bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deviating Alternative Splicing as a Molecular Subtype of Microsatellite Stable Colorectal Cancer
Authors: Meier Strømme Jonas , Johannessen Bjarne , Skotheim Rolf I. 
Published: February 2023

PURPOSE Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Biomarkers to aid in prognostication and treatment decisions are in high demand, and to facilitate their development, a better understanding of the underlying biology of the highly heterogeneous disease is needed. METHODS A genome-scale alternative splicing (AS) analysis using RNA-sequencing data from primary microsatellite stable (MSS) CRCs from 127 patients was performed. Splice variant–specific expression levels of individual cancer samples were compared with the total set of samples, and a metric for a tumor sample's global amount of deviating AS was developed. This metric varied considerably across the cohort and ranged from 6 to 282 deviating AS events per tumor sample. A threshold of 45 or more deviating events was set to distinguish cancers with high (n = 44) and low (n = 83) levels of deviating AS. RESULTS Patients with high amounts of AS deviations had significantly shorter time to relapse compared with patients with fewer deviations ( P = .04). Furthermore, differential gene expression analysis revealed nine known cancer-critical genes that are significantly upregulated in samples with high amounts of deviating AS. Validation of the results in an independent cohort of MSS CRCs showed the same tendency toward shorter progression-free survival among the high-deviation group. In both cohorts, enrichment for growth factors was identified among upregulated genes associated with this phenotype. CONCLUSION There is a large variation in the amount of deviating AS among MSS CRCs, and we provide evidence that those with high amounts of deviations represent different cancer biology.
Pharmacokinetics and RP2D analysis from ETCTN 10388: A phase I trial of triapine and lutetium Lu-177 dotatate in well-differentiated somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Chauhan Aman , Christner Susan M. , Beumer Jan Hendrik , Kunos Charles , Khurana Aman , El Khouli Riham , Weiss Heidi , Yan Donglin , Soares Heloisa P. , Halfdanarson Thorvardur Ragnar , Li Daneng , Carson William Edgar , Evers Mark B , Ivy Percy , Kohn Elise C. , Rubinstein Larry , Arnold Susanne M. , Kolesar Jill , Anthony Lowell Brian , Konda Bhavana 
Published: February 2023

648 Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate, and thus repair of DNA in this setting. ETCTN 10388 evaluated safety of combination Lu-177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Methods: This investigator initiated, NCI sponsored, multicenter phase 1 trial, enrolled a total of 31 patients in the dose escalation [using the Bayesian optimal interval design (BOIN)] and dose expansion cohorts. Oral triapine was administered on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. All enrolled patients had blood samples collected for triapine pharmacokinetic (PK) analysis in EDTA tubes prior to and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after oral administration during cycle 1. Results: Five patients were enrolled in triapine Dose Level 1 (100 mg/day), twenty-five to dose level two (150 mg/day), and one patient to dose level three (200 mg/day). PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Triapine PK parameter values observed in this trial, were comparable to previous reports that used a previous formulation [ 1 ]. While exposure was similar, variability appeared smaller with the current oral formulation. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. A total of one DLT in dose level 1, seven DLTs (Transient cytopenia; primarily neutropenia and rarely thrombocytopenia) in dose level 2, and one grade 5 DLT (Death probably from progressive cancer and carcinoid heart disease but possibly from trial drugs) in dose level 3 were observed. Detailed AE profile will be presented at the meeting. Conclusions: The RP2D of triapine is 150 mg QD on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Clinical trial information: 04234568 .
Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non–Small-Cell Lung Cancer
Authors: Sánchez-Magraner Lissete , Gumuzio Juan , Miles James , Quimi Nicole , Martínez del Prado Purificación , Abad-Villar María Teresa , Pikabea Fernando , Ortega Laura , Etxezarraga Carmen , Martín-Algarra Salvador , Lozano María D. , Saiz-Camin Mónica , Egurrola-Izquierdo Mikel , Barredo-Santamaría Inmaculada , Saiz-López Alberto , Gomez-Mediavilla Jenifer , Segues-Merino Nerea , Juaristi-Abaunz María Aranzazu , Urruticoechea Ander , Geraedts Erica J. , van Elst Kim , Claessens Niels J.M. , Italiano Antoine , Applebee Christopher J. , del Castillo Sandra , Evans Charles , Aguirre Fernando , Parker Peter J. , Calleja Véronique 
Published: February 2023

PURPOSE In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non–small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti–PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non–small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.
Association Between Metabolic Syndrome Inflammatory Biomarkers and COVID-19 Severity
Authors: Pham Thaidan T , Zu Yuanhao , Ghamsari Farhad , Oh Janice , Mauvais-Jarvis Franck , Zheng Hui , Filbin Michael , Denson Joshua L 
Published: February 2023

Abstract

Context
Metabolic syndrome (MetS) is associated with increased risk of severe COVID-19. MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored.

Objective
Biomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity, and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity.

Methods
In this prospective observational study, at a large academic emergency department in Boston, Massachusetts, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation, or required supplemental oxygen.

Results
Among 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared with the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]), and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19.

Conclusions
MetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted.
Barriers and facilitators to refugees, asylum seekers and people experiencing homelessness accessing non hospital based care: A mixed methods systematic review protocol
Authors: Fitzharris Laura , McGowan Emer , Broderick Julie 
Published: February 2023

Context: Social exclusion is characterised by and represents a form of disadvantage and marginalisation of vulnerable groups of people in society, who cannot fully participate in the normal activities of daily living. Socially excluded groups consist of, but are not limited to the following groups: people experiencing homelessness, asylum seekers and refugees. People from socially excluded groups have complex healthcare needs including infectious and non-communicable diseases. People from socially excluded groups tend to present more to the acute hospital setting as emergency presentations. Little is known about barriers and facilitators experienced by these groups to accessing non hospital based care. Objectives: This mixed methods systematic review, will critically examine the concept of barriers and facilitators for refugees, asylum seekers and people experiencing homelessness, to accessing non hospital based care. Methods: This methodological review will follow the Joanna Briggs Institute guidance for conducting mixed methods reviews. The following databases will be searched: Central Medline, PubMed, Embase, CINAHL, and the Cochrane Library. Relevant grey literature will be included. Title and abstract screening, followed by full-text screening will be undertaken independently by two reviewers. The Joanna Briggs Institute extraction tool will be adapted for data extraction. Discussion: This mixed method review will comprehensively evaluate quantitative and qualitative data, synthesise both barriers and facilitators and follow a systematic approach through establishing use of mixed methods research across a number of marginalised groups, and how they affect accessing non hospital based care. It will explore conceptual models of access to healthcare and how they influence these factors.
Platform Governance in the Presence of Within-Complementor Interdependencies: Evidence from the Rideshare Industry
Authors: Chung Hyuck David , Zhou Yue Maggie , Ethiraj Sendil 
Published: February 2023

Existing studies suggest that platform access restriction may cause restricted complementors to switch to competing platforms, which will increase complement quantity on competing platforms. We re-examine this prediction by accounting for the impact of economies of scope on complementor responses to platform access restriction. We argue that restricting a complementor’s access on a platform may prevent it from achieving economies of scope from multi-homing, thereby incentivizing it to abandon both the restricted and (unrestricted) competing platforms. Using rideshare data in New York City, we compare the numbers of trips made by Lyft and Uber drivers, respectively, before and after Lyft restricted drivers’ access on its platform. We find that Lyft’s access restriction reduced trip numbers not only on Lyft but also on Uber. In addition, both Lyft’s and Uber’s trip numbers decreased not only during the restricted low-demand periods (e.g., non-rush hours) but also during the unrestricted high-demand periods (e.g., rush hours). In contrast, after a substantial number of multi-homing drivers left both platforms following Lyft’s access restriction, a subsequent access restriction by Uber led to an increase in trip numbers on Lyft. These results highlight the importance of accounting for interdependencies across complementor activities when designing platform governance policies. This paper was accepted by Alfonso Gambardella, business strategy. Funding: H. D. Chung acknowledges support from the Strategic Research Foundation’s Dissertation Research [Grant SRF-2021-DRG-8363]. Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2023.4706 .
Packing Feedback Arc Sets in Tournaments Exactly
Authors: Chen Xujin , Ding Guoli , Zang Wenan , Zhao Qiulan 
Published: February 2023

Let [Formula: see text] be a tournament with a nonnegative integral weight w(e) on each arc e. A subset F of arcs is called a feedback arc set (FAS) if [Formula: see text] contains no cycles (directed). A collection [Formula: see text] of FASs (with repetition allowed) is called an FAS packing if each arc e is used at most w(e) times by the members of [Formula: see text]. The purpose of this paper is to give a characterization of all tournaments [Formula: see text] with the property that, for every nonnegative integral weight function w defined on A, the minimum total weight of a cycle is equal to the maximum size of an FAS packing. Funding: This work was supported by the National Natural Science Foundation of China [Grants 11801266 and 11971228]; the Chinese Academy of Sciences [Grants XDA27000000 and ZDBS-LY-7008]; the Ministry of Science and Technology of China [Grant 2018AAA0101002]; the Research Grants Council of Hong Kong; the Fundamental Research Funds for the Central Universities [Grant 020314380035].
End-of-life support and after-death body care for pets: what pet owners want
Authors: Kogan Lori R , Cooney Kathleen A , Brooks Summer L , Ellis Coleen 
Published: February 2023

Background/Aims:Pet owners caring for a pet during the end of its life are faced with numerous aftercare choices and decisions. This study was undertaken to explore the perceptions and expectations of pet owners regarding end-of-life issues.Methods:An anonymous online survey was distributed via Amazon's Mechanical Turk, an open online marketplace providing access to potential survey respondents.Findings:A total of 2043 dog and/or cat owners (41.4% male, 57.9% female) responded to the survey. The majority of these owners indicated they preferred to work with a specific crematorium (43%) or cemetery (70%) and over 95% reported feeling it is important to work with their preferred after-death body care service. Eighty-six per cent of owners reported relying on their veterinary team to help them with end-of-life decisions and arrangements with pet aftercare services and companies. Participants expressed significant concern over several aspects of after-death body care (e.g. body mislabelling or the type of container used for short-term and long-term storage).Conclusions:Results suggest that owners look to their veterinary teams to offer ethical after-death body care. These findings can help guide veterinary teams' efforts related to end-of-life communication and services.
NEW ZEALAND PROVINCIAL ORTHOPAEDIC TRAUMA STUDY (NZPOTS): THE EFFECTS OF INCREASING TRAUMA ON ELECTIVE ORTHOPAEDIC SURGERY IN PROVINCIAL NEW ZEALAND
Authors: Roffe L. , Peterson R. , Smith G. , Penumarthy R. , Atkinson N. , Ross M. , Singelton L. , Bodian C. , Timoko-Barnes S. 
Published: February 2023

Trauma and elective orthopaedic demands in New Zealand are increasing. In this study, prospective and retrospective data has been collected at Nelson Hospital and across New Zealand to identify the percentage of elective theatre time lost due to cancellation for acute patient care. Data has been collected from theatre management systems, hospital data systems and logged against secretarial case bookings, to calculate a percentage of elective theatre time lost to acute operating or insufficient bed capacity.Data was collected over a five-month period at Nelson Hospital, with a total of 215 elective and 226 acute orthopaedic procedures completed. A total of 95 primary hip or knee arthroplasties were completed during this trial while 53 were cancelled. The total number of elective operative sessions (one session is the equivalent of a half day operating theatre time) lost to acute workload was 47.9. Thirty-three percent of allocated elective theatre time was cancelled - an equivalent of approximately one-full day elective operating per week.Over a five-week period data was collected across all provincial hospitals in New Zealand, with an average of 18% of elective operating time per week lost due to acute workload. Elective cancellations were due to acute operating 40% of the time and bed shortages 60% of the time. The worst effected centre was Palmerston North which had an average of 33% of elective operating cancelled per week to accommodate acute surgery or due to bed shortages.New Zealand's provincial orthopaedic surgeons are under immense pressure from acute operating that impedes provision of elective surgery. The New Zealand government definition of an ‘acute case’ does not reflect the nature of today's orthopaedic burden. Increasing and aging populations along with staff and infrastructure shortages have financial and societal impacts beyond medicine and require better definitions, further research, and funding from governance.
OVER 50% OF PATIENTS AT RISK OF IMPINGEMENT AFTER THA SURGERY ARE NOT CAPTURED WITH NEUTRAL BONY ALIGNMENT
Authors: Hardwick-Morris M. , Twiggs J. , Miles B. , Jones E. , Bruce W. J. M. , Walter W. L. 
Published: February 2023

Dislocation is one of the most common complications in total hip arthroplasty (THA) and is primarily driven by bony or prosthetic impingement. The aim of this study was two-fold. First, to develop a simulation that incorporates the functional position of the femur and pelvis and instantaneously determines range of motion (ROM) limits. Second, to assess the number of patients for whom their functional bony alignment escalates impingement risk.468 patients underwent a preoperative THA planning protocol that included functional x-rays and a lower limb CT scan. The CT scan was segmented and landmarked, and the x-rays were measured for pelvic tilt, femoral rotation, and preoperative leg length discrepancy (LLD). All patients received 3D templating with the same implant combination (Depuy; Corail/Pinnacle). Implants were positioned according to standardised criteria.Each patient was simulated in a novel ROM simulation that instantaneously calculates bony and prosthetic impingement limits in functional movements. Simulated motions included flexion and standing-external rotation (ER). Each patient's ROM was simulated with their bones oriented in both functional and neutral positions.13% patients suffered a ROM impingement for functional but not neutral extension-ER. As a result, 48% patients who failed the functional-ER simulation would not be detected without consideration of the functional bony alignment. 16% patients suffered a ROM impingement for functional but not neutral flexion. As a result, 65% patients who failed the flexion simulation would not be detected without consideration of the functional bony alignment.We have developed a ROM simulation for use with preoperative planning for THA surgery that can solve bony and prosthetic impingement limits instantaneously. The advantage of our ROM simulation over previous simulations is instantaneous impingement detection, not requiring implant geometries to be analysed prior to use, and addressing the functional position of both the femur and pelvis.
DETERMINATION OF PREOPERATIVE RISK FACTORS FOR ILIOPSOAS TENDONITIS
Authors: Hardwick-Morris M. , Twiggs J. , Miles B. , Balakumar J. , Walter W. L. 
Published: February 2023

Iliopsoas impingement occurs in between 5-30% of patients after hip arthroplasty and has been thought to only be caused by an oversized cup, cup malpositioning, or the depth of the psoas valley. However, no study has associated the relationship between preoperative measurements with the risk of impingement. This study sought to assess impingement between the iliopsoas and acetabular cup using a novel validated model to determine the risk factors for iliopsoas impingement.413 patients received lower limb CT scans and lateral x-rays that were segmented, landmarked, and measured using a validated preoperative planning protocol. Implants were positioned according to the preference of ten experienced surgeons. The segmented bones were transformed to the standing reference frame and simulated with a novel computational model that detects impingement between the iliopsoas and acetabular cup. Definitions of patients at-risk and not at-risk of impingement were defined from a previous validation study of the simulation. At-risk patients were propensity score matched to not at-risk patients.21% of patients were assessed as being at-risk of iliopsoas impingement. Significant differences between at-risk patients and not at-risk patients were observed in standing pelvic tilt (p << 0.01), standing femoral internal rotation (p << 0.01), medio-lateral centre-of-rotation (COR) change (p << 0.01), supine cup anteversion (p << 0.01), pre- to postoperative cup offset change (p << 0.001), postoperative gross offset (p = 0.009), and supero-inferior COR change (p = 0.02).Impingement between the iliopsoas and acetabular cup is under-studied and may be more common than is published in the literature. Previously it has been thought to only be related to cup size or positioning. However, we have observed significant differences between at-risk and not at-risk patients in additional measurements. This indicates that its occurrence is more complex than simply being related to cup position.