bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression
Authors: Lheureux Stephanie , Prokopec Stephenie D. , Oldfield Leslie E. , Gonzalez-Ochoa Eduardo , Bruce Jeffrey P. , Wong Derek , Danesh Arnavaz , Torti Dax , Torchia Jonathan , Fortuna Alexander , Singh Sharanjit , Irving Matthew , Marsh Kayla , Lam Bernard , Speers Vanessa , Yosifova Aleksandra , Oaknin Ana , Madariaga Ainhoa , Dhani Neesha C. , Bowering Valerie , Oza Amit M. , Pugh Trevor J.
Published: August 2023

AbstractPurpose:
To evaluate the use of blood cell–free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC).
Patients and Methods:
We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues.
Results:
At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001).
Conclusions:
Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.
Data from Development and multicenter case-control validation of urinary comprehensive genomic profiling for urothelial carcinoma diagnosis, surveillance, and risk prediction
Authors: Salari Keyan , Sundi Debasish , Lee Jason J. , Wu Shulin , Wu Chin-Lee , DiFiore Gabrielle , Yan Q. Robert , Pienkny Andrew , Lee Chi K. , Oberlin Daniel , Barme Greg , Piser Joel , Kahn Robert , Collins Edward , Phillips Kevin G. , Caruso Vincent M. , Goudarzi Mahdi , Garcia-Ransom Monica , Lentz Peter S. , Evans-Holm Martha E. , MacBride Andrew R. , Fischer Daniel S. , Haddadzadeh Iden J. , Mazzarella Brian C. , Gray Joe W. , Koppie Theresa M. , Bicocca Vincent T. , Levin Trevor G. , Lotan Yair , Feldman Adam S.
Published: August 2023

Abstract
Purpose: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma (UC) and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. Experimental Design: This is a multicenter case-control study utilizing banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or UC surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmpTM platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting UC tumor presence, grade, and recurrence risk were compared to cytology, cystoscopy, and pathology. Results: uCGP algorithms had a validation sensitivity/specificity of 96%/90% for initial cancer diagnosis in hematuria patients and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary UC classification demonstrated an NPV of 91%. uCGP recurrence risk prediction significantly prognosticated future recurrence (hazard ratio 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable to cytology (45% vs 42%) with much higher sensitivity (79% vs 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. Conclusions: uCGP enables noninvasive, accurate UC diagnosis and risk stratification in both hematuria and UC surveillance patients.
Data from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: August 2023

AbstractPurpose:
Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase I/IIa pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC.
Patients and Methods:
Patients with Child-Pugh score ≤ 7 and locally advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B HCC or BCLC-C disease without extrahepatic metastases, received Y90-radioembolization followed by intravenous durvalumab 1,500 mg 7 to 14 days after Y90-radioembolization and every 4 weeks thereafter. Primary endpoint was time to progression (TTP) assessed by modified RECIST (mRECIST). Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) determined by mRECIST, and safety.
Results:
All 24 patients enrolled received Y90-radioembolization and 23 received at least one dose of durvalumab. Median follow-up duration was 19.0 months (range, 2.2–24.2). Median TTP was 15.2 months [95% confidence interval (CI), 6.1–not estimated]. Median OS was not reached and 18-month OS rate was 58.3% (95% CI, 36.4–75.0). Median PFS was 6.9 months (95% CI, 5.4–15.2). Seven (29.2%) patients had a complete response and 13 (54.2%) had a partial response; ORR was 83.3% (95% CI, 62.6–95.3). Eleven (47.8%) patients experienced any-grade treatment-related adverse events. Two (8.7%) patients had grade 3 treatment-related adverse events (neutropenia and fever). None experienced any treatment-related serious adverse events.
Conclusions:
In patients with locally advanced unresectable HCC, the combination of Y90-radioembolization and durvalumab demonstrated promising efficacy and safety, warranting further evaluation in large-scale controlled trials.
MCR-21-0354_SF8 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 8 depicts regulated pathways of the FET/ETS fusions in Ewing sarcoma cells.
MCR-21-0354_SF4 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 4 depicts the overlap analysis of EWS/ETS and FUS/ETS proteins at both the genomic localization and transcriptional regulatory levels.
MCR-21-0354_SF1 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 1 depicts EWS/ETV4 and FUS/ETV4 expression in the Ewing sarcoma cell model after knockdown of endogenous EWS/FLI mRNA, as well as RNA-seq and CUT&Tag tracks for comparison of protein function between the two.
FIGURE 7 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

Effective antagonism of PGE2 signaling modulates significant transcriptional shifts in the TME. A, Volcano plots of selected genes. Blue coloration represents significantly (Padj < 0.05) downregulated genes while red correlation represents significantly upregulated genes. Genes in gray did not meet the significance cutoff. B, Heat map depicting significantly upregulated gene sets from GSEA performed on RNA sequencing analysis above and representative GSEA plot from IFNγ signature. All results represent data from one experiment with 4 animals per group. *** indicates FDR < 0.25 for that gene set compared with vehicle-treated animals.
FIGURE 1 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

Expression profiles of PGE2 receptors EP2 and EP4 across diverse human malignancies. A, Expression of EP2 (PTGER2) and EP4 (PTGER4) across cancer indications indicated in the figure using RNA sequencing data from TCGA Pan Cancer dataset obtained through cBIO Portal. Selected cancer types are labeled with TCGA abbreviations. B, Heat map of EP2 and EP4 expression across the selected malignancies, with definition of TCGA tumor type abbreviations defined. C, Heat map analysis of percent positive samples for designated prostaglandin pathway genes, including PTGER4, PTGS2, PTGES2, and PTGES from the Protein Atlas database.
Incidence of Hyper Progressive Disease in Combination Immunotherapy and Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Monotherapy for Unresectable Hepatocellular Carcinoma
Authors: Aoki Tomoko , Kudo Masatoshi , Ueshima Kazuomi , Morita Masahiro , Chishina Hirokazu , Takita Masahiro , Hagiwara Satoru , Ida Hiroshi , Minami Yasunori , Tsurusaki Masakatsu , Nishida Naoshi
Published: August 2023

Introduction: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4. Results: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05–3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25–33.79) when compared to the combined VEGF antibody group. Conclusion: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.
Indications, Resource Allocation, and Outcomes Associated with Ex-Utero Intrapartum Treatment Procedures: A North American Fetal Therapy Network Survey
Authors: Joshi Devashish , Stellon Michael , Antony Kathleen , Beninati Michael , Luks Francois I. , Puricelli Michael , Lobeck Inna Neyman
Published: August 2023

Introduction: Neonates with cardiorespiratory compromise at delivery are at substantial risk of hypoxic neurologic injury and death. Though mitigation strategies such as ex-utero intrapartum treatment (EXIT) exist, the competing interests of neonatal beneficence, maternal non-maleficence, and just distribution of resources require consideration. Due to the rarity of these entities, there are few systematic data to guide evidence-based standards. This multi-institutional, interdisciplinary approach aims to elucidate the current scope of diagnoses that might be considered for such treatments and examine if treatment allocation and/or outcomes could be improved. Methods: After IRB approval, a survey investigating diagnoses appropriate for EXIT consultation and procedure, variables within each diagnosis, occurrence of maternal and neonatal adverse outcomes, and instances of suboptimal resource allocation in the last decade was sent to all North American Fetal Treatment Network center representatives. One response was recorded per center. Results: We received a 91% response rate and all but one center offer EXIT. Most centers (34/40, 85%) performed 1–5 EXIT consultations per year and 17/40 (42.5%) centers performed 1–5 EXIT procedures in the last 10 years. The diagnoses with the highest degree of agreement between centers surveyed to justify consultation for EXIT are head and neck mass (100%), congenital high airway obstruction (90%), and craniofacial skeletal conditions (82.5%). Maternal adverse outcomes were noted in 7.5% of centers while neonatal adverse outcomes in 27.5%. A large percentage of centers report cases of suboptimal selection for risk mitigation procedures and several centers experienced adverse neonatal and maternal outcomes. Conclusion: This study captures the scope of EXIT indications and is the first to demonstrate the mismatch in resource allocation for this population. Further, it reports on attributable adverse outcomes. Given suboptimal allocation and adverse outcomes, further examination of indications, outcomes, and resource use is justified to drive evidence-based protocols.
Acute Myeloid Leukemia Treatment in the Elderly: A Comprehensive Review of the Present and Future
Authors: Choi Jun H. , Shukla Mihir , Abdul-Hay Maher
Published: August 2023

Background: Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology in the past decade. It is also an affliction of the elderly that predominantly affects patients over 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate. Summary: Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA-approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low-intense therapy remains a challenge, and it requires careful assessment of individual patient’s fitness and disease characteristics. Key Messages: This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for the elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.
Characteristics of Hematologic Parameters in Young Patients with Retinal Vein Occlusion
Authors: Wang Xiaoyun , Wang Lei , Li Xinying , Liu Shaohua , Liu Bing
Published: August 2023

Introduction: The aim of this study was to investigate the characteristics of hematologic parameters in young patients with retinal vein occlusion (RVO). Methods: All participants underwent routine ocular examinations and blood sample tests. Hematologic parameters obtained from a complete blood count, as well as the calculation of specific inflammatory indices, were compared between young patients with RVO and the control subjects. Correlations between hematologic inflammatory biomarkers and aqueous humor inflammatory cytokines were also investigated. Results: A total of 64 patients with RVO and 64 age- and gender-matched control subjects were included in this study. The white blood cell count, neutrophil cell count, mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI) in young patients with RVO were significantly higher than in the controls (all p < 0.05). Compared to patients with nonischemic RVO, patients with ischemic RVO had higher NLR, SII, and SIRI values (p = 0.032, p = 0.035, and p = 0.039, respectively). The areas under the receiver operator characteristic curve were 0.725, 0.651, 0.649, and 0.634 for the MPV, NLR, SII, and SIRI, respectively. In addition, a higher NLR was related to higher levels of interleukin 6 (IL-6; p = 0.046, R = 0.463), and a higher SII was related to higher levels of IL-6 (p = 0.034, R = 0.488) and vascular endothelial growth factor (p = 0.020, R = 0.528). Conclusion: The NLR, SII, and SIRI were significantly elevated in young patients with RVO, especially in young patients with ischemic RVO. NLR and SII were positively correlated with IL-6 levels in aqueous humor, which indicated that systemic inflammation plays an important role in the onset of RVO in young patients.
Myocardial Function in Fetuses with Congenital Cytomegalovirus Infection
Authors: Giorgione Veronica , Krajden Haratz Karina , Gull Ilan , Brusilov Michael , Birnbaum Roee , Blecher Yair , Malinger Gustavo , Kaplan Alon , Beer Gil , Kapusta Livia
Published: August 2023

Introduction: The objective of this study was to investigate myocardial deformation of left (LV) and right ventricle (RV) using 2-dimensional speckle-tracking echocardiography (2D-STE) in fetuses with and without congenital cytomegalovirus (CMV) infection. Methods: This was a prospective single-center study. Vertical transmission was defined by a positive CMV polymerase chain reaction (PCR) test on the amniotic fluid or on the neonate’s urine. Fetuses were divided into group 1 and group 2 if CMV-PCR was positive or negative, respectively. LV and RV global longitudinal strain (GLS) values were obtained and adjusted for gestational age by calculating Z-scores. Univariate analysis was carried out to compare cardiac indices between group 1 and group 2. Results: Fetuses from group 1 (n = 11) had a significantly lower LV myocardial shortening than those from group 2 (n = 32). GLS was −20.7 ± 5.2% and −26.3 ± 4.1%, respectively (p = 0.001). Similarly, GLS Z-score was lower (0.02 ± 0.72) in group 1 than in group 2 (−0.80 ± 0.59) (p = 0.001). Similarly, RV GLS Z-score was significantly impaired in group 1 compared to group 2 (−0.44 ± 1.03 vs. −1.04 ± 0.71, p = 0.041). Conclusion: Fetuses with congenital CMV showed subclinical biventricular myocardial dysfunction. Further studies are needed to confirm the potential role of 2D-STE in identifying fetuses with congenital CMV at risk of postnatal cardiovascular morbidities.
Fetal Laryngoscopy and Endoscopic Tracheal Intubation to Avoid ex utero Intrapartum Treatment in the Management of Fetuses with Suspected Airway Obstruction
Authors: Cruz-Martínez Rogelio , Gil-Pugliese Savino , Villalobos-Gómez Rosa , Martínez-Rodríguez Miguel , Márquez-Dávila Alejandra , López-Briones Hugo , Chávez-González Eréndira , Méndez-González Antonio , Pineda-Alemán Hugo , Rebolledo-Fernández Carlos , Barrios-Prieto Ernesto , Fajardo-Dueñas Sergio
Published: August 2023

Introduction: Large congenital neck tumors can cause neonatal death due to airway obstruction. The aim of this study was to report outcomes of the first cohort of fetuses with neck masses and suspected airway obstruction managed with fetal laryngoscopy (FL) and fetal endoscopic tracheal intubation (FETI) to secure fetal airways and avoid ex utero intrapartum treatment (EXIT) procedure. Methods: A prospective observational cohort of consecutive fetuses with neck masses that were candidates for an EXIT procedure due to suspicion of laryngeal and/or tracheal occlusion on ultrasonographic (US) or magnetic resonance imaging (MRI) examination were recruited for FL in a tertiary referral center in Queretaro, Mexico. FETI was performed if the obstruction was confirmed by FL. Maternal and perinatal outcomes were evaluated. Results: Between January 2012 and March 2023, 35 cases with neck masses were evaluated. Airway obstruction was suspected in 12/35 (34.3%), either by US in 10/35 (28.6%) or by fetal MRI in 2/35 (5.7%). In all cases, FL was successfully performed at the first attempt at a median gestational age (GA) of 36+5 (range, 33+5–39+6) weeks+days, with a median surgical time of 22.5 (12–35) min. In 4 cases, airway patency was confirmed during FL and an EXIT procedure was avoided. In 8/12 cases (66.7%), airway obstruction was confirmed during fetoscopy and FETI was successfully performed at a median GA of 36+3 (33+2–38+5) weeks+days, with a median surgical time of 25.0 (range, 12–45) min. No case required an EXIT procedure. All patients underwent conventional cesarean delivery with no maternal complications and all neonates were admitted to the neonatal intensive care unit with a correctly positioned endotracheal tube (ETT) immediately after delivery. Three neonatal deaths (37.5%) were reported due to postnatal unplanned extubation, failed ETT replacement, and tumoral bleeding. Conclusion: In fetuses with neck masses and suspected airway obstruction, FL and FETI are feasible and could replace EXIT procedures with good maternal and perinatal outcomes.
Association between Body Composition and Chronic Low Back Pain in Korean Adults Aged over 50 Years: The Korea National Health and Nutrition Examination Survey (KNHANES) 2010–2011
Authors: Shim Jae-Geum , Ryu Kyoung-Ho , Cho Eun-Ah , Ahn Jin Hee , Park Jiyeon , Lee Hyo-Won , Kang Suji , Han So Young , Lee Sung Hyun
Published: August 2023

Background: The relationship between overweight or obesity and low back pain (LBP) has previously been investigated. Several recent studies have focused on the relationship between other indicators of obesity, particularly indicators of fat, and the risk of LBP. However, the results of body composition and LBP have been inconsistent. Methods: All data for the present retrospective, cross-sectional study were extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) versions V-1 and 2 conducted in 2010 and 2011 by the Korea Centers for Disease Control and Prevention. In KNHANES V-1 (2010) and V-2 (2011), those over 50 years of age who completed the surveys on LBP, body weight, and body composition assessed using dual-energy X-ray absorptiometry were included. The multivariable logistic regression analysis was used to examine the relationship between the presence of chronic LBP and body composition adjusting for confounders. Results: We analyzed 3,579 persons who completed the question. In the multivariable analyses adjusting for age and sex, none of the variables, including fat mass and fat-free mass, remained positively or negatively associated with LBP. Additionally, when depression, smoking, alcohol intake, physical activity, diabetes mellitus, osteoporosis, and fat or lean tissue mass were included in the multivariable logistic model, no significant associations were found between all measures of fat mass, fat-free mass, and LBP. Conclusion: The results of this study are contrary to previous studies which concluded that there is a correlation between obesity and fat mass and LBP. Our study shows that LBP is not associated with increased levels of obesity and fat mass.
Level of Inferior Mesenteric Artery Ligation in Sigmoid Colon and Rectal Cancer Surgery: Analysis of Apical Lymph Node Metastasis and Recurrence
Authors: Nakamura Yuya , Yamaura Tadayoshi , Kinjo Yousuke , Harada Kazu , Kawase Makoto , Kawabata Yusuke , Kanto Satoshi , Ogo Yasumasa , Kuroda Nobukazu
Published: August 2023

Introduction: Whether high or low ligation of the inferior mesenteric artery (IMA) is optimal for treating sigmoid colon and rectal cancers is controversial. The present study aimed to compare outcomes of high and low ligation of the IMA and determine the adequate extent of IMA lymph node dissection. Methods: Subjects were 455 consecutive stage I–III colorectal cancer patients who underwent curative surgery between 2011 and 2019. We assessed the association between the level of IMA ligation and overall survival and recurrence-free survival (RFS) by propensity score matching analysis. Clinicopathological features of IMA lymph node metastasis and recurrence patterns were analyzed. Results: After propensity score matching, the low ligation group had a significantly worse prognosis than that of the high ligation group for RFS (p = 0.039). Positive IMA lymph nodes were associated with pathological T3 or T4 stage and N2 stage. IMA lymph node recurrences in the high ligation group occurred at the superior left side of the IMA root. In contrast, all recurrences in the low ligation group occurred at the left colic artery bifurcation. Conclusion: High ligation of IMA is oncologically safe. However, even with high ligation, care must be taken to ensure adequate lymph node dissection.
A Common Genetic Factor Underlies Genetic Risk for Gynaecological and Reproductive Disorders and Is Correlated with Risk to Depression
Authors: Kiewa Jacqueline , Mortlock Sally , Meltzer-Brody Samantha , Middeldorp Christel , Wray Naomi R. , Byrne Enda M.
Published: August 2023

Introduction: Sex steroid hormone fluctuations may underlie both reproductive disorders and sex differences in lifetime depression prevalence. Previous studies report high comorbidity among reproductive disorders and between reproductive disorders and depression. This study sought to assess the multivariate genetic architecture of reproductive disorders and their loading onto a common genetic factor and investigated whether this latent factor shares a common genetic architecture with female depression, including perinatal depression (PND). Method: Using UK Biobank and FinnGen data, genome-wide association meta-analyses were conducted for nine reproductive disorders, and genetic correlation between disorders was estimated. Genomic Structural Equation Modelling identified a latent genetic factor underlying disorders, accounting for their significant genetic correlations. SNPs significantly associated with both latent factor and depression were identified. Results: Excellent model fit existed between a latent factor underlying five reproductive disorders (χ2 (5) = 6.4; AIC = 26.4; CFI = 1.00; SRMR = 0.03) with high standardised loadings for menorrhagia (0.96, SE = 0.05); ovarian cysts (0.94, SE = 0.05); endometriosis (0.83, SE = 0.05); menopausal symptoms (0.77, SE = 0.10); and uterine fibroids (0.65, SE = 0.05). This latent factor was genetically correlated with PND (rG = 0.37, SE = 0.15, p = 1.4e−03), depression in females only (rG = 0.48, SE = 0.06, p = 7.2e−11), and depression in both males and females (MD) (rG = 0.35, SE = 0.03, p = 1.8e−30), with its top locus associated with FSHB/ARL14EP (rs11031006; p = 9.1e−33). SNPs intronic to ESR1, significantly associated with the latent factor, were also associated with PND, female depression, and MD. Conclusion: A common genetic factor, correlated with depression, underlies risk of reproductive disorders, with implications for aetiology and treatment. Genetic variation in ESR1 is associated with reproductive disorders and depression, highlighting the importance of oestrogen signalling for both reproductive and mental health.
Translation of an Excerpt from Anna Livia Plurabelle’s Final Monologue
Authors: Ferreira Luis Henrique Garcia
Published: August 2023

This is a translation of an excerpt from the last three pages of Finnegans Wake (FW 626.30 – 628.16), in which the river-character Anna Livia Plurabelle (ALP) presents a bitter farewell monologue, motivated by the abandonment of her family and the supposed betrayal of her mountain-husband Humphrey Chimpden Earwicker (HCE) with her cloud-daughter, young Issy. While remembering the past, ALP feels old, alone and without the strength to continue, disintegrating herself from a world in which she no longer fits. She, who monologues at the same time that her family sleeps, goes to meet the father-sea in a flow that closes the last page of the work with the excerpt “A way a lone a last a loved a long the” (no period). However, this absence of punctuation provokes a circular movement that takes the reader back to the initial page, which begins with the word riverrun, in lowercase, which connects itself with the incomplete sentence “A way a lone a last a loved a long the” from page 628. In this way, what seemed to be the end of the character and also of the book soon becomes the restart of both. It is as if the river-woman who disappears into the sea evaporates herself and reappears on the front page after raining from her cloud-daughter, being vigorously reborn through her rival.
Wilder’s Joyce: Inspiration, Borrowing, Appropriation, Plagiarism
Authors: Gontarski S. E.
Published: August 2023

American novelist and playwright Thornton Wilder’s lifelong attraction to and passion for if not obsession with the work of James Joyce has led to unintended consequences. Wilder was writing what would become his second Pulitzer Prize winning play, The Skin of Our Teeth, while in the midst of “unriddling” Joyce’s final novel, Finnegans Wake. Accusations of plagiarism would subsequently arise from two major Joyce scholars, Joseph Campbell and Henry Morton Robinson as they raised questions about the tipping point in creative practice, the point at which common practices of textual influence and reference cross the line into excessive borrowings and plagiarism. Such accusations, which Wilder failed to acknowledge and to fully address in a timely fashion, have lingered to his discredit and have obscured his achievements both as a playwright and a major scholar of experimental literature with a particular emphasis on James Joyce. The essay details the need to return to and to reassess the issues of Wilder’s creative practice within the current theoretical climate of intertextuality and thus to reassess Wilder’s pioneering work on both Ulysses and Finnegans Wake.
Devouring Hometowns: James Joyce’s Dublin and Dalton Trevisan’s Curitiba
Authors: Giacomassi Priscila Célia
Published: August 2023

The issue of geographical escape permeates the texts of Dubliners (1914) by James Joyce and Em busca de Curitiba perdida (1992) by Dalton Trevisan. In both works we come across characters who try to run away from a reality marked by frustration, decadence and paralysis. The impossibility of being able to leave the physical space of the city invariably leads them to sublimate this need through other types of evasion, such as the dream or daydream; the idealization of exotic and distant places; the temporal flight – by valuing the past at the expense of the present time; vices – mostly, drinking; superficial and fleeting relationships and, in the extreme, death as the ultimate solution to the hardships of which they are victims. Thus, Joyce’s Dublin and Trevisan’s Curitiba are not idealized, much less understood as places of protection and warmth – characteristics generally associated with the idea of hometown. In the fictional context in which they are presented, these cities function not only as settings, but as a large and stifling persona that imprisons its inhabitants and inexorably outlines their destinies.
Prosthetic-Driven Autotransplantation with the Assistance of Medical Image-Processing Software and a Real-Time Navigation System: A Case Report
Authors: Chang Hung-Ming , Ko Hui-Hsin , Chi Chih-Wen , Deng Yi-Ting , Lin I-Ping , Chen Szu-Han
Published: August 2023

Autotransplantation has been proven as a viable method of reconstructing missing teeth. While preparing the recipient site, the bone reduction location depends largely on the surgeon’s experience. Inappropriate overpreparation can cause biologic and esthetic complications, such as buccal or lingual bone resorption. This paper provides an innovative method to aid clinicians in precisely preparing a recipient site with the assistance of medical image-processing software and a real-time navigation system. This case report presents the autotransplantation of a mandibular molar using this technique with good short-term (6 months) clinical outcomes, including radiographic bone fill, normal probing pocket depth, physiologic tooth mobility, acceptable gingival level, and satisfactory restoration.
Lifelong Heterogeneous Contribution of Cardiovascular Risk Factors to Slow and Fast Progression of Arterial Stiffness
Authors: Tomiyama Hirofumi , Imai Takumi , Shiina Kazuki , Higashi Yukihito , Nakano Hiroki , Takahashi Takamichi , Fujii Masatsune , Matsumoto Chisa , Yamashina Akira , Chikamori Taishiro
Published: August 2023

Background:

Although some cardiovascular risk factors (CVRFs) are known to be associated with increased arterial stiffness, increased arterial stiffness does not mediate the cardiovascular risk associated with all CVRFs. Here, based on long-term repeated-measurement data, we examined the association of the lifelong status of each CVRF with the rate of progression of arterial stiffness.

Methods:

We utilized the data from annual health checkups with the brachial-ankle pulse wave velocity measurements over a 16-year period in middle-aged Japanese occupational cohort.

Results:

Totally, 29 090 brachial-ankle pulse wave velocity data were obtained during the follow-up of 3763 subjects ranging in age from around 30 to 70 years. Smoking, heavy alcohol intake, hypertension, diabetes, hypertriglyceridemia, and hyperuricemia were independently associated with the fast progression of arterial stiffness. Also, lower values in nondisease range in blood pressure, glycosylated hemoglobin A1c, triglyceride, and uric acid were independently associated with the slow progression of arterial stiffness. For body mass index and low-density lipoprotein cholesterol, no clear associations with the progression of arterial stiffness were observed.

Conclusions:

The present prospective study provided more robust epidemiological evidence for the heterogeneity of the significance of contribution of lifelong status of each CVRF to the slow and fast rate of progression of arterial stiffness. These findings suggest the important need to examine, in further studies, the effects of global early interventions to control the levels of the culprit CVRFs, even from middle age, not only to prevent a fast progression of the arterial stiffness but also to maintain a relatively slow progression of arterial stiffness.
Relationship Between State Legitimacy, Economic Policy Uncertainty, and Entrepreneurship: Empirical Evidence From Europe
Authors: Paule-Vianez Jessica , Fernández-Portillo Antonio , Miotto Giorgia , Coca-Pérez José Luis
Published: August 2023

This study aims to analyze the relationships between economic policy uncertainty (EPU), state legitimacy, entrepreneurial activity, and business opportunities. To achieve this goal, 13 European countries are selected for the period 2002 to 2018. Applying partial least squares structural equation modeling, relevant findings were obtained. The results show that higher economic uncertainty is associated with an increase in a country’s entrepreneurial activity, although the perception of entrepreneurial opportunities does not increase. We also observed an inverse relationship between EPU and legitimacy. A higher perception of legitimacy is related to lower entrepreneurial activity and higher opportunities for entrepreneurship. These findings have relevant implications. From the academic point of view, the results make new contributions to research related to the importance of the institutional context and entrepreneurial activity, considering the relationships between EPU and legitimacy and their influence on entrepreneurial activity. We also highlight how policymakers may influence the perception of state legitimacy and, therefore, have an impact on entrepreneurial activities and opportunities.
When Do Humans Heed AI Agents’ Advice? When Should They?
Authors: Dunning Richard E. , Fischhoff Baruch , Davis Alex L.
Published: August 2023

Objective

We manipulate the presence, skill, and display of artificial intelligence (AI) recommendations in a strategy game to measure their effect on users’ performance.

Background

Many applications of AI require humans and AI agents to make decisions collaboratively. Success depends on how appropriately humans rely on the AI agent. We demonstrate an evaluation method for a platform that uses neural network agents of varying skill levels for the simple strategic game of Connect Four.

Methods

We report results from a 2 × 3 between-subjects factorial experiment that varies the format of AI recommendations (categorical or probabilistic) and the AI agent’s amount of training (low, medium, or high). On each round of 10 games, participants proposed a move, saw the AI agent’s recommendations, and then moved.

Results

Participants’ performance improved with a highly skilled agent, but quickly plateaued, as they relied uncritically on the agent. Participants relied too little on lower skilled agents. The display format had no effect on users’ skill or choices.

Conclusions

The value of these AI agents depended on their skill level and users’ ability to extract lessons from their advice.

Application

Organizations employing AI decision support systems must consider behavioral aspects of the human-agent team. We demonstrate an approach to evaluating competing designs and assessing their performance.
Last train timetabling with transfer accessibility in metro networks: integer linear programing model and schedule-based transfer network
Authors: Xu Wenkai
Published: August 2023

Last train timetable plays an important role in actual operation of metro systems, especially in big cities. Appreciable transfer passengers rely on last train connections to reach their destinations, which requires a coordinated last train timetable. This study is devoted to dealing with the last train timetabling problem in metro networks, and proposes an integer linear programing model to coordinate last train connections at transfer stations to improve the transfer accessibility in terms of served transfer passengers and effective last train connections. Several measures at the planning level are used to guarantee feasibility of the optimized last train timetable when applied in practice. Then, the schedule-based transfer network and pre-process method are presented to shrink the scale of binary variables, which can expedite the solution process when solving problems in large-scale networks. Finally, some experiments based on the Qingdao metro network are carried out to verify the effectiveness of the timetabling method, and results show that dwell time and service ending time have direct influence on network accessibility. Comparison analyses show that the proposed model is able to generate a coordinated enough last train timetable with higher transfer accessibility and better practicality, which can provide support for operators to improve the last train service in a metro network.
Imaginary Views of Death: Cemetery, Identity, and Memory (The Case of Yazidis in Turkey)
Authors: Sağır Adem , Tayanç Mehmet
Published: August 2023

The present study attempts to explore how death and beliefs fashion burial spaces. Building on in-depth interviews, we investigate Yazidis’ images and symbols employed in their cemeteries and how those materials carry traces of their beliefs and cultural practices. To put it another way, we attempt to expound on the belief practices of Yazidis, the smallest minority indigenous to Turkey, through their cemeteries with the help of the visual ethnography approach. Accordingly, we collected the data through interviews with 14 Yazidis living in 5 different villages of Batman and Siirt provinces and observations in four cemeteries. The distinct contribution of this study may root in its addressing of how funeral rituals and symbols play a role in maintaining community memory in beliefs. Our findings suggest that religious memory plays a significant role in preserving religious culture and keeping the past alive.
A framework for modeling human behavior in large-scale agent-based epidemic simulations
Authors: de Mooij Jan , Bhattacharya Parantapa , Dell’Anna Davide , Dastani Mehdi , Logan Brian , Swarup Samarth
Published: August 2023

Agent-based modeling is increasingly being used in computational epidemiology to characterize important behavioral dimensions, such as the heterogeneity of the individual responses to interventions, when studying the spread of a disease. Existing agent-based simulation frameworks and platforms currently fall in one of two categories: those that can simulate millions of individuals with simple behaviors (e.g., based on simple state machines), and those that consider more complex and social behaviors (e.g., agents that act according to their own agenda and preferences, and deliberate about norm compliance) but, due to the computational complexity of reasoning involved, have limited scalability. In this paper, we present a novel framework that enables large-scale distributed epidemic simulations with complex behaving social agents whose decisions are based on a variety of concepts and internal attitudes such as sense, knowledge, preferences, norms, and plans. The proposed framework supports simulations with millions of such agents that can individually deliberate about their own knowledge, goals, and preferences, and can adapt their behavior based on other agents’ behaviors and on their attitude toward complying with norms. We showcase the applicability and scalability of the proposed framework by developing a model of the spread of COVID-19 in the US state of Virginia. Results illustrate that the framework can be effectively employed to simulate disease spreading with millions of complex behaving agents and investigate behavioral interventions over a period of time of months.
Management of a Complex Case of a Recurrent Paraganglioma
Authors: Petrovic Masa , Borrelli Michela , Shohet Jack A.
Published: August 2023

Paragangliomas are rare, slow-growing, hypervascular, catecholamine-secreting neuroendocrine tumors arising from the paraganglia. Paragangliomas are rarely found in the head and neck and are typically benign, presenting as a painless, slow-growing mass. Surgical extirpation in combination with long-term surveillance has been long regarded as the standard of care; however, the advances in imaging, radiation therapy, and embolization techniques have improved diagnostic and therapeutic modalities. We present a case of an 87-year-old female who had previously undergone resection of a paraganglioma in 1998, with no evidence of disease in 2002. Eighteen years later, the patient presented to the clinic with otogenic complaints. Imaging showed an expansive mass from the jugular foramen with bone destruction and opacification within the ear canal. The patient opted for observation. The patient eventually presented to the emergency room with neurologic manifestations. Imaging showed a cerebellar abscess prompting emergency drainage. Intraoperative cultures grew Prevotella loescheii and S. intermedius, and the patient was started on 6 weeks of IV antibiotic therapy. Debulking of the paraganglioma was performed followed several months by mastoid and ear canal obliteration; however, the patient experienced complications, including dehiscence of the external auditory canal and Clostridium difficile infection. The patient was eventually treated successfully, marked by a reduction in complaints, a return to baseline activities, and imaging showing no increase in tumor size.
Cogan Syndrome: A Case Study and Review of the Literature
Authors: Nasrollahi Tasha , Borrelli Michela , Lin Harrison W. , Djalilian Hamid R.
Published: August 2023

Cogan syndrome is an autoimmune disease characterized by vestibular symptoms, bilateral sensorineural hearing loss, and inflammatory ocular manifestations, which may be accompanied by systemic vasculitis. We herein present the case of a patient with bilateral sensorineural hearing loss who presented with pain over her cochlear implantation incision site. She was later found to have evidence of ocular disease and underlying vasculitis leading to a diagnosis of Cogan syndrome.
A Literature Review on Cochlear Implant Activation: From Weeks to Hours
Authors: Alahmadi Asma , Abdelsamad Yassin , Alothman Noura I. , Alshalan Afrah , Almuhawas Fida , AlAmari Nouf A. , Alyousef Mohammed Y. , Alhabib Salman F. , Hagr Abdulrahman
Published: August 2023

Objectives: The present literature review discusses the chronological evolution of Cochlear Implant (CI) activation and its definition among the relevant studies in the literature. In addition, the benefits of standardizing the early activation process in implantation centers worldwide are discussed. Methods: A comprehensive literature search was conducted in the major databases such as PubMed, Scopus, and Embase to retrieve all the relevant articles that reported early activation approaches following CI. Results: The evolution of the timing of early activation after CI has been remarkable in the past few years. Some studies reported the feasibility of early activation 1 day after the CI surgery in their users. Conclusions: Within the last decade, some studies have been published to report the feasibility and outcomes of its early activation. However, the process of early activation was not adequately defined, and no apparent guidelines could be found in the literature.