bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of a novel prognostic model for overall survival in patients with micropapillary urothelial carcinoma.
Authors: Diamantopoulos Leonidas Nikolaos , Korentzelos Dimitrios , Bountziouka Vasiliki , Vadikolias Konstantinos , Lambropoulou Maria , Tripsianis Gregory
Published: June 2024

e16618

Background: Micropapillary urothelial carcinoma (MUC) is a rare variant of bladder cancer with limited prognostic data in the literature. We hereby present a novel prognostic model for overall (OS), for patients with MUC, derived from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The SEER database (18 registries/November 2020) was queried with the case listing method by using the ICD-10 topography codes C67.0-C67.9 (bladder cancer), and the morphologic code 8131 (MUC). Patients were randomly divided into a training (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with OS were identified with multivariate Cox regression and backwards stepwise conditional approach; each variable received “points” according to its beta coefficient, based on the formula: Probability of an event at time t=S0(t)exp(β1x1, β2x2...), (β = regression coefficients, x = observed covariate values, S0(t) = survival function). Cumulative risk points were assigned to each patient and three distinct risk categories for OS were constructed. Harrel’s optimism-corrected C-statistic with bootstrap resampling was used for internal (TC) and external (VC) validation. Discriminatory performance of the model was compared to the AJCC 8th edition with the likelihood ratio test (LRT). Results: 548 patients were included in the study (374 TC, 174 VC). No statistically significant differences in baseline characteristics and survival outcomes were identified between TC and VC. Age, marital status, tumor size, AJCC stage, radical cystectomy, radiation and chemotherapy were significant variables inserted in the multivariate model. Patients were stratified to three risk groups (low, intermediate, high) based on the total risk points collected (<100, 100-150 and >150, Table). Median OS was NR (95%CI; NR, NR), 41 (95% CI; 25-57) and 14 months (95% CI; 11-17) for the low, intermediate, and high-risk categories respectively (log-rank p<.001). Optimism-corrected C-statistic for the prognostic score was 0.74 (95%CI;0.71-0.78) in the TC and 0.70 (95%CI; 0.65-0.78) in the VC. C-statistic for AJCC 8th edition was 0.65 (95% CI; 0.61-0.69) and 0.62 (95% CI; 0.56-0.68) in the TC and VC respectively. The LRT demonstrated superior discriminatory performance of our prognostic model compared to AJCC (p<.001). Conclusions: We present a novel prognostic model for OS of patients with MUC composed of clinicopathologic and treatment variables. Our model had superior performance to the AJCC system and may serve as a useful tool for individualized risk assessment in patients with MUC. [Table: see text]
How febrile neutropenia affects hospitalization in patients with bladder cancer: Nationwide insights.
Authors: Rodriguez Evadne , Javaid Saad , Frasier Kelly , Li Vivian , Vinagolu-Baur Julia , Ortega Yaguachi Nataly , Del Castillo Olivia , Batista Raquel , Jonas Kenlee , Palma Laura
Published: June 2024

e16625

Background: Bladder cancer is the most prevalent form of malignancy in the urinary tract and is a leading global health concern. Febrile neutropenia is a severe and potentially life-threatening complication of cancer treatment, and limited research exists on the impact of Febrile Neutropenia in bladder cancer. Our study examined its effects on adverse outcomes for hospitalized bladder cancer patients. Methods: The National Inpatient Sample (2017-2020) was employed to identify Bladder cancer patients with regional and advanced metastatic disease as the primary diagnosis and were stratified based on the presence or absence of a secondary diagnosis of Febrile neutropenia (FN). The primary outcome measure was mortality, while the secondary outcomes included length of stay, total cost of hospitalization, and other adverse in-hospital outcomes. Multivariate regression analysis was used to adjust for the confounding variables. Results: A total of 102,485 patients were hospitalized for Bladder cancer, among whom 865 had concurrent FN. The mean age of patients with FN was 67.31±17.44, while that of patients without FN was 72.19±11.48, p<0.001. As compared to Patients without FN, those with FN had a greater percentage of patients with Medicaid (8.77% vs. 6.15%) and private insurance (30.41% vs. 19.74%), while fewer patients with Medicare (58.48% vs. 72.17%), p=0.001. After multivariate regression analysis, patients with FN had increased odds of mortality (OR=4.33,(2.52-7.45); p<0.001). FN patients had a longer length of stay (+2.69 days (1.32-4.05); p<0.001) and higher total cost of hospitalization (+$23,229(3,907-4,255); p<0.001). Patients with FN were more likely to have fluid and electrolyte disorders (OR=1.57(1.11-2.20); p=0.009). However, no significant differences were observed in the odds of Sepsis (OR=1.34(0.62-2.85); p=0.45), Acute kidney injury (OR=1.10 (0.74-1.63); p=0.61), Acute respiratory failure (OR=1.11(0.50-2.50); p=0.78) and ICU admission (OR=0.56(0.20-1.57); p=0.27) between the two groups. Conclusions: In patients with bladder cancer, febrile neutropenia has been identified as an independent predictor of mortality. It is associated with increased healthcare resource utilization and fluid and electrolyte disorders. Proactive management of risk factors can help control febrile neutropenia and reduce the occurrence of adverse events in patients hospitalized with bladder cancer. [Table: see text]
Unveiling the pathologic predictor in patients with metastatic hormone-sensitive prostate cancer treated with abiraterone: Intraductal carcinoma of the prostate and its subtypes.
Authors: Wei Xinyuan , Zhao Jinge , Shi Yifu , Shen Pengfei , Liu Zhenhua , Zeng Hao
Published: June 2024

e17077

Background: Intraductal carcinoma of the prostate (IDC-P) is a distinct pathological type of prostate cancer (PCa). Its association with poor prognosis in patients has gained widespread recognition. In this study, we aimed to assess whether metastatic hormone-sensitive prostate cancer (mHSPC) patients with different IDC-P statuses and subtypes exhibited varying responses to abiraterone treatment, with the goal of exploring its potential as a predictive pathological marker. Methods: We conducted a retrospective analysis of data from 165 mHSPC patients who received abiraterone treatment. Propensity score matching (PSM) was employed to minimize the potential impact of selection bias and confounding factors. We evaluated PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) based on IDC-P status and its subtypes (pattern 1: loose cribriform or micropapillary; pattern 2: solid or dense cribriform). We also conducted subgroup analyses to explore their predictive value in different patient populations. Results: Following PSM, a cohort of 108 mHSPC patients was established, among whom IDC-P was confirmed in 54 out of 108 (50%) individuals. Of these, 12/54 (22.2%) exhibited IDC-P pattern 1, while 42/54 (77.8%) had IDC-P pattern 2. The median follow-up duration for the entire cohort was 32.5 months, with median PSA-PFS, rPFS, and OS values of 24.3 months, 31.9 months, and not reached, respectively. No statistically significant difference was observed in PSA responses among patients with different IDC-P statuses. However, patients with IDC-P demonstrated poorer survival outcomes (PSA-PFS: 18.6 vs. NR months, p = 0.002; rPFS: 23.6 vs. NR months, p = 0.020). Patients with IDC-P pattern 1 exhibited clinical outcomes similar to those without IDC-P, whereas patients with IDC-P pattern 2 had significantly worse prognosis compared to those without IDC-P (PSA-PFS: 18.6 vs. NR months, p = 0.002; rPFS: 22.4 vs. NR months, p = 0.010). Subgroup analyses revealed a significant association between IDC-P pattern 2 and poorer prognosis across most population subgroups. Conclusions: Our study assessed the predictive value of IDC-P and its subtypes in prostate biopsy specimens of mHSPC patients undergoing abiraterone treatment. IDC-P, particularly IDC-P pattern 2, serves as an adverse prognostic indicator in these patients. Therefore, routine reporting of IDC-P and its pattern is important for treatment strategy making for prostate cancer patients.
Apa-RP: Multicenter phase 2 study of apalutamide (Apa) and androgen deprivation therapy (ADT) for the treatment of high-risk localized prostate cancer (HR LPC) following radical prostatectomy (RP)—Results in Black and non-Black patients (pts).
Authors: Hafron Jason , Saltzstein Daniel , Brown Gordon , Belkoff Laurence , Aggarwal Pankaj , Phillips Jennifer , Bhaumik Amitabha , McGowan Tracy , Shore Neal D.
Published: June 2024

e17100

Background: Approximately 50% of pts with HR LPC have disease recurrence ≤2 years after RP. Apa-RP (NCT04523207) studied adjuvant Apa + ADT in pts with HR LPC who had undergone RP to determine if the combination improved biochemical recurrence (BCR)-free rate vs historical data from pts who received RP alone. Data are presented for subgroups of Black and non-Black pts. Methods: In this multicenter, open-label, single-arm, phase 2 study conducted at 28 US sites, treatment-naïve pts with HR LPC who had RP received Apa (240 mg; QD) for 12 cycles (28 day cycles) + ADT for 12 months. The study had a diversity goal to enroll ~15% Black pts. The primary endpoint was confirmed BCR-free rate at 24 months, where BCR is defined as two sequential prostate-specific antigen (PSA) levels of >0.2 ng/mL. Secondary endpoints included testosterone recovery (≥150 ng/mL) rate and safety. Modified intention-to-treat analysis set is reported. Results: 108 pts were enrolled (n=15 Black, n=93 non-Black). Black pts were younger than non-Black pts (mean 58.4 vs 66.3 years). Other baseline characteristics were similar, including: median pre-operative PSA 7.6 ng/dL (range 2.2–62.7) and baseline testosterone 340.0 ng/dL (range 43.0–939.0). Confirmed BCR-free rate was 100% (90% CI 93.4, 100.0) (Table); unconfirmed BCR-free rate was 98.4% (90% CI 92.2, 99.7) (Table). Serum testosterone recovery (≥150 ng/dL) event rate at 24 months was 77.4% (95% CI 66.6, 85.1) (Table). Treatment-emergent adverse events were reported in 99.1% (n=107) of pts; 22.2% (n=24) were grade 3–4, 14.8% (n=16) were serious AEs. In total, 13.0% (n=14) and 10.2% (n=11) of pts had treatment dose reductions/interruptions or discontinued due to AEs, respectively. Conclusions: Based on the high BCR-free rate, that persisted for 12 months following treatment, these results suggest that both Black and non-Black pts with HR LPC undergoing RP may benefit from 12 months of treatment intensification with Apa + ADT. Most pts had testosterone recovery. The safety profile of Apa + ADT was consistent with previous reports. Clinical trial information: NCT04523207 . [Table: see text]
Impact of surgical margins on mortality after robotic radical prostatectomy.
Authors: Ahlering Tom Edward , Zeidan Zaki , Tran Joshua , Hwang Yeagyeong , Huynh Linda My , Nguyen Mai Xuan , Zhang Whitney
Published: June 2024

e17101

Background: Positive surgical margins (PSMs) following radical prostatectomy (RP) have long been seen as inherently unfavorable. Despite this belief, there has not been as much evidence supporting unifocal PSMs (UPSM) and prostate cancer-specific mortality (PCSM). Some have reported that multifocal PSM (MPSM) seems to be associated with PCSM. In this study, we examine and compare the impact on PCSM between percent tumor volume (PTV) and MPSMs. Methods: Prospectively collected data for 1552 patients with complete data who underwent RARP by a single surgeon between 2002 and 2018. The primary outcome was comparing risk of PCSM versus increasing pTV. Patients were categorized into pTV groups at a cutoff 40%. PSMs were categorized as negative (NSM), unifocal (UPSM), or multifocal (MPSM). Kaplan-Meier (KM) was used to assess time to OM and PCSM. Results: Men with 40-100% PTV were significantly older and had more advanced grades and stages. High PTV demonstrated a significantly greater risk of PSMs (both unifocal and multifocal), BCR, PCSM, and OM at 15 years. Before including PTV in the multivariate analysis, MPSM independently predicted PCSM, but UPSM did not. However, MPSMs lost their predictive significance when PTV was included. High-stage and Gleason grade group were independent predictors in both analyses. High PTV demonstrated shorter time to PCSM. Conclusions: Our study further challenges the common belief that PSMs are inherently oncologically adverse. Instead, MPSMs appear to signify more voluminous but more importantly aggressive underlying disease, which is the contributing factor for the adverse oncologic outcomes. We emphasize monitoring PTV as a key predictor of long-term adverse oncologic effects as a more reliable predictor of PCSM. Minimizing PSMs remains a critical surgical principle, but in prostate cancer, it needs to be weighed against urinary and sexual function outcomes.
Evaluation of body weight and race on pembrolizumab response in patients with endometrial cancer: A case control study.
Authors: Welp Annalyn , Johnson Kendall , Gehrig Paola A.
Published: June 2024

e17579

Background: Recent studies demonstrate improvement in PFS when pembrolizumab, a humanized monoclonal antibody (mAB) that inhibits the PD-1 receptor, is used with platinum-based regimens for advanced or recurrent endometrial cancer (EC). ASCO recommends studies evaluate the effect of weight on efficacy of anticancer agents to guide dosing. In addition, most studies evaluating the pharmacokinetic effects of mABs typically include only white patients. Pembrolizumab is administered at a flat dose and there are currently no adjustments for weight or race. Therefore, this study was performed to evaluate the impact of weight and race on outcomes in patients with EC treated with pembrolizumab. Methods: This retrospective IRB-approved case-control study included EC patients from 04/2014-12/2022 treated with pembrolizumab. Any patient >18 years with EC who received pembrolizumab was included; carcinosarcoma excluded. Chart review was performed. Response was recorded using RECIST criteria and based on imaging and/or primary oncologist’s determination. Associated toxicities were graded by CTCAE. Statistical testing performed as appropriate. Results: Fifty patients met inclusion criteria, with a mean age of 66.0 years. The majority presented with advanced EC (Stage III or greater) at diagnosis (n=33, 66%). Twenty-eight (56%) had endometroid histology, and 42% (n=21) were MMRd. Most patients received single-agent pembrolizumab (n=26; 52%) or pembrolizumab with lenvatinib (42%), with an average of 8.44 cycles (either 200 mg every 3 weeks or 400 mg every 6 weeks). The table details the objective response rate (ORR) and PFS for patients by race and weight. There was no significant difference in PFS between non-obese (normal weight + overweight) and obese (obese + severely obese) overall. Conclusions: No difference was seen in ORR or PFS between non-obese and obese patients. The study was underpowered to perform tests of statistical significance by race. These data preliminarily suggest pembrolizumab may not need to be adjusted for weight. Larger scale multi-institution trials with a particular emphasis on the recruitment of non-Hispanic Black patients can help clarify whether race-based differences in dosing pembrolizumab may be needed. [Table: see text]
Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO).
Authors: McGregor Bradley Alexander , Kwak Lucia , Sonpavde Guru P. , Berg Stephanie A. , CHOUEIRI Toni K. , Bellmunt Joaquim , Mantia Charlene
Published: June 2024

TPS4618

Background: In the DAD study (NCT04724018) the combination of SG+EV demonstrated favorable safety determining a maximum tolerated dose of 10 mg/kg and 1.25 mg/kg IV D1,8 every 21 days along with encouraging efficacy in treatment resistant mUC as evidenced by an objective response rate (ORR) of 70% in 23 evaluable patients. Given cumulative toxicities and efficacy across dose levels, the recommended phase 2 dose was SG 7.5 mg/kg and EV 1.25 mg/kg D1,8 of 21-day cycle. As EV+P is now a standard of care for front line urothelial carcinoma, NCT04724018 was amended to include 2 cohorts of distinct patient populations; one expanding SG+EV (DAD) and a second exploring the SG+EV+P (DAD-IO) combination. Methods: In DAD cohort, patients with mUC progressing on platinum and immunotherapy or on one line of therapy receive SG 7.5 mg/kg + EV 1.25 mg/kg intravenously (IV) on day(D)s 1 and 8 every 3 weeks (1 cycle) until progression or intolerable toxicities. In DAD-IO cohort, patients with treatment naïve mUC are given SG 7.5 mg/kg+EV 1.25 mg/kg IV D1, 8 of a 21-day cycle with P 200 mg every 3 weeks or 400 mg every 6 weeks per investigator discretion. In both cohorts, prophylactic granulocyte colony stimulating factor (GCSF) support is given per supportive care guidelines with cycle 1. Following first dose on trial, SG and EV can be reduced and held independently for toxicity with reductions of SG to 5 mg/kg, and EV to 1, 0.75 and 0.5 mg/kg. P dose reductions are not allowed but can be held as needed for immune related adverse events. Laboratory evaluation is performed on days 1 and 8 every cycle. Imaging is performed at baseline and every 6 weeks for the first 4 cycles followed by every 9 weeks thereafter. In both cohorts, the primary endpoint is RECIST 1.1 ORR with secondary endpoints being progression free survival, overall survival, and safety. DAD aims to enroll 41 eligible patients, assuming an ORR of 65% for EV+SG, to detect a 25% improvement with over 90% power at a one-sided type I error rate of 0.05 using a single-stage exact one-sample binomial design; ³ 23 responses would rule out a null of 40% ORR. DAD-IO plans to enroll 41 eligible patients, assuming an ORR of 75% for SG+EV+P to detect a 20% improvement with 90% power at a one-sided type I error rate 0.09 based on a Simon optimal two-stage design. If ³ 11 responses are observed in the first 18 patients, an additional 23 patients will be enrolled. At least 27 responses among a total of 41 will be needed to confirm its efficacy. The study includes a 12-patient safety lead in using a Bayesian toxicity monitoring. If ≤2 dose limiting toxicities (DLTs) occur in the first 6 patients, the next 6 are enrolled. The study halts if ≥5 DLTs occur among 12 evaluable patients. Clinical trial information: NCT04724018 . [Table: see text]
CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA: Phase 3 MK-5684-004 study.
Authors: Fizazi Karim , Vile Donald Charles , Chen Zheng Hong , Poehlein Christian Heinrich , Todoric Jelena , Gratzke Christian
Published: June 2024

TPS5114

Background: Activating androgen receptor (AR) somatic mutation is a known mechanism of resistance to AR-directed therapies in mCRPC, and it may permit continued hormone dependence. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Thus, MK-5684 has the potential to suppress the production of all steroid hormones and precursors that may activate the AR signaling pathway. MK-5684 demonstrated antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations, in the phase 1/2 CYPIDES study. The efficacy and safety of MK-5684 in patients with molecularly unselected mCRPC after 1 prior NHA will be evaluated in the randomized, open-label, phase 3 MK-5684-004 study (NCT06136650). Methods: Eligible patients have mCRPC unselected for AR-LBD mutations that progressed during androgen deprivation therapy ≤6 months before screening and during or after 1 NHA for hormone-sensitive prostate cancer (HSPC) or nonmetastatic CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior NHA + docetaxel for HSPC is permitted if patients received ≤6 cycles of docetaxel without radiographic disease progression. Approximately 1500 patients (AR-LBD mutation–positive, 375 patients; AR-LBD mutation–negative, 1125 patients) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO BID (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Randomization will be stratified by metastasis (bone only/liver/other), AR-LBD mutation status (positive/negative), and prior docetaxel for HSPC (yes/no). Treatment will continue until unacceptable toxicity, radiographic disease progression (verified per Prostate Cancer Working Group 3 [PCWG3]–modified RECIST v1.1 by BICR), or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks through week 24, then every 12 weeks thereafter. Dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in patients with AR-LBD mutation–positive and –negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen (PSA) progression; PSA response rate; time to first symptomatic skeletal-related event; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT06136650 .
Simulating Healthy Participant Pharmacokinetics for Renal and Hepatic Impairment Studies: Retrospective Assessment of the Approach
Authors: Prybylski John P. , Wang Yuchen , Sahasrabudhe Vaishali , Purohit Vivek
Published: June 2024

The recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.

Graphical Abstract
Self-consistent equilibrium of a force-free magnetic flux rope
Authors: Cheremnykh Oleg K. , Lashkin Volodymyr M.
Published: June 2024

We present an exact solution to the problem of a self-consistent equilibrium force-free magnetic flux rope. Unlike other approaches, we use magnetostatic equations and assume only a relatively rapid decrease in the axial magnetic field at infinity. For the first time we obtain a new nonlinear equation for the axial current density, the derivation of which does not require any phenomenological assumptions. From the resulting nonlinear equation, we analytically find the radial profiles of the components of the magnetic field strength and current density.
Classicism in Digital Times
Authors: Yang Zhiyi , Wang David Der-Wei
Published: June 2024

This article, the introduction to the special issue, proposes “Sinophone classicism” as a new paradigm to investigate Chineseness as an identity shaped by cultural and digital memories in the global cyberspace. Digital technology has drastically transformed the world we inhabit, particularly the way in which we symbiotically remember and imagine our cultural legacies and visions. To rethink the relations between the humanities and digital technicity, we seek to invoke “classicism” as a keyword through which to engage questions from temporality to virtuality and “Sinophone” as a topos through which to discover the pluriverse of China. Being “Chinese” in cyberspace, therefore, entails a constant and dynamic process of remembering, performing, (re)imagining, and (re)negotiating one's cultural identities.
China in the Skin
Authors: Sh-Chen Yedong
Published: June 2024

How do video games tell “the good China story”? In reviewing Chinese official media's months-long criticism of the mobile MOBA game, Honor of Kings (Wangzhe rongyao 王者榮耀), and the game's rounds of responses in 2017 and 2018, this article investigates a unique digital object that affords storytelling in video games: skin (pifu 皮膚). Neither a playable character per se nor a player's avatar, skin constitutes a special digital milieu where China stories are told, debated, and their “goodness” performed. It traverses various composing strata of video games and distributes narrative into a game's mechanics, procedure, representation, playing experience, and more. Skin, the author argues, is a yet-theorized differentiator that anchors “Chineseness” in the world of video gaming. It is a new site in a digital age in which the theoretical problem of Chineseness manifests different kinds of difficulty. The article ends with a discussion of the significance of researching skin to our understanding of what a Chinese video game is. The author calls for a new conceptualization of a Chinese video game that accounts for video game's medium specificity. Speaking to scholars of both Chinese studies and digital game studies, this article anticipates more scholarly interest in the intersection of the two fields.
Digital Preoperative Huddle Platform Use Leads to Decreased Surgical Cost
Authors: Eremiev Alexander , London Dennis , Ber Roee , Kurland David B. , Sheerin Kathleen , Dennett Haleigh , Pacione Donato , Laufer Ilya
Published: June 2024

BACKGROUND AND OBJECTIVES:

Communication has a well-established effect on improving outcomes. The current study evaluated the effect of multidisciplinary preoperative team communication using a digital huddle software platform on operating room costs.

METHODS:

A digital huddle software platform was implemented in March 2022 for neurosurgical procedures performed at a single tertiary care center. Surgeons were encouraged, but not required, to participate. General linear models were used to test the association between participation and the difference in supply-related cost and case length, using intergroup comparison and historical controls.

RESULTS:

A total of 29626 cases (performed by 97 surgeons), conducted between March 2021 and June 2023, were included in our analysis. Cases from participating neurosurgeons (12 surgeons, 4064 cases) were compared with cases from nonparticipating neurosurgeons (6 surgeons, 2452 cases), non-neurosurgery cases carried out by the same operating room staff (20 orthopedic spine surgeons, 6073 cases), and non-neurosurgery cases performed in a different operating room unit (59 surgeons, 21 996 cases). In aggregate, operating room (OR) costs increased by 7.3% (95% CI: 0.9-14.1, P = .025) in the postintervention period. In the same period, participation in the digital huddle platform was associated with an OR utilization and supply-related cost decrease of 16.3% (95% CI: 8.3%-23.6%, P < .001). Among neurosurgeons specifically, participation was associated with a supply-related cost decrease of 17.5% (95% CI: 6.0%-27.5%, P = .0037). There was no change in case length (median case length 171 minutes, change: +2.7% increase, 95% CI:-2.2%-7.9%, P = .28).

CONCLUSION:

The implementation of a digital huddle software platform resulted in an OR utilization and supply cost decrease among participants during a period when the overall nonparticipating control cohort experienced an increase in cost.
Histone acylation at a glance
Authors: Bhattacharya Saikat , Tu Benjamin P.
Published: June 2024

An important mechanism of gene expression regulation is the epigenetic modification of histones. The cofactors and substrates for these modifications are often intermediary metabolites, and it is becoming increasingly clear that the metabolic and nutritional state of cells can influence these marks. These connections between the balance of metabolites, histone modifications and downstream transcriptional changes comprise a metabolic signaling program that can enable cells to adapt to changes in nutrient availability. Beyond acetylation, there is evidence now that histones can be modified by other acyl groups. In this Cell Science at a Glance article and the accompanying poster, we focus on these histone acylation modifications and provide an overview of the players that govern these acylations and their connections with metabolism.
CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses
Authors: Prajapati Bina , Sokolova Maria , Sidorenko Ekaterina , Kyriacou Mikael , Kyheröinen Salla , Vihervaara Anniina , Vartiainen Maria K.
Published: June 2024

Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in transcription of heat shock protein (HSP)-encoding genes in fly ovaries, but the mechanisms remain unclear. Here, we demonstrate that, in mammalian cells, MRTFs are dispensable for gene induction of HSP-encoding genes. However, the widely used small-molecule inhibitors of the MRTF-SRF transcription pathway, derived from CCG-1423, also efficiently inhibit gene transcription of HSP-encoding genes in both fly and mammalian cells in the absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF-SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
Strong acclimation effect of temperature and humidity on heat tolerance of the Arctic collembolan Megaphorura arctica
Authors: Christoffersen Sara Nørris , Pertoldi Cino , Sørensen Jesper Givskov , Kristensen Torsten Nygård , Bruhn Dan , Bahrndorff Simon
Published: June 2024

The Arctic is a highly variable environment in which extreme daily and seasonal temperature fluctuations can occur. With climate change, an increase in the occurrence of extreme high temperatures and drought events is expected. While the effects of cold and dehydration stress on polar arthropods are well studied in combination, little is known about how these species respond to the combined effects of heat and dehydration stress. In this paper, we investigated how the heat tolerance of the Arctic collembola Megaphorura arctica is affected by combinations of different temperature and humidity acclimation regimes under controlled laboratory conditions. The effect of acclimation temperature was complex and highly dependent on both acclimation time and temperature, and was found to have a positive, negative or no effect depending on experimental conditions. Further, we found marked effects of the interaction between temperature and humidity on heat tolerance, with lower humidity severely decreasing heat tolerance when the acclimation temperature was increased. This effect was more pronounced with increasing acclimation time. Lastly, the effect of acclimation on heat tolerance under a fluctuating temperature regime was dependent on acclimation temperature and time, as well as humidity levels. Together, these results show that thermal acclimation alone has moderate or no effect on heat tolerance, but that drought events, likely to be more frequent in the future, in combination with high temperature stress can have large negative impacts on heat tolerance of some Arctic arthropods.
Coronary circulation enhances the aerobic performance of wild Pacific salmon
Authors: Van Wert Jacey C. , Ekström Andreas T. , Gilbert Matthew J. H. , Hendriks Brian J. , Cooke Steven J. , Patterson David A. , Hinch Scott G. , Eliason Erika J.
Published: June 2024

Female Pacific salmon often experience higher mortality than males during their once-in-a-lifetime up-river spawning migration, particularly when exposed to secondary stressors (e.g. high temperatures). However, the underlying mechanisms remain unknown. One hypothesis is that female Pacific salmon hearts are more oxygen-limited than those of males and are less able to supply oxygen to the body's tissues during this demanding migration. Notably, female hearts have higher coronary blood flow, which could indicate a greater reliance on this oxygen source. Oxygen limitations can develop from naturally occurring coronary blockages (i.e. coronary arteriosclerosis) found in mature salmon hearts. If female hearts rely more heavily on coronary blood flow but experience similar arteriosclerosis levels as males, they will have disproportionately impaired aerobic performance. To test this hypothesis, we measured resting (RMR) and maximum metabolic rate (MMR), aerobic scope (AS) and acute upper thermal tolerance in coho salmon (Oncorhynchus kisutch) with an intact or artificially blocked coronary oxygen supply. We also assessed venous blood oxygen and chemistry (cortisol, ions and metabolite concentrations) at different time intervals during recovery from exhaustive exercise. We found that coronary blockage impaired MMR, AS and the partial pressure of oxygen in venous blood (PvO2) during exercise recovery but did not differ between sexes. Coronary ligation lowered acute upper thermal tolerance by 1.1°C. Although we did not find evidence of enhanced female reliance on coronary supply, our findings highlight the importance of coronary blood supply for mature wild salmon, where migration success may be linked to cardiac performance, particularly during warm water conditions.
Individual differences in the boldness of female zebrafish are associated with alterations in serotonin function
Authors: Beigloo Fatemeh , Davidson Cameron J. , Gjonaj Joseph , Perrine Shane A. , Kenney Justin W.
Published: June 2024

One of the most prevalent axes of behavioral variation in both humans and animals is risk taking, where individuals that are more willing to take risk are characterized as bold while those that are more reserved are regarded as shy. Brain monoamines (i.e. serotonin, dopamine and noradrenaline) have been found to play a role in a variety of behaviors related to risk taking. Using zebrafish, we investigated whether there was a relationship between monoamine function and boldness behavior during exploration of a novel tank. We found a correlation between serotonin metabolism (5-HIAA:5-HT ratio) and boldness during the initial exposure to the tank in female animals. The DOPAC:DA ratio correlated with boldness behavior on the third day in male fish. There was no relationship between boldness and noradrenaline. To probe differences in serotonergic function in bold and shy fish, we administered a selective serotonin reuptake inhibitor, escitalopram, and assessed exploratory behavior. We found that escitalopram had opposing effects on thigmotaxis in bold and shy female animals: the drug caused bold fish to spend more time near the center of the tank and shy fish spent more time near the periphery. Taken together, our findings indicate that variation in serotonergic function has sex-specific contributions to individual differences in risk-taking behavior.
Flies on the rise: acclimation effect on mitochondrial oxidation capacity at normal and high temperatures in Drosophila melanogaster
Authors: Blanchard Arianne , Aminot Mélanie , Gould Nathalie , Léger Adèle , Pichaud Nicolas
Published: June 2024

Increased average temperatures and extreme thermal events (such as heatwaves) brought forth by climate change impose important constraints on aerobic metabolism. Notably, mitochondrial metabolism, which is affected by both long- and short-term temperature changes, has been put forward as an important determinant for thermal tolerance of organisms. This study examined the influence of phenotypic plasticity on metabolic and physiological parameters in Drosophila melanogaster and the link between mitochondrial function and their upper thermal limits. We showed that D. melanogaster acclimated to 15°C have a 0.65°C lower critical thermal maximum (CTmax) compared with those acclimated to 24°C. Drosophila melanogaster acclimated to 15°C exhibited a higher proportion of shorter saturated and monounsaturated fatty acids, concomitant with lower proportions of polyunsaturated fatty acids. No mitochondrial quantitative changes (fractional area and number) were detected between acclimation groups, but changes of mitochondrial oxidation capacities were observed. Specifically, in both 15°C- and 24°C-acclimated flies, complex I-induced respiration was increased when measured between 15 and 24°C, but drastically declined when measured at 40°C. When succinate and glycerol-3-phosphate were added, this decrease was however compensated for in flies acclimated to 24°C, suggesting an important impact of acclimation on mitochondrial function related to thermal tolerance. Our study reveals that the use of oxidative substrates at high temperatures is influenced by acclimation temperature and strongly related to upper thermal tolerance as a difference of 0.65°C in CTmax translates into significant mitochondrial changes.
Few incidentally found interesting foreign objects in human body: a case series
Authors: HATGAONKAR ANAND , HATGAONKAR KAJAL , DHOTE SANDEEP , DHAWAN VAISHALI
Published: June 2024

Foreign bodies are objects that do not typically belong in the human body but can be ingested, inserted, or entered due to injuries. This article presents various cases and examples of foreign bodies, including objects swallowed, objects inserted into the rectum, vagina, urethra, ear, and nose, or due to injuries caused by falls, puncture wounds, and gunshot wounds. Foreign bodies can be difficult to detect, particularly if they are not inherently radio-opaque, and may be overlooked by patients who cannot provide an adequate history. These foreign bodies may cause harm to the patient. Interpretation is done on radiographs, computed tomography (CT), Ultrasonography (USG), and magnetic resonance imaging (MRI) studies. Most foreign objects pass through the gastrointestinal tract without problem; sharp and elongated objects can cause significant injury, and even if they only partially perforate the bowel wall, they can produce chronic inflammatory processes that produce symptoms months or years later. Hence, searching for foreign bodies should be done throughout the gastrointestinal tract, particularly in children and people with mental illness who are more likely to swallow multiple items more than once. Although rare, various materials can be left behind in the body of a patient after surgery, including large and small wire sutures, surgical drains, and retained sponges, which can cause potential complications and foreign body reactions. This article highlights the importance of being aware of the presence of foreign bodies in clinical practice, and a thorough search should be carried out using different modalities, especially CT. Great suspicion and early diagnosis of foreign bodies can avoid potential complications and morbidity. In general, it provides information on the diagnosis and treatment of various types of foreign bodies.
Systematic review: Effect of feeding rich in CYP2A6 and glutathione enzymes on decreasing nicotine levels in the body of smokers
Authors: Haqi Dani Nasirul , Tualeka Abdul Rohim , Afsari Indah Ayu , Aziz Mohd Yusmaidie , Jalaludin Juliana , Ahsan Ahsan , Rahmawati Pudji , Novianti Salsabila
Published: June 2024

CYP2A6 enzyme is an enzyme that is responsible for the metabolism of nicotine into cotinine. Meanwhile, glutathione is a tripeptide -L-glutamyl-L-cysteineyl-glycine, which has high concentrations in the liver. This literature review study aims to determine the effect of giving foods rich in CYP2A6 enzymes and glutathione to reduce nicotine levels in the body of smokers. The inclusion criteria used were the year of publication of articles from the last 5 years, discussing the effect of food doses with CYP2A6 enzymes and glutathione on reducing nicotine levels, experimental research methods, and full-text journals that can be accessed free of charge. The data source comes from Pubmed and Writing a Literature Review began in May to June 2022. Based on the results of 4 literature review articles, it was found that there was an effect of feeding with CYP2A6 enzymes and glutathione on reducing nicotine levels in smokers.
Effect of Pulmonary Complications on Neonates with Bronchopulmonary Dysplasia: A Systematic Review Protocol
Authors: Brahmane Neha , Hullumani Sharath , Umale Neha , Raghumahanti Raghuveer , Qureshi Irshad
Published: June 2024

Introduction Bronchopulmonary dysplasia (BPD) is a common chronic lung disease that affects premature infants and is characterized by disrupted alveolar and vascular development. Pulmonary complications significantly affect morbidity and mortality rates in neonates with BPD. Aim This systematic review aimed to outline a protocol for investigating the effects of pulmonary complications in neonates diagnosed with BPD. Methods A comprehensive search strategy will be implemented across electronic databases, including PubMed, MEDLINE, Embase, and Cochrane Library. Eligible studies will include primary research articles reporting pulmonary complications, such as pulmonary hypertension, respiratory infections, ventilator-associated events, and airway abnormalities among neonates diagnosed with BPD. Two independent reviewers screened the titles, abstracts, and full text of the identified articles for eligibility. Data extraction will be conducted using a predefined form, including study characteristics, participant demographics, types of pulmonary complications, and relevant outcomes. The methodological quality of the included studies will be assessed using appropriate tools, such as the Cochrane Risk of Bias Tool for randomized controlled trials. Outcome measures The primary outcomes of interest will include the prevalence and incidence of pulmonary complications among neonates diagnosed with BPD. Secondary outcomes will encompass the impact of pulmonary complications on clinical outcomes, such as respiratory morbidity, mortality rates, length of hospital stay, and neurodevelopmental outcomes. Narrative synthesis will be employed to summarize the findings of the included studies, and where applicable, a meta-analysis will be conducted to quantify the effects of pulmonary complications on neonatal outcomes. Discussion This systematic review protocol outlines a rigorous methodology for investigating the effects of pulmonary complications in neonates with BPD. The findings of this review will provide valuable insights into the burden of pulmonary complications in this vulnerable population, and inform clinical practice and future research endeavors aimed at improving the care and management of neonates with BPD. Systematic Review Registration no. CRD42024524133
Allocation of Funds in Bilevel Subsidy Welfare Programs
Authors: Wei Wei , Arora Priyank , Solak Senay
Published: June 2024

Problem definition: Most subsidy welfare programs operate in a bilevel hierarchical structure, wherein a funding agency allocates funds to multiple service organizations. These service organizations invest in activities within their areas to generate societal impact for beneficiaries by enhancing the quantity and quality of services at local providers. The funds allocation decisions in such programs are complicated by the funding agency’s equity consideration, intricate relationships among contextual factors in societal impact generation, and information asymmetry between different entities about availability of additional funds for an agency. Methodology/results: We propose a model to analyze how the funding agency should allocate funds to generate the most societal impact equitably across areas. We show that the funding agency should direct more funds toward an area with a relatively balanced mix of subsidy-accepting and nonaccepting providers, or with fewer nonaccepting providers, and outreach activity is more likely to yield a higher investment return. Further, comparing the inequity levels and total societal impact under the proposed equity-ensuring method with those under other methods, we find that an efficiency-focused method enhances total societal impact, but can result in greater inequity, especially when there is a large across-area disparity in the size of beneficiaries. A simple formula-based method could achieve greater total societal impact, while not severely sacrificing equity in certain situations. Conversely, the equity-ensuring method always eliminates inequity by not severely sacrificing the total societal impact under a wide range of parameter values. Managerial implications: Given the growing impetus to consider equity within their operations, our equity-ensuring method helps the funding agencies adjust their allocation strategies to generate the greatest equitable impact. Finally, using a case study based on Massachusetts’ child care subsidy program, we illustrate that the proposed method achieves equity while enhancing the overall societal impact by approximately 3% versus the current formula-based method.

Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2022.0474 .