristol Myers Squibb, Celgene, and Bayer; Advisory Role: Amgen. SB: Ownership: Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK abello A/S; Managing Board Memberships: Proscion A/S and Intomics A/S. The authors declare that this study received funding from the Danish Comprehensive Cancer Center, the Lundbeck Foundation, Varian, and the Novo Nordisk Foundation. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2023 Johansen, Novitski, Hjaltelin, Theile, Boisen, Brunak, Madsen, Nielsen and Chen.)

Background: According to current evidence, the best treatment for fit patients with non-resectable pancreatic cancer (PC) is combination chemotherapy, whereas frail patients are recommended gemcitabine (Gem) monotherapy. Randomized controlled trials in colorectal cancer and a post-hoc analysis of gemcitabine and nab-paclitaxel (GemNab) in PC suggest, however, that reduced dose of combination chemotherapy may be feasible and more efficient compared to monotherapy in frail patients. The aim of this study is to investigate whether reduced dose GemNab is superior to full dose Gem in patients with resectable PC, who are not candidates for full dose combination chemotherapy in first line., Methods: The Danish Pancreas Cancer Group (DPCG)-01 trial is a national multicenter prospective randomized phase II trial. A total of 100 patients in ECOG performance status 0-2 with non-resectable PC, not candidate for full dose combination chemotherapy in first line, but eligible for full dose Gem, will be included. Patients are randomized 1:1 to either full dose Gem or GemNab in 80% of recommended dose. The primary endpoint is progression-free survival. Secondary endpoints are overall survival, overall response rate, quality of life, toxicity and rate of hospitalizations during treatment. The correlation between blood inflammatory markers, including YKL-40 and IL-6, circulating tumor DNA, and tissue biomarkers of resistance to chemotherapy and outcome will be explored. Finally, the study will include measures of frailty (G8, modified G8, and chair-stand-test) to assess whether scoring would enable a personalized allocation to different treatments or indicates a possibility for interventions., Discussion: Single-drug treatment with Gem has for frail patients with non-resectable PC been the main treatment option for more than thirty years, but the impact on outcome is modest. If improved results and sustained tolerability with reduced dose combination chemotherapy can be shown, this could change the future practice for this increasing group of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT05841420. Secondary Identifying No: N-20210068. EudraCT No: 2021-005067-52., Protocol Version: 1.5, 16-MAY-2023., (© 2023. The Author(s).)

Background: The superiority of the new-generation self-expanding Evolut R compared with the first-generation CoreValve with regards to outcomes after transcatheter aortic valve replacement (TAVR) is unclear. The aim of this study was to investigate the hemodynamic and clinical performance of Evolut R compared with its direct predecessor, CoreValve, in a Taiwanese population., Methods: This study included all consecutive patients who underwent TAVR with either CoreValve or Evolut R between March 2013 and December 2020. Thirty-day Valve Academic Research Consortium-2 (VARC-2)-defined outcomes and hemodynamic performances were investigated., Results: There were no significant differences in baseline demographic characteristics between the patients receiving CoreValve (n = 117) or Evolut R (n = 117). Aortic valve-in-valve procedures for failed surgical bioprosthesis and procedures under conscious sedation were performed significantly more often with Evolut R. Pre-dilatation was performed significantly more often and contrast media volume was significantly higher with CoreValve. Stroke (0% vs. 4.3%, p = 0.024) and the need for emergent conversion to open surgery (0% vs. 5.1%, p = 0.012) were significantly lower in Evolut R than in CoreValve recipients. Evolut R significantly reduced 30-day composite safety endpoint (4.3% vs. 15.4%, p = 0.004)., Conclusions: Advancements in transcatheter valve technologies have resulted in improved outcomes for patients undergoing TAVR with self-expanding valves. With the new-generation Evolut R, device success was high and the 30-day composite safety endpoint was significantly reduced after TAVR compared with CoreValve., Competing Interests: Dr. Ying-Hwa Chen and Dr. Hsiao-Huang Chang are proctors for the Medtronic CoreValve and Evolut R. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Subjective sleep quality may reflect the mental well-being of migrant care workers; however, the related occupational factors remain unclear. This study examines the association between the characteristics of care labor and the subjective sleep quality of female migrants., Methods: In this cross-sectional study, Southeast Asian migrant care workers in Taiwan were recruited using convenience sampling. Data on working conditions, including workplace setting, wage, working hours, psychiatric symptoms of care recipients, and sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI), were collected through computer-assisted personal interviews. Multiple linear regression analyses were performed to determine the independent relationship between working conditions and the PSQI global score., Results: There were 220 institution-(47.7%) and home-based (52.3%) care workers, and 47.7% had a PSQI score higher than 5. After controlling for covariates, the lowest tertile of wages and daily working hours (> 8 h) were independently correlated with poor sleep quality. Moreover, in the stepwise regression model, wage and working hours remained the most explainable correlates of poor sleep quality., Conclusion: This study lent support to the notion that low wages and long working hours are significant occupational factors that negatively impact the subjective sleep quality of female Southeast Asian migrant care workers in Taiwan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Lin, Chien, Chen, Chan, Liao, Kuo and Chen.)

Identifying the relevant factors for suicidality in individuals with conduct problems is a public health concern, especially if they were under the influence of mood disorders later in life. This study investigates the relationship between youth conduct problems and mood disorders and adulthood suicidality, and to further explore the mediating effects of personality on this relationship. A retrospective cohort study was administered to 308 individuals aged 20-65 years, with or without mood disorders diagnosed by psychiatrists. The Composite International Diagnosis Interview was used to evaluate conduct problems in youth and suicidality (i.e., suicide plan and suicide attempt) in the past year. Personality traits were assessed using Eysenck Personality Questionnaire-Revised for extraversion and neuroticism. Multiple-mediator analysis was used to investigate the mediation effects of personality traits on the relationship between conduct problems and suicidality. The average age of enrolled participants was 31.6 years, and 42.5% of them were female. 39.2% reported suicidality and 43.2% reported conduct problems in youth. Participants who were diagnosed with mood disorders (p < 0.001) and reported having conduct problems (p = 0.004) were associated with high suicidality. Multiple-mediator analysis showed that conduct problems in youth increased the risk of adulthood suicidality through the indirect effects of higher neuroticism (suicide plan: OR = 1.30, BCA 95% CI = 1.04-1.83; suicide attempt: OR = 1.27, BCA 95% CI = 1.05-1.66). Neuroticism mediates the association between youth conduct problems and adulthood suicidality. This finding raises our attention to assess personality traits in individuals with youth conduct problems for designing proper intervention strategies to reduce the risk of suicide., (© 2023. The Author(s).)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a pronounced fibrotic tumor microenvironment, which impairs treatment response. Type I and V collagens are responsible for the densely packed fibrils in the tumor fibrosis environment. While the role of the major type I collagen in cancer is well described, less is known about the minor type V collagen. Quantifying collagen propeptides in serum has been shown to have prognostic and predictive value. In this study, we evaluated the clinical utility of measuring the propeptide of type V collagen (PRO-C5) in serum from a discovery cohort and a validation cohort of patients with PDAC as well as in non-pancreatic solid tumor types to explore the relevance of the PRO-C5 biomarker in cancer. Methods: Serum PRO-C5 was measured in three cohorts: a discovery cohort (19 healthy controls, 12 patients with chronic pancreatitis and 33 patients with PDAC (stage I-IV)), a validation cohort (800 patients with PDAC (stage I-IV)), and a non-pancreatic solid tumor type cohort of 33 healthy controls and 200 patients with 10 different non-pancreatic solid tumor types. The levels of serum PRO-C5 in patients with cancer were compared to levels in healthy controls. The association between PRO-C5 levels and overall survival (OS) was evaluated in patients with PDAC after adjusting for established prognostic factors. Results: PRO-C5 was significantly increased in serum from patients with PDAC compared to healthy controls ( p < 0.001). High PRO-C5 levels were significantly associated with short OS in both the discovery- and the validation cohort, especially in early stages of PDAC (validation cohort stage II, HR = 2.0, 95%CI1.2-3.4). The association was independent of other prognostic parameters including stage, performance status and CA19-9. Furthermore, serum levels of PRO-C5 were significantly increased in serum from patients with other non-pancreatic solid tumor types compared to healthy controls. Conclusion: High levels of serum PRO-C5 is prognostic for short OS in patients with PDAC and may provide clinical value in many other tumor types beyond PDAC. This underlines the importance of type V collagen in tumor fibrosis. PRO-C5 could have the potential to be used in several aspects within drug discovery, patient stratification and drug efficacy., Competing Interests: NN, CJ, EM, JT-U, MK, and NW are all employed by Nordic Bioscience A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nissen, Johansen, Chen, Jensen, Madsen, Hansen, Thorlacius-Ussing, Karsdal, Johansen, Diab, Jørgensen and Willumsen.)

Video laryngoscope is available for visualizing the motion of vocal cords and aid in the assessment of analyzing the larynx-related lesion preliminarily. Laryngeal Electromyography (EMG) needs to be performed to diagnose the factors of vocal cord paralysis, which may cause patient feeling unwell. Thus, the problem is the lack of credible larynx indicators to evaluate larynx-related diseases in the department of otolaryngology. Therefore, this paper aims to propose a 3D VOSNet model, which has the characteristics of sequence segmentation to extract the time-series features in the video laryngoscope. The 3D VOSNet model can keep the time-series features of three images before and after of the specific image to achieve translation and occlusion invariance, which explicitly signifies that our model can segment and classify each item in the video of laryngoscopy not affected by extrinsic causes such as shaking or occlusion during laryngoscope. Numerical results revealed that the testing accuracy rates of the glottal, right vocal cord, and the left vocal cord are 89.91%, 94.63%, and 93.48%, respectively. Our proposed model can segment glottal and vocal cords from the sequence of laryngoscopy. Finally, using the proposed algorithm computes six larynx indicators, which are the area of the glottal, area of vocal cords, length of vocal cords, deviation of length of vocal cords, and symmetry of the vocal cords. In order to assist otolaryngologists in staying credible and objective when making decisions without any doubt during diagnosis and also explaining the clinical symptoms of the larynx such as vocal cord paralysis to patients after diagnosis, our proposed algorithm provides otolaryngologists with explainable indicators (X-indicators)., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Background: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC)., Methods: Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry., Results: PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15., Conclusion: A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC., Competing Interests: Competing interests: MHA has made an invention based on the use of TGF-β for vaccinations. The rights of the invention have been transferred to Copenhagen University Hospital Herlev, according to the Danish Law of Public Inventions at Public Research Institutions. The capital region has licensed the rights to the company IO Biotech ApS. The patent application was filed by IO Biotech ApS. MHA is founder, advisor and shareholder in IO Biotech. IMS is co-founder, advisor and shareholder in IO Biotech. The additional authors declare no competing financial interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Biliary tract cancer (BTC) is characterized by a desmoplastic extracellular matrix (ECM). We tested the diagnostic and prognostic use of seven circulating biomarkers of ECM remodeling: pro-peptides of type III collagen (PRO-C3), VI (PRO-C6) and XI (PRO-C11), matrix metalloprotease (MMP) degraded type III collagen (C3M) and type IV collagen (C4M) fragments, granzyme B degraded type IV collagen fragments (C4G) and MMP degraded and citrullinated vimentin (VICM) a marker of macrophage activation. The study included 269 patients with all stages of BTC and 49 patients with benign biliary tract diseases. Serum samples from BTC patients were collected before surgery, or before first- or second-line chemotherapy. C3M, C4M, PRO-C3, PRO-C6, PRO-C11 and VICM levels were elevated in patients with BTC compared to patients with benign disease. Receiver operating characteristics curve analyses identified PRO-C3 (area under curve [AUC] = 0.87) as the ECM marker with the best diagnostic performance. The ECM biomarkers correlated with inflammation biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6] and YKL-40) but not with CA19-9. To investigate prognostic performance, patients were split into three cohorts (first-line, second-line and surgery). Elevated ECM biomarker levels were associated with short overall survival (OS), but only pretreatment PRO-C3 and PRO-C6 were associated with OS in both the first-line and second-line settings when adjusting for CA19-9, performance status and stage in a multivariate Cox-regression analyses. Our results indicate that collagen remodeling is increased in patients with BTC and associated with survival. The collagen pro-peptides (PRO-C3 and PRO-C6) could be used as novel biomarkers in these patients., (© 2022 UICC.)

Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC ( n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort ( n = 202), first-line validation cohort ( n = 118), second-line cohort ( n = 56), and surgery cohort ( n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08-1.46) and IL-15 (HR = 2.23, 95% CI 1.48-3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds.

Background: Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC)., Methods: Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%., Results: Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events., Conclusion: The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Less than 20% of patients are diagnosed with resectable disease. Identifying truly resectable disease is challenging because 20%-40% of the patients subjected to resection are found to have advanced disease during surgery. The aim of our study was to identify panels of circulating proteins that could be used to distinguish patients with unresectable PDAC from patients with resectable PDAC and to identify prognostic signatures for both groups., Methods: We measured 92 circulating immuno-oncology-related proteins using the proximity extension assay from Olink Proteomics in 273 patients eligible for surgery for PDAC. Two bioinformaticians worked independently of one another on the same data. LASSO and Ridge regression were used in the statistical analyses., Results: One protein index for determining resectability had an AUC value of 0.66. Several indices for prognosis had AUC values between 0.50 and 0.75 and were therefore not better than existing prognostic markers., Discussion: Our study did not reveal any new high-performing protein panels that could be used to identify patients with inoperable PDAC before surgery. The panel of 92 proteins investigated has previously been found to be applicable for diagnostic use in patients with PDAC, but it does not seem to warrant further investigation regarding resectability in the subgroup of patients with PDAC referred to surgery., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The objective of this study was to evaluate the diagnostic and prognostic potential of soluble CD163 (sCD163) in patients with pancreatic ductal adenocarcinoma (PDAC). Preoperative serum samples from 255 patients with PDAC were analyzed for sCD163 using a commercially available enzyme-linked immunosorbent assay. The diagnostic value of sCD163 was evaluated using receiver operating characteristic (ROC) curves. The prognostic significance of sCD163 was evaluated by Cox regression analysis and Kaplan-Meier survival curves. sCD163 was significantly increased in patients with PDAC, across all stages, compared to healthy subjects (stage 1: p value = 0.033; stage 2-4: p value ≤ 0.0001). ROC curves showed that sCD163 combined with CA 19-9 had the highest diagnostic potential compared to sCD163 and CA 19-9 alone both in patients with local PDAC and patients with advanced PDAC. Univariate and multivariate analysis showed no association between sCD163 and overall survival. This study found elevated levels of circulating sCD163 in patients with PDAC, regardless of stage, compared to healthy subjects. This suggests that sCD163 may have a clinical value as a novel diagnostic biomarker in PDAC.

The 12-Year Basic Education Curricula not only follow the objectives of previous curriculum syllabus development, but they place more focus on competence-oriented instruction, which aims to emphasize the importance of combining the curriculum with life situations that are not solely based on learning knowledge and skills. This study aims to investigate the results of the students' learning effectiveness and learning engagement after adding competence-oriented instructional strategies into electrical engineering practical subjects offered by the Department of Electrical Engineering in skills-based senior high schools, and, at the same time, to figure out the difference in learning effectiveness using different instructional strategies. Two classes of students from the Department of Electrical Engineering major in electrical engineering practical subjects in one skills-based senior high school in Central Taiwan were chosen as the participants for this study. By way of pre-test-post-test research design and heterogeneous grouping, a 10-week instruction experiment consisting of two groups and occurring over the course of 30 classes was conducted, wherein competence-oriented instructional strategies were used in an experimental group, while traditional didactic instructional strategies were used in a control group. By analyzing the collection of quantitative and qualitative data through competence-oriented instructional strategies, the instruction effectiveness and feasibility of the basic electricity practical curriculum were developed as the study topic for understanding how competence-oriented instruction can be implemented into the practical curriculum of the electrical engineering and electronic engineering group. According to the research objective, the results were concluded as follows: (1) Students of the Department of Electrical Engineering have a slightly better learning effectiveness in electrical engineering practice under competence-oriented instructional strategies compared with those who learned under the traditional didactic instructional strategies; (2) there is a significant difference in the students' learning engagement in electrical engineering practice from the Department of Electrical Engineering under competence-oriented instructional strategies compared with those who learned under the traditional didactic instructional strategies. The conclusion of this study emphasizes designing questions based on life situations, thereby applying what students have learned to solve problems they encounter in their daily lives. Compared with traditional didactic instructional strategies, competence-oriented instructional strategies not only have a better learning effectiveness and provide flexibility for the students to solve problems and provide analysis for situations, they also have broader applicability and an increased number of positive benefits when it comes to students' group interactions and sharing.