bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability in competitive fitness among environmental and clinical azole-resistant
Aspergillus fumigatus
isolates
Authors: Chen Shu , Zhu Guoxing , Lin Huiping , Guo Jian , Deng Shuwen , Wu Wenjuan , Goldman Gustavo H. , Lu Ling , Zhang Yuanwei 
Published: February 2024

ABSTRACT

Azoles are the primary antifungal drugs used to treat infections caused by
Aspergillus fumigatus
. However, the emergence of azole resistance in
A. fumigatus
has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in
A. fumigatus
remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted
cyp51A
mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant
A. fumigatus
isolates in the environment and clinic. By constructing
in situ cyp51A
mutations in a parental azole-susceptible strain and reintroducing the wild-type
cyp51A
gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on
cyp51A
mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates.

IMPORTANCE

Azole resistance in the human fungal pathogen
Aspergillus fumigatus
presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14α-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical
cyp51A
-mutated isolates. We have shown that this fitness cost is not reliant on
cyp51A
mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of
A. fumigatus
, highlighting the significant role of fitness cost in the spread of resistant strains.
Supplemental Material: Episodic magmatism of the Gongga batholith (eastern Tibet) revealed by detrital zircon U-Pb geochronology: Insights into phased Xianshuihe fault activity and plateau growth
Authors: Zhao Yanglin , al. et , Shen Xiaoming 
Published: February 2024

<p>U-Pb geochronology analytical conditions and zircon U-Pb data </p>
The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells
Authors: Zhang Qunfang , Zheng Fang , Chen Yuchao , Liang Chun-Ling , Liu Huazhen , Qiu Feifei , Liu Yunshan , Huang Hongfeng , Lu Weihui , Dai Zhenhua 
Published: February 2024

Abstract
Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell–originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.
High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance
Authors: Saeed Muhammad A. , Peng Bo , Kim Kevin , Rawat Kavita , Kuehm Lindsey M. , Siegel Zoe R. , Borkowski Ariel , Habib Nabih , Van Tine Brian , Sheikh Nadeem , Tuyen Vu , Thorek Daniel L.J. , Fehniger Todd A. , Pachynski Russell K. 
Published: February 2024

Abstract
Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC.
Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC
Authors: Nakazawa Mari , Harada Guilherme , Ghanem Paola , Bubie Adrian , Kiedrowski Lesli A. , Murray Joseph C. , Marrone Kristen A. , Scott Susan C. , Houseknecht Stefanie , Falcon Christina J. , Evans Patrick , Feliciano Josephine , Hann Christine L. , Ettinger David S. , Smith Kellie N. , Anagnostou Valsamo , Forde Patrick M. , Brahmer Julie R. , Levy Benjamin , Drilon Alexander , Lam Vincent K. 
Published: February 2024

Abstract

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non–small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62–4.09 and HR: 1.93; 95% CI: 1.17–3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P &lt; 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03–2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P &lt; 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.

Significance:
In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.
Dose Response to Upper Extremity Stroke Rehabilitation Varies by Individual: Early Indicators of Treatment Response
Authors: Gauthier Lynne V. , Ravi Roshan , DeLuca David , Zhou Wenjin 
Published: February 2024

BACKGROUND:
Dose response has remained a priority area in motor rehabilitation research for decades, prompting several large randomized trials and meta-analyses. These between-subjects comparisons have revealed equivocal relationships between the duration of motor practice and rehabilitation response. Prior reliance on time-consuming clinical assessments made it infeasible to capture within-subjects dose response, as tracking the dose-response trajectory of an individual requires dozens of repeated administrations.

METHODS:
This secondary observational cohort analysis of existing data from the gaming arms of the VIGoROUS multisite trial (Video Game Rehabilitation for Outpatient Stroke) describes the rehabilitation dose response of 80 participants with mild-moderate chronic stroke. The 3-dimensional joint position data were captured via the Kinect v2 optical sensor as participants completed a prescribed 15 hours of in-home unsupervised game-based motor practice. Kinematic dose response trajectories were fitted from hundreds to thousands of in-game repetitions for 4 separate upper extremity movements for each participant.

RESULTS:
Of 75 participants with sufficient data for dose-response analysis, 85% showed improved motor capacity for at least 1 movement. Dose response was bimodal; 42% required <5 hours of motor practice before reaching a plateau in movement kinematics, whereas 55% required >10 and 34% required >30 hours. We could predict with 93% accuracy whether or not an individual would ultimately respond to game-based motor practice within 5 hours of gameplay.

CONCLUSIONS:
Dose response varies considerably between individuals. About half of chronic stroke patients benefit from higher doses of motor practice than the current standard of care. Individualized dose-response data from motion capture rehabilitation gaming can guide clinical decision-making early on in treatment.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02631850.
The Utility of Stress Ultrasound in Identifying Risk Factors for Elbow Ulnar Collateral Ligament Tear: A Longitudinal Study of 203 Professional Baseball Players
Authors: Hanna Adeeb Jacob , Popper Hannah R. , Sonnier John Hayden , Erickson Brandon J. , Jack Robert A. , Cohen Steven B. 
Published: February 2024

Background: Injuries to the medial ulnar collateral ligament (UCL) are common among baseball pitchers due to repetitive stress on the soft tissue stabilizers of the elbow during pitching. Dynamic stress ultrasound (SUS) can be used to evaluate the UCL and ulnohumeral joint to identify anatomic risk factors of those who will require UCL reconstruction (UCLR). Purpose: To determine whether any adaptive or morphological changes detectable on SUS can predict injury to the UCL in professional baseball pitchers. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 203 professional baseball pitchers who underwent SUS at preseason training sessions over the course of 18 years were categorized into 1 of 2 groups: those without a history of shoulder, arm, elbow, or forearm surgery or injuries (healthy cohort; n = 184) and those who underwent UCLR the same season as SUS (UCLR cohort; n = 19). Ligament thickness, joint spacing, and laxity were compared. An additional matched cohort analysis was conducted using 10 players from each group to detect differences in the progression of UCL and ulnohumeral joint measures in the year before injury. Results: The UCLR cohort, when compared with the healthy cohort, had higher relative (ie, nondominant-side measurements subtracted from dominant-side measurements) resting ulnohumeral joint space (median, 0.50 vs 0.20 mm, respectively; P = .006) and higher rates of hypoechoic foci (57.9% vs 30.4%, respectively; P = .030). Players of both groups had similar dominant UCL thickness ( P = .161), ulnohumeral joint space at rest ( P = .321), space under stress ( P = .498), and laxity ( P = .796). Groups did not differ in terms of relative UCL thickness, ulnohumeral joint space under stress, or relative laxity. In the year before UCL injury, the UCLR cohort, compared with the matched healthy cohort, had a greater increase in mean dominant UCL thickness (0.94 vs –0.60 mm, respectively; P = .038) and a greater increase in relative median UCL thickness (1.35 vs –0.35 mm, respectively; P = .045). Players in the healthy cohort were statistically older than those in the UCLR cohort (23 vs 22 years, respectively; P = .004). No differences in ulnohumeral stress spacing or laxity were detected. Conclusion: SUS of players who underwent UCLR demonstrated a progressive increase in UCL thickness over 1 year, higher rates of hypoechoic foci, and increased ulnohumeral rest space compared with SUS of uninjured players.
Association of Shock Indices with Peri-Intubation Hypotension and Other Outcomes: A Sub-Study of the KEEP PACE Trial
Authors: Smischney Nathan J. , Seisa Mohamed O. , Schroeder Darrell R. 
Published: February 2024

Background Based on current evidence, there appears to be an association between peri-intubation hypotension and patient morbidity and mortality. Studies have identified shock indices as possible pre-intubation risk factors for peri-intubation hypotension. Thus, we sought to evaluate the association between shock index (SI), modified shock index (MSI), and diastolic shock index (DSI) and peri-intubation hypotension along with other outcomes. Methods The present study is a sub-study of a randomized controlled trial involving critically ill patients undergoing intubation. We defined peri-intubation hypotension as a decrease in mean arterial pressure <65 mm Hg and/or a reduction of 40% from baseline; or the initiation of, or increase in infusion dosage of, any vasopressor medication (bolus or infusion) during the 30-min period following intubation. SI, MSI, and DSI were analyzed as continuous variables and categorically using pre-established cut-offs. We also explored the effect of age on shock indices. Results A total of 151 patients were included in the analysis. Mean pre-intubation SI was 1.0  ±  0.3, MSI 1.5  ±  0.5, and DSI 1.9  ±  0.7. Increasing SI, MSI, and DSI were significantly associated with peri-intubation hypotension (OR [95% CI] per 0.1 increase  =  1.16 [1.04, 1.30], P  =  .009 for SI; 1.14 [1.05, 1.24], P  =  .003 for MSI; and 1.11 [1.04, 1.19], P  =  .003 for DSI). The area under the ROC curves did not differ across shock indices (0.66 vs 0.67 vs 0.69 for SI, MSI, and DSI respectively; P  =  .586). Increasing SI, MSI, and DSI were significantly associated with worse sequential organ failure assessment (SOFA) score (spearman rank correlation: r  =  0.30, r  =  0.40, and r  =  0.45 for SI, MSI, and DSI, respectively, all P < .001) but not with other outcomes. There was no significant impact when incorporating age. Conclusions Increasing SI, MSI, and DSI were all significantly associated with peri-intubation hypotension and worse SOFA scores but not with other outcomes. Shock indices remain a useful bedside tool to assess the potential likelihood of peri-intubation hypotension. Trial registration ClinicalTrials.gov identifier - NCT02105415
Don’t Say “Beans” When Promoting Plant Protein to Family Meal Planners
Authors: Kottke Thomas E. , Dinh Jennifer M. , Henderson Maren S. G. , Zibley Laura , Rivard Rachael L. , Ziegenfuss Jeanette Y. , Ellefson Katherine J. , Peterson Hikaru , Canterbury Marna 
Published: February 2024

Purpose To identify “headlines” that would engage recipients to consider plant protein over red meat. Design Mail and web survey. Setting Urban Minnesota community. Subjects 144 survey respondents from our health plan and community program distribution lists who live with at least 1 other person and eat meat. Intervention We asked respondents how likely they would be to click on each of 24 headlines with a motivator (eating plant protein for health vs for environmental reasons) and a barrier (family preferences, knowledge about plant proteins, or cooking skills). 16 headlines contained the word “beans”. Measures We created categorical variables for each headline construct: (1) motivator, (2) barrier, and (3) reference to beans. Using a mixed model with random effects, we compared, for each construct, respondents’ self-reported likelihood to click on a headline. Results Health-related headlines performed significantly better than environmental headlines ( P = .0019, 95% CI .01, .11). Family-oriented headlines performed slightly better than skills-oriented ( P = .0927, 95% CI -.01, .11) and knowledge-oriented ( P = .0960, 95% CI -.01, .11) headlines. Headlines containing the word “beans” performed significantly worse than those not containing “beans” ( P < .0001, 95% CI -.22, -.12). Conclusions The population represented by our survey respondents report being most likely to click on headlines that emphasize health and family. They report they are significantly less likely to click on headlines that promote beans.
Incidence of Hypertriglyceridemia in Patients on Propofol, Clevidipine, or Both
Authors: Johns Christopher B. , Fleming Travis W. , Brown Skyler R. , Black Rebekah B. , Rowe A. Shaun 
Published: February 2024

Background: Propofol and clevidipine (PC) are commonly used in the treatment of critically ill patients. While both medications are lipid emulsions, there is limited evidence concerning the incidence of hypertriglyceridemia (HTG) when these agents are used individually or concurrently. Objective: The objective of this study is to determine the effects of propofol, clevidipine, or concurrent PC on triglycerides (TGs) and related outcomes in critically ill adults. Methods: This was a retrospective cohort study conducted at an academic medical center. Patients were included if they received ≥24 hours of continuous propofol and/or clevidipine. Excluded were those without TG levels after ≥24 hours of infusion, baseline HTG, acute pancreatitis at admission, or receiving total parenteral nutrition with lipids. The primary outcome was incidence of HTG (defined as a TG level >400 mg/dL). Secondary outcomes included median and peak TG levels, hospital length of stay, intensive care unit length of stay, total lipid infused, time to peak TG level, peak lipase level, and development of pancreatitis. Results: In total, 190 patients were studied: 109 in the propofol group, 50 in the clevidipine group, and 31 in the PC group. Incidence of HTG was similar (19 [17.4%] vs 6 [12%] vs 4 [12.9%] patients, P = 0.6246). Peak and median TG levels were similar for propofol, clevidipine, and PC groups (216 mg/dL vs 189.5 mg/dL vs 205 mg/dL, P = 0.7069; 177 mg/dL vs 185.5 mg/dL vs 177 mg/dL, P = 0.6791). Conclusions and Relevance: There was a similar incidence of HTG in all groups. The results of this study suggest that the concurrent use of PC should not modify the frequency of TG level monitoring.
Infection Prevention and the Protective Effects of Unidirectional Displacement Flow Ventilation in the Turbulent Spaces of the Operating Room
Authors: Ziegler Mareike , Seipp Hans-Martin , Steffens Thomas , Walter Dirk , Büttner-Janz Karin , Rodger Daniel , Herzog-Niescery Jennifer 
Published: February 2024

Background: Unidirectional displacement flow (UDF) ventilation systems in operating rooms are characterized by a uniformity of velocity ≥80% and protect patients and operating room personnel against exposure to hazardous substances. However, the air below the surgical lights and in the surrounding zone is turbulent, which impairs the ventilation system’s effect. Aim: We first used the recovery time (RT) as specified in International Organization for Standardization 14644 to determine the particle reduction capacity in the turbulent spaces of an operating room with a UDF system. Methods: The uniformity of velocity was analyzed by comfort-level probe grid measurements in the protected area below a hemispherical closed-shaped and a semi-open column-shaped surgical light (tilt angles: 0°/15°/30°) and in the surrounding zone of a research operating room. Thereafter, RTs were calculated. Results: At a supply air volume of 10,500 m3/h, the velocity, reported as average uniformity ± standard deviation, was uniform in the protected area without lights (95.8% ± 1.7%), but locally turbulent below the hemispherical closed-shaped (69.3% ± 14.6%), the semi-open column-shaped light (66.9% ± 10.9%), and in the surrounding zone (51.5% ± 17.6%). The RTs ranged between 1.1 and 1.7 min below the lights and 3.5 ± 0.28 min in the surrounding zone and depended exponentially on the volume flow rate. Conclusions: Compared to an RT of ≤20 min as required for operating rooms with mixed dilution flow, particles here were eliminated 12–18 times more quickly from below the surgical lights and 5.7 times from the surrounding zone. Thus, the effect of the lights was negligible and the UDF’s retained its strong protective effect.