bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a highly efficacious, first-in-class antibody-drug conjugate against a novel MUC1-C oncoprotein for metastatic colorectal cancer.
Authors: Raina Deepak , Panchamoorthy Govind , Ahmad Rehan , Jasuja Ravi , Kharbanda Surender 
Published: June 2024

e15600 Background: Poor prognosis and mortality due to metastatic colorectal cancer (mCRC) remains a stiff challenge and the management of mCRC continues to be a significant unmet medical need. An aberrantly glycosylated Mucin 1 (MUC1) is overexpressed in > 80% of CRC and development of novel approaches for targeting of MUC1 are critically needed. MUC1 is a heterodimeric oncoprotein expressed on the cell surface and consists of two (MUC1-N and MUC1-C) terminal subunits. MUC1-N subunit is shed in the blood from cancer cells and MUC1-C subunit retains at the cell surface. Multiple attempts at targeting the MUC1-N terminal shed protein have been failed earlier due to all the MUC1-N binding antibodies bind to the shed domain in blood that act as a sink. Methods: We have generated a panel of novel, first-in-class antibodies against the extra cellular domain (ECD) of MUC1-C that remains intact on the cell surface. The development of antibody-drug conjugates (ADCs) has been a major advancement in the field of oncology as ADCs are the emerging class of anti-cancer drugs consisting of tumor targeting MAbs with highly cytotoxic payloads attached through cleavable chemical linkers. We present here making of MUC1-C (3D1)-MMAE as well as generation of MUC1-C (3D1 + 7B8)-biparatopic-MMAE with preclinical characterization. Results: We demonstrate that two MAbs, 3D1 and 7B8, bind to different epitopes (3D1 binding to a3 helix; 7B8 binding to a4 helix) in the MUC1-C-ECD with high affinity and more importantly, do not cross compete with each other. Reactivity of both MAbs is specific for MUC1 expressing human cancer cells as demonstrated by both knock-in and knock-out cell line models. Both antibodies have substantial internalization by 3 hours at 37oC. Both 3D1 and 7B8 were separately conjugated to monomethyl auristatin E (MMAE) with vc-PAB linkers. The results demonstrate that treatment of diverse mCRC cell lines, SW620, SK-CO-1 and HCT116/MUC1 with 3D1-MMAE or 7B8-MMAE is associated with substantial killing with low nM IC50. To further access in vivo efficacy of 3D1-MMAE, nude mice with established HCT-116/MUC1 tumor xenografts were treated with 7.5 mg/kg once a week x 3 weeks. Significant tumor growth inhibition was observed with 3D1-MMAE without any weight loss. A bi-paratopic antibody can bind to the same antigen either on same cell or at two different cells and thereby will increase internalization substantially. Since MAbs 7B8 and 3D1 do not cross compete with each other for binding to MUC1-C-ECD, we are developing 3D1-7B8 bi-paratopic-MMAE for increasing the efficacy further. Studies are underway to test 3D1-7B8 bi-paratopic-MMAE for activity in vitro and in vivo. Conclusions: MUC1-C-ADC has demonstrated a favorable toxicity profile and potent anti-tumor activities in the mCRC. Together, these results suggest advancing the anti-MUC1-C-MMAE ADCs as a novel therapeutic for mCRC.
FOLFOX-based hepatic arterial infusion chemotherapy combined with regorafenib for unresectable colorectal liver metastases.
Authors: Song Songlin , Liu Jiacheng , Ren Yanqiao , Zheng Chuansheng , Liang Bing 
Published: June 2024

e15601 Background: Hepatic arterial infusion chemotherapy (HAIC) stands out as a compelling local therapeutic strategy for patients with unresectable colorectal liver metastases (CRLM). Meanwhile, regorafenib has established itself as a systemic treatment for CRLM. The potential synergistic antitumor effect of combining HAIC and regorafenib in the treatment of unresectable CRLM remains intriguing, yet clinical evidence supporting the efficacy of this combination therapy is lacking. This study aims to evaluate the safety profile and therapeutic benefit of FOLFOX-HAIC plus regorafenib in the management of unresectable CRLM. Methods: In this retrospective analysis, we included 35 patients with unresectable CRLM who underwent FOLFOX-HAIC plus regorafenib between July 2020 and January 2023. The mFOLFOX6 regimen was employed for HAIC, comprising oxaliplatin (85 mg/m2 for 2 h on day 1), calcium folinate (200 mg/m2 for 2 h on day 1), and 5-fluorouracil (5-Fu) administered as a bolus of 400 mg/m2 on day 1, followed by 2400 mg/m2 over 46 h. Regorafenib was administered orally at a dose of 160 mg (four 40 mg tablets) once daily for the first 21 days of each 28-day cycle, with HAIC performed during the 7 days of discontinuation. The primary outcome was overall survival (OS), and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Factors affecting the OS were also analyzed. Results: Kaplan-Meier analyses revealed a median OS of 29.0 months (95% confidence interval [CI], 17.9-40.1) and a median PFS of 13.0 months (95% CI, 9.3-16.7). Post-HAIC ORRs at 3, 6, and 12 months were 71.4%, 80.0%, and 57.2%, respectively, while DCRs were 88.6%, 91.4%, and 74.3%. In univariable and multivariable Cox regression models, ascites (HR = 5.640, 95%CI: 1.204-30.176, P = 0.033) and carcinoembryonic antigen levels > 10μg/L (HR = 11.49, 95%CI: 1.232-88.758, P = 0.012) emerged as independent prognostic factors for OS. AEs associated with HAIC encompassed nausea, vomiting, abdominal pain, and fever. In the context of regorafenib, the prevailing AEs included hand-foot skin reactions and hypertension. Importantly, during the follow-up period, no life-threatening AEs were reported in patients receiving HAIC or regorafenib. Conclusions: The combination of regorafenib with FOLFOX-HAIC exhibits substantial promise in managing unresectable CRLM, providing meaningful effectiveness without exacerbating toxicity. [Table: see text]
Randomized study to assess colonic microbiome changes in response to energy drink consumption (ROSANNA trial).
Authors: Jang Tim , Kahramangil Doga , Lee Ji-Hyun , Kim George P. , Rogers Sherise C. , Sahin Ilyas , Ramnaraign Brian Hemendra , Terracina Krista P. , Nordenstam Johan , Read Thomas , Thomas Ryan M. , Yang Ye , Jobin Christian , George Thomas J. 
Published: June 2024

TPS3630 Background: Colorectal cancer (CRC), the second leading cause of cancer deaths in the US, is increasingly diagnosed in individuals under 50. This rise in early-onset CRC (eoCRC) led the U.S. Preventative Services Task Force to recommend a reduction in the age to begin colorectal cancer screening in average-risk persons, from 50 to 45. The etiology of eoCRC is multifaceted, with one postulated theory pointing to alterations in the young adult colonic microbiome. Hydrogen sulfide (H2S) producing bacteria, like Bilophila wadsworthia, Fusobacterium nucleatum and Atopobium parvulum, are typically minor gut microbiota components but are overrepresented in CRC cases, linked to inflammation, and may promote a pro-carcinogenic environment. These bacteria preferentially use taurine, an essential amino acid, as a primary energy source. Energy drinks represent one of the largest dietary sources (6-16x normal daily intake) of taurine in contemporary diets. Our hypothesis is that high taurine levels in energy drinks could exacerbate CRC risk by promoting preferential growth and metabolic activities of already present H2S-producing bacteria, contributing to the rise of eoCRC. Methods: This randomized open-label trial is actively enrolling up to 60 young adults (18-40 years) without personal or family history of CRC, other major GI disease/distress, and baseline infrequent energy drink consumption. Group 1 (Arm A; n=30), will consist of subjects consuming at least one of two protocol-specified energy drinks daily for 4 weeks. Group 2 (Arm B; n=30), will consist of usual dietary intake. Enrollments are randomized 1:1 and stratified, by gender, age (18-25 vs. 26-40), and baseline energy drink consumption (rare/none vs. 1-2 per week). Every subject will complete: 1) a daily dietary and fitness log, 2) a weekly wellness log, 3) collection of stool/saliva/skin/urine at 3 sequential time points (baseline, after 2 weeks, after 4 weeks), and 4) blood collection at the same time points. The primary endpoint is the change in H2S-metabolizing bacterial communities between baseline and 1 month of energy drink exposure within Arm A and also compared to those in Arm B using microbiome analysis (diversity, taxonomy, sulfur-enriched gene pathways). Several secondary and exploratory assessments include changes related to subject demographic and dietary differences, concordance of microbiome changes with dietary logs and in other biospecimens beyond stool, H2S-production measurements, and analyses of subject metabolic and immune function. Trial opened in February 2024 with active enrollment ongoing. Updated data on trial status and any amendment modifications will be presented at the meeting. Clinical trial information: NCT06137248 .
Huxley's Karma and Lu Xun's Ghosts
Authors: Ying Lei 
Published: June 2024

Abstract
This article questions the secularist assumption in the received narrative of Chinese modernity by uncovering the religious ideas and imaginations that have since the outset mediated and shaped the Chinese discovery of evolutionary science, a massive phenomenon that has conventionally been understood in a scientistic and secularistic light. Adopting an interdisciplinary approach, this article revisits Tianyan lun—the Chinese translation of Thomas Henry Huxley's Evolution and Ethics and the single most influential book in initiating late-Qing intellectuals into social Darwinism—as a site for Buddhist global exchange and translingual practice, when the notion of “karma” offered Huxley and his Chinese translator and readers at once a ground of convergence and a point of departure. To Lu Xun and his brother Zhou Zuoren, from a hereditary perspective, karma has assumed the other name of history, while evolution unfolded in perpetual entanglements of humans and ghosts under a samsaric temporal scheme. Lu Xun's obsession with the netherworld has fostered, on the one hand, a deep pessimism about human developmental agency and the promise of the revolution and, on the other hand, an existential courage to confront the “realm of darkness.”
Benjamin Britten's Musical Characterization of the Madwoman in Curlew River
Authors: Fink Stanley Ralph 
Published: June 2024

Abstract
This article focuses on the musical depiction of madness in Benjamin Britten's parable for church performance, Curlew River. The article demonstrates that Britten transforms motives by chromatic (modulo-12) transposition and inversion when associating them with the Madwoman, and diatonic (modulo-7) transposition when associating them with the rational, masculine characters of the story. Consequently, he forges familiar associations between chromaticism and madness, on the one hand, and diatonicism and rationality, on the other. Furthermore, Britten marks the Madwoman's music for difference through immobilizing harmonies (i.e., dissonant vertical stacks of notes) and inversional symmetry. Though inversional symmetry in music carries many potential meanings, two pertinent interpretations—coded sexuality and disability—formerly were accompanied with a shared stigmatization. In contrasting the post-tonal relationships present in the Madwoman's music with the, at times, diatonic and stable music of the other characters, the article will show the familiar framing of madness with normal rationality. The article suggests varied methods of pitch organization as a possibility to be considered alongside other means of musical characterization (such as motive and tonal symbolism) in the analysis of twentieth-century dramatic musical works.
Defining an Individualized Functional Range of Motion in Resistance Exercises for the Shoulder
Authors: Landolfi Emilio , Bernardes Rogerio (Roger) 
Published: June 2024

Apply It!
By reading this article, the reader will:
• Explore biomechanical and structural/anatomical considerations for resistance training exercises.
• Learn practical examples to avoid resistance-training–related injuries for the shoulder.
• Know safe, optimal options for shoulder press, pulling, and abduction exercises.
Unintended Consequences of Unemployment Insurance Benefits: The Role of Banks
Authors: Arslan Yavuz , Degerli Ahmet , Kabas Gazi 
Published: June 2024

We use disaggregated U.S. data and a border discontinuity design to show that more generous unemployment insurance (UI) policies lower bank deposits. We test several channels that could explain this decline and find evidence consistent with households lowering their deposit holdings due to reduced precautionary savings. Because deposits are the largest and most stable source of funding for banks, the decrease in deposits affects bank lending. Banks that raise deposits in states with generous UI policies reduce their loan supply to small businesses. Furthermore, counties that are served by these banks experience a higher unemployment rate and lower wage growth. This paper was accepted by Lukas Schmid, finance. Funding: G. Kabas acknowledges financial support from the European Research Council [ERC ADG 2016-GA 740272 lending]. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2022.03217 .
Differences in mental illness stigma by disorder and gender: Population-based vignette randomized experiment in rural Uganda
Authors: Lee Yang Jae , Christ Ryan , Mbabazi Rita , Dabagia Jackson , Prendergast Alison , Wykoff Jason , Dasari Samhitha , Safai Dylan , Nakaweesi Shakira , Aturinde Swaib Rashid , Galvin Michael , Akena Dickens , Ashaba Scholastic , Waiswa Peter , Rosenheck Robert , Tsai Alexander C. 
Published: June 2024

Understanding and eliminating mental illness stigma is crucial for improving population mental health. In many settings, this stigma is gendered, from the perspectives of both the stigmatized and the stigmatizers. We aimed to find the differences in the level of stigma across different mental disorders while considering the gender of the study participants as well as the gender of the people depicted in the vignettes. This was a population-based, experimental vignette study conducted in Buyende District of Eastern Uganda in 2023. We created 8 vignettes describing both men and women with alcohol use disorder, major depressive disorder, generalized anxiety disorder, and schizophrenia consistent with DSM-5 criteria. Participants from 20 villages in rural Buyende District of Uganda (N = 379) were first read a randomly selected vignette and administered a survey eliciting their attitudes (Personal Acceptance Scale [PAS] and Broad Acceptance Scale [BAS]) towards the person depicted in the vignette. We used analysis of variance (ANOVA) with Bonferroni-adjusted, empirical p-values to compare levels of acceptance across disorders and genders. Attitudes towards people with mental illness, as measured by the PAS, varied across different mental disorders (p = 0.002). In pairwise mean comparisons, the greater acceptance of anxiety disorder vs. schizophrenia was statistically significant (Mean [SD] PAS: 2.91 [3.15] vs 1.62 [1.95], p = 0.008). Secondary analyses examining differences in acceptance across gender combinations within mental disorders showed that PAS varied across gender combinations for depression (p = 0.017), suggesting that acceptance is higher for women with depression than men with depression. In this population-based vignette study from rural Uganda, we found that people with schizophrenia were less accepted compared to people with anxiety disorders. We also found that there was greater acceptance of women with depression than men with depression. Anti-stigma initiatives may need to be targeted to specific disorders and genders.Trial registration:The experimental procedures for this study were registered with ClinicalTrials.gov as “Survey Experiment to Estimate Level of Mental Illness Stigma Based on Condition and Gender” (NCT 06279962).
Performance of two rapid antigen tests against SARS-CoV-2 in neighborhoods of socioeconomic vulnerability from a middle-income country
Authors: Zeballos Diana , Magno Laio , Aranha Rossi Thais , Soares Fabiane , Pinto Junior Jony Arrais , Ferreira Orlando , Carvalho dos Santos Carina , Reis Joice Neves , Torres Thiago S. , Veloso Valdilea G. , Dourado Inês 
Published: June 2024

Background
As new and improved antigen-detecting rapid diagnostic tests for SARS-CoV-2 infection (Ag-RDT) continue to be developed, assessing their diagnostic performance is necessary to increase test options with accurate and rapid diagnostic capacity especially in resource-constrained settings. This study aimed to assess the performance of two Ag-RDTs in a population-based study.

Methods
We conducted a diagnostic accuracy study in neighborhoods with high socioeconomic vulnerability in Salvador-Brazil, including individuals aged ≥12 years old who attended primary health services, between July and December 2022, with COVID-19 symptoms or who had been in contact with a confirmed case. Two Ag-RDTs were compared in parallel using reverse transcription polymerase chain reaction (RT-PCR) as reference standard, the PanbioTM COVID-19 Ag test (Abbott®) and Immuno-Rapid COVID-19 Ag (WAMA Diagnostic®). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated.

Results
For the Abbott test the sensitivity was 52.7% (95% CI: 44.3% - 61.0%), specificity 100% (95% CI: 98.7% - 100%), PPV 100% (95% CI: 95.4% - 100%) and NPV 80.4% (95% CI: 75.9% - 84.4%). For the WAMA test, the sensitivity was 53.4% (95% CI: 45.0% - 61.6%), specificity 100% (95% CI: 98.7% - 100%), PPV 100% (95% CI: 95.4% - 100%) and NPV 80.7% (95% CI: 76.2% - 84.6%). Sensitivity for the group with Cycle Threshold (CT) <24 was 82.3% (95%CI: 72.1–90.0, n = 83) for PanbioTM COVID-19 Ag test and 87.3% (95%CI: 77.9–93.8, n = 83) for Immuno-Rapid COVID-19 Ag test.

Conclusion
Sensitivity for both Ag-RDT was lower than reported by manufacturers. In the stratified analysis, sensitivity was higher among those with lower CT values <24. Specificity was high for both rapid antigen tests. Both Ag-RDT showed to be useful for rapid diagnostic of potential cases of COVID-19. Negative results must be assessed carefully according to clinical and epidemiological information.
Bounding systems: A qualitative study exploring healthcare coordination between the emergency youth shelter system and health system in Toronto, Canada
Authors: Hudani Alzahra , Schwan Kaitlin , Labonté Ronald , Yaya Sanni 
Published: June 2024

Background
Several youth staying at emergency youth shelters (EYSs) in Toronto experience poorly coordinated care for their health needs, as both the EYS and health systems operate largely in silos when coordinating care for this population. Understanding how each system is structurally and functionally bound in their healthcare coordination roles for youth experiencing homelessness (YEH) is a preliminary step to identify how healthcare coordination can be strengthened using a system thinking lens, particularly through the framework for transformative system change.

Methods
Forty-six documents, and twenty-four semi-structured interviews were analyzed to explore how the EYS and health systems are bound in their healthcare coordination roles. We continuously compared data collected from documents and interviews using constant comparative analysis to build a comprehensive understanding of each system’s layers, and the niches (i.e., programs and activities), organizations and actors within these layers that contribute to the provision and coordination of healthcare for YEH, within and between these two systems.

Results
The EYS and health systems are governed by different ministries, have separate mandates, and therefore have distinct layers, niches, and organizations respective to coordinating healthcare for YEH. While neither system takes sole responsibility for this task, several government, research, and community-based efforts exist to strengthen healthcare coordination for this population, with some overlap between systems. Several organizations and actors within each system are collaborating to develop relevant frameworks, policies, and programs to strengthen healthcare coordination for YEH. Findings indicate that EYS staff play a more active role in coordinating care for YEH than health system staff.

Conclusion
A vast network of organizations and actors within each system layer, work both in silos and collaboratively to coordinate health services for YEH. Efforts are being made to bridge the gap between systems to improve healthcare coordination, and thereby youths’ health outcomes.
Application of the Sepsis-3 criteria to describe sepsis epidemiology in the Amsterdam UMCdb intensive care dataset
Authors: Williams Christopher Y. K. , Edinburgh Tom , Elbers Paul W. G. , Thoral Patrick J. , Ercole Ari 
Published: June 2024

Introduction
Sepsis is a major cause of morbidity and mortality worldwide. In the updated, 2016 Sepsis-3 criteria, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, where organ dysfunction can be represented by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more. We sought to apply the Sepsis-3 criteria to characterise the septic cohort in the Amsterdam University Medical Centres database (Amsterdam UMCdb).

Methods
We examined adult intensive care unit (ICU) admissions in the Amsterdam UMCdb, which contains de-identified data for patients admitted to a mixed surgical-medical ICU at a tertiary academic medical centre in the Netherlands. We operationalised the Sepsis-3 criteria, defining organ dysfunction as an increase in the SOFA score of 2 points or more, while infection was defined as a new course of antibiotics or an escalation in antibiotic therapy, with at least one antibiotic given intravenously. Patients with sepsis were determined to be in septic shock if they additionally required the use of vasopressors and had a lactate level >2 mmol/L.

Results
We identified 18,221 ICU admissions from 16,408 patients in our cohort. There were 6,312 unique sepsis episodes, of which 30.2% met the criteria for septic shock. A total of 4,911/6,312 sepsis (77.8%) episodes occurred on ICU admission. Forty-seven percent of emergency medical admissions and 36.7% of emergency surgical admissions were for sepsis. Overall, there was a 12.5% ICU mortality rate; patients with septic shock had a higher ICU mortality rate (38.4%) than those without shock (11.4%).

Conclusions
We successfully operationalised the Sepsis-3 criteria to the Amsterdam UMCdb, allowing the characterization and comparison of sepsis epidemiology across different centres.