bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium in elderly patients undergoing craniotomy: a protocol of randomised clinical trial
Authors: Cui Qianyu , Ma Tingting , Liu Minying , Shen Zhongyuan , Li Shu , Zeng Min , Liu Xiaoyuan , Zhang Liyong , Peng Yuming
Published: January 2023

Introduction

Postoperative delirium (POD) is a common surgical complication. The incidence is 19% in neurological procedures, and advanced age is a risk factor for neurological procedures. Many studies have shown that dexmedetomidine (DEX) reduced the incidence of delirium after non-cardiac surgery in elderly patients. However, there are few studies focus on the effect of DEX on POD in elderly patients undergoing neurosurgery.

Methods and analysis

This is a randomised, double-blinded, paralleled-group and controlled trial. Patients older than 65 years and scheduled for elective craniotomy will be randomly assigned to the DEX group and the control group. After endotracheal intubation, patients in the DEX group will be administered with continuous DEX infusion at rate of 0.4 µg/kg/hour until the surgical haemostasis. In the control group, patients will receive the identical volume of normal saline in the same setting. The primary outcome is the incidence of POD during the first 5 days. Delirium will be evaluated through a combination of three methods, including the Richmond Agitation Sedation Scale (RASS), the confusion assessment method for ICU (CAM-ICU) and the 3 min diagnostic interview for CAM (3D-CAM). The RASS, CAM-ICU and 3D-CAM will be evaluated two times per day (08:00–10:00 and 18:00–20:00 hours) during the first postoperative 5 days. Secondary outcomes include pain severity score, quality of recovery, quality of sleep, cognitive function, psychological health state, intraoperative data, physiological status, length of stay in ICU and hospital, hospitalisation costs, non-delirium complications, and 30-day all-cause mortality.

Ethics and dissemination

The protocol (V.4.0) has been approved by the medical ethics committee of Beijing Tiantan Hospital, Capital Medical University (KY2021-194-03). The findings of the study will be disseminated in a peer-reviewed journal and at a scientific conference.

Trial registration number

NCT05168280.
Changes in consultation mode during different phases of the COVID-19 pandemic in Croatian family medicine: a cross-sectional study
Authors: Vučak Jasna , Popovic Branislava , Ljubotina Aleksandar , Vojvodić Željko , Sabljak Diana , Zavidić Tina
Published: January 2023

Objectives

To describe the changes in the type, length and reasons for consultations in primary healthcare during the COVID-19 pandemic in Croatia. This study aimed to test a hypothesis regarding the increased workload of general practitioners (GPs) by introducing more virtual consultations (VCs).

Design

The study design was cross-sectional and comprised two phases: retrospective and prospective. The retrospective phase included data from April, May and June of 2019, 2020 and 2021, and the prospective phase included data from 2 weeks in June 2021. Additionally, the number, length and reasons for face-to-face consultations (FTFC), VCs and telephone consultations (TCs) with nurses were collected.

Setting and participants

Overall, 6 GPs from different regions in Croatia with 10 125 enlisted patients.

Main outcomes measures

The retrospective phase compared data for consultation types obtained from electronic medical records. The prospective phase collected the number, length and reasons for FTFCs, VCs and TCs with nurses.

Results

FTFCs decreased from 58.1% of the total number of visits in 2019 to 41.2% in 2020, while VC increased from 41.9% in 2019 to 58.8% in 2020. Furthermore, an eightfold increase in email consultations was recorded. The average lengths of an FTFC and TC were 7.13±3.38 and 4.01±2.09 min, respectively; FTFCs were significantly longer than TCs (t=7.038, p<0.0001). There was an increase in the total workload (9.4%) in 2021 compared with 2019.

Conclusion

Croatian GPs faced changes in work organisation along with increased workload during the pandemic. Despite the shortening of time in FTFCs, the workload has increased due to the increase in VCs. An appropriate legal framework should be implemented for this new form of consultation. Future research is needed to address the impact of these changes on healthcare quality.
Overcoming roadblocks in clinical innovation via high fidelity simulation: use of a phantom simulator to achieve FDA and IRB approval of a clinical trial of fetal embolization of vein of Galen malformations
Authors: Orbach Darren B , Wilkins-Haug Louise E , Benson Carol B , Rangwala Shivani D , Pak Christopher , Saffarzadeh Mona , Weinstock Peter
Published: January 2023

Background

Vein of Galen malformation (VOGM) is a rare, life-threatening vascular malformation in neonates and is treated with embolization. However, even at the most experienced centers, patients face high mortality and morbidity. In utero treatment options have been limited by lack of animal models or simulations.

Objective

To create a novel ultrasound phantom simulator for a preclinical feasibility study of in utero fetal intervention for VOGM.

Methods

Novel phantoms were designed and built in two configurations of spherical and windsock shape from cryogel material to mimic the salient vasculature of the fetal VOGM, based on real-patient fetal MR imaging dimensions. Critical anatomy was realistically mimicked within this model and transtorcular ultrasound-guided coil deployment was simulated. Each phantom model was assessed before and after treatment to evaluate coil mass deposition within the target.

Results

The two phantoms underwent pretreatment T2-weighted MR imaging assessment, ultrasound-guided embolization, post-treatment MR and fluoroscopic imaging, and visual inspection of the sliced phantoms for target embolization verification. Postoperative MR scans confirmed realistic compact deposition of the coil masses within the central cavity. Phantom embolization results were submitted as part of the institutional review board and US Food and Drug Administration investigative device exemption approval for a first-in-humans clinical trial of fetal intervention for VOGM.

Conclusions

A phantom simulator for fetal intervention of VOGM produces lifelike results during trial interventions, removing obstacles to feasibility and safety evaluations, typically precluded by non-availability of appropriate animal models. The study provides a proof of concept for potentially wider applications of medical simulation to enable novel procedural advancements in neurointerventions.
Gallic acid markedly stimulates GLUT1-mediated glucose uptake by the AsPC-1 pancreatic cancer cell line
Authors: Torres Sílvia M. , Carmo Francisca P. , Monteiro Luís C. , Silva Cláudia , Andrade Nelson , Martel Fátima
Published: January 2023

Phenolic acids are recognized as chemopreventive and chemotherapeutic agents. Altered glucose and glutamine metabolism are recognized hallmarks of cancer cells. We aimed to test the influence of phenolic acids on glucose and glutamine cellular uptake by a breast (MCF-7) and a pancreatic (AsPC-1) cancer cell line. Several phenolic acids (caffeic, ferrulic, proctocatechuic, coumaric and gallic acid) affected 3H-glutamine and/or 3H-deoxy-d-glucose (3H-DG) uptake. Gallic acid (100 µM) caused a 3-fold increase in 3H-DG uptake by AsPC-1 cells, associated with a 3.7-fold increase in lactic acid production. Gallic acid stimulated GLUT1-mediated 3H-DG uptake and increased the affinity of this transporter for 3H-DG. We further verified that gallic acid does not change GLUT1 transcription rates and cellular redox state and that its effect does not involve PI3K, mTOR and MAP kinases and is not associated with a proproliferative effect. Gallic acid also increased 3H-DG uptake by MCF-7 cells, although less potently. Further investigation is necessary to elucidate the cellular pathways involved in this effect of gallic acid.
Arthropod and Pathogen Damage on Fossil and Modern Plants: Exploring the Origins and Evolution of Herbivory on Land
Authors: Labandeira Conrad C. , Wappler Torsten
Published: January 2023

The use of the functional feeding group–damage type system for analyzing arthropod and pathogen interactions with plants has transformed our understanding of herbivory in fossil plant assemblages by providing data, analyses, and interpretation of the local, regional, and global patterns of a 420-Myr history. The early fossil record can be used to answer major questions about the oldest evidence for herbivory, the early emergence of herbivore associations on land plants, and later expansion on seed plants. The subsequent effects of the Permian–Triassic ecological crisis on herbivore diversity, the resulting formation of biologically diverse herbivore communities on gymnosperms, and major shifts in herbivory ensuing from initial angiosperm diversification are additional issues that need to be addressed. Studies ofherbivory resulting from more recent transient spikes and longer-term climate trends provide important data that are applied to current global change and include herbivore community responses to latitude, altitude, and habitat. Ongoing paleoecological themes remaining to be addressed include the antiquity of modern interactions, differential herbivory between ferns and angiosperms, and origins of modern tropical forests. The expansion of databases that include a multitude of specimens; improvements in sampling strategies; development of new analytical methods; and, importantly, the ability to address conceptually stimulating ecological and evolutionary questions have provided new impetus in this rapidly advancing field.
The Mechanisms of Silkworm Resistance to the Baculovirus and Antiviral Breeding
Authors: Hu Zhaoyang , Zhu Feifei , Chen Keping
Published: January 2023

Silkworm ( Bombyx mori) is not only an economic insect but also a model organism for life science research. Bombyx mori nucleopolyhedrovirus (BmNPV) disease is a major infectious disease in the world's sericulture industry. The cocoon loss caused by this disease accounts for more than 60% of the total loss caused by all silkworm diseases. To date, there has been no effective solution for preventing and treating this disease. The most effective measure is to breed disease-resistant varieties. The quickest way to breed disease-resistant varieties is to apply genetic modification. However, this requires that we obtain disease resistance genes and know the mechanism of disease resistance. Since the discovery of disease-resistant resources in 1989, scholars in the sericulture industry around the world have been inspired to search for resistance genes. In the past two decades, with the help of multi-omics technologies, screening of resistance genes, gene localization, protein modification, virus–host interactions, etc., researchers have found some candidate genes that have been proposed to function at the cellular or individual level. Several disease-resistant varieties have been obtained and used in production through hybrid breeding, RNA interference, and genetic modification. This article summarizes and reviews the discovery of and research advances related to silkworm resistance to BmNPV. It is anticipated that the review will inspire scientific researchers to continue searching for disease resistance genes, clarify the molecular mechanism of silkworm disease resistance, and promote disease-resistant silkworm breeding.
Laying the Foundation for the Challenge–Hindrance Stressor Framework 2.0
Authors: Podsakoff Nathan P. , Freiburger Kristen J. , Podsakoff Philip M. , Rosen Christopher C.
Published: January 2023

Although traditional views of workplace stress assume that all job demands have deleterious consequences, research indicates that some job demands may benefit employees. Notably, the Challenge–Hindrance Stressor Framework (CHSF) proposes that, although job demands that constrain, hinder, or thwart personal growth and achievement (hindrance stressors) have negative effects on work-related outcomes, job demands that provide the potential for personal growth and achievement (challenge stressors) have positive effects on these outcomes. Despite the attention generated by the CHSF, several criticisms and limitations hinder the potential of this framework. Thus, this article reviews our current understanding of the CHSF, addresses important criticisms about the nature and effects of challenge and hindrance stressors, and discusses how future research should approach conceptual and methodological challenges to lay the foundation for the next iteration of this framework—CHSF 2.0. Building on this new framework, we discuss some implications for cross-cultural research and for practitioners.
Mitochondrial creatine sensitivity is lost in the D2.mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime
Authors: Bellissimo Catherine A. , Delfinis Luca J. , Hughes Meghan C. , Turnbull Patrick C. , Gandhi Shivam , DiBenedetto Sara N. , Rahman Fasih A. , Tadi Peyman , Amaral Christina A. , Dehghani Ali , Cobley James N. , Quadrilatero Joe , Schlattner Uwe , Perry Christopher G.R.
Published: January 2023

Duchenne muscular dystrophy (DMD) is associated with distinct mitochondrial stress responses. Here, we aimed to determine whether the prospective mitochondrial-enhancing compound Olesoxime, prevents early-stage mitochondrial stress in limb and respiratory muscle from D2. mdx mice using a proof-of-concept short-term regimen spanning 10–28 days of age. As mitochondrial-cytoplasmic energy transfer occurs via ATP- or phosphocreatine-dependent phosphate shuttling, we assessed bioenergetics with or without creatine in vitro. We observed that disruptions in Complex I-supported respiration and mH2O2 emission in D2. mdx quadriceps and diaphragm were amplified by creatine demonstrating mitochondrial creatine insensitivity manifests ubiquitously and early in this model. Olesoxime selectively rescued or maintained creatine sensitivity in both muscles, independent of the abundance of respiration-related mitochondrial proteins or mitochondrial creatine kinase cysteine oxidation in quadriceps. Mitochondrial calcium retention capacity and glutathione were altered in a muscle-specific manner in D2. mdx but were generally unchanged by Olesoxime. Treatment reduced serum creatine kinase (muscle damage) and preserved cage hang-time, microCT-based volumes of lean compartments including whole body, hindlimb and bone, recovery of diaphragm force after fatigue, and cross-sectional area of diaphragm type IIX fiber, but reduced type I fibers in quadriceps. Grip strength, voluntary wheel-running and fibrosis were unaltered by Olesoxime. In summary, locomotor and respiratory muscle mitochondrial creatine sensitivities are lost during early stages in D2. mdx mice but are preserved by short-term treatment with Olesoxime in association with specific indices of muscle quality suggesting early myopathy in this model is at least partially attributed to mitochondrial stress.
Ion dynamics and the regulation of circadian cellular physiology
Authors: Stangherlin Alessandra
Published: January 2023

Circadian rhythms in physiology and behavior allow organisms to anticipate the daily environmental changes imposed by the rotation of our planet around its axis. Although these rhythms eventually manifest at the organismal level, a cellular basis for circadian rhythms has been demonstrated. Significant contributors to these cell-autonomous rhythms are daily cycles in gene expression and protein translation. However, recent data revealed cellular rhythms in other biological processes, including ionic currents, ion transport, and cytosolic ion abundance. Circadian rhythms in ion currents sustain circadian variation in action potential firing rate, which coordinates neuronal behavior and activity. Circadian regulation of metal ions abundance and dynamics is implicated in distinct cellular processes, from protein translation to membrane activity and osmotic homeostasis. In turn, studies showed that manipulating ion abundance affects the expression of core clock genes and proteins, suggestive of a close interplay. However, the relationship between gene expression cycles, ion dynamics, and cellular function is still poorly characterized. In this review, I will discuss the mechanisms that generate ion rhythms, the cellular functions they govern, and how they feed back to regulate the core clock machinery.
Core-EP-Nilpotent Decomposition and Its Applications
Authors: Zhang Yang , Jiang Zongyang
Published: January 2023

We give the illustration of a new decomposition: the core-EP-nilpotent decomposition, which is on the basis of the core-EP decomposition and EP-nilpotent decomposition for some square matrices in this thesis. According to the new decomposition, we show the definitions and characteristics of two new orders: core-E-N partial order and core-E-S partial order. We also illustrate relations of the two orders under some restricted conditions.
Implementation of Uterine Artery Doppler Scanning: Improving the Care of Women and Babies High Risk for Fetal Growth Restriction
Authors: Ekanem Emmanuel , Karouni Faris , Katsanevakis Emmanuoil , Kapaya Habiba
Published: January 2023

Introduction. While stillbirth rates have declined in many countries, these declines are less marked in the UK. Fetal growth restriction (FGR) affects about 3% to 7% of all pregnancies and is by far the single strongest risk factor for stillbirth. FGR implies a pathological restriction of the genetic growth potential and is not synonymous with small-for-gestational age (SGA). The Royal College of Obstetricians and Gynaecologists (RCOG) defines SGA as an estimated fetal weight (EFW) or abdominal circumference (AC) less than the 10th centile. The likelihood of FGR is higher in severe SGA defined as an EFW or AC less than the 3rd centile. The second version of Saving Babies’ Lives Care Bundle (SBLCBv2) recommends the second trimester uterine artery Doppler (UtAD) pulsatility index (PI) screening for pregnancies at high risk of FGR. This study was aimed at determining the prevalence of FGR and assess pregnancy outcomes following the implementation of UtAD at the United Lincolnshire Hospitals NHS Trust (ULHT). Methods. One-year retrospective cohort study (1st September 2020-31st August 2021) was conducted across both ULHT hospitals in the UK (Lincoln County Hospital in Lincoln and Pilgrim Hospital in Boston). Results. During the study period, 5197 women were booked at ULHT. Of 5197, 349 were identified as high risk for FGR. When numbers were compared for the two hospitals, FGR rate was higher in Lincoln 8.10% vs. 4.51% in Boston. In addition, an increased proportion of abnormal UtAD scans was observed in Lincoln (35.7%) vs. in Boston (22%) (

P
=
0.014

). Of the 349 UtAD scans, 237 were normal (67.9%), 41 showed unilateral notching (11.7%), 43 bilateral notching (12.3%), and 28 raised PI (8%). Babies in the bilateral notching group exhibited the lowest birth weight (

P
=
0.005

), born at an earlier gestation (

P
=
0.029

), and with low Apgar scores at 1 (

P
=
0.007

) and 5 minutes (

P
<
0.001

). Discussion. UtAD is a useful second trimester screening tool for women identified as high risk for FGR and helps stratify the intensity of surveillance. However, the findings call into question a focus solely on the UtAD PI for improving FGR detection without taking into account bilateral notching.
Coexpression of PD-L1/PD-1 with CXCR3/CD36 and IL-19 Increase in Extranodal Lymphoma
Authors: Saber Manal Mohamed
Published: January 2023

Many studies have demonstrated that PD-L1/PD-1 signaling is an immune evasion mechanism in tumors. PD-L1/PD-1 coexpression with CXCR3/CD36 in peripheral lymphocytes in lymphoma still needs to be clarified. The current study investigated PD-L1/PD-1 coexpression with CXCR3/CD36 in circulating lymphocytes, serum IL-19 levels, and their correlation with clinical outcome and extranodal involvement in lymphoma. Subjects and Methods. The coexpression of PD-L1/PD-1 with CXCR3/CD36 on circulating lymphocytes was analyzed by flow cytometry in 78 lymphoma patients before and after therapy and in 50 healthy controls. The concentration levels of IL-19 in serum were assessed by an ELISA. Results. PD-L1 and PD-1 were expressed on circulating CXCR3+ and CD36+ lymphocytes in lymphoma and were significantly higher in patients with extranodal involvement than in lymphoma patients without extranodal involvement (

P
<
0.001

). Elevated IL-19 levels were observed in lymphoma patients and increased significantly in extranodal involvement (

P
<
0.001

). High percentages of PD-L1+CXCR3+ and PD-1+CXCR3+ lymphocytes were associated with high LDH levels, hepatomegaly, lymphedema, advanced tumor stage, and recurrence. Furthermore, patients with splenomegaly and generalized lymphadenopathy had high percentages of PD-L1+CXCR3+ lymphocytes. In addition, levels of PD-L1/PD-1 coexpression with CXCR3 and IL-19 were significantly associated with bone marrow, lung, and lymph vessel involvement. Further analysis revealed that high percentages of PD-L1+CD36+ and PD-1+CD36+ lymphocytes were associated with lung and bone marrow involvement. Patients with high levels of PD-L1/PD-1 coexpression with CXCR3 and IL-19 had inferior event-free survival (EFS) compared with that in lymphoma patients with low levels. EFS was decreased in patients with high percentages of PD-L1+CD36+ and PD-1+CD36+ lymphocytes. When using the receiver operating characteristic (ROC) curve, the superiority of IL-19 (area under the curve (AUC): 0.993) and PD-L1+CXCR3+% (AUC: 0.961) to PD-1+CXCR3+% (AUC: 0.805), PD-L1+CD36+% (AUC: 0.694), and PD-1+CD36+% (AUC 0.769) was evident in the diagnosis of extranodal involvement, identifying lymphoma patients with extranodal involvement from patients without extranodal involvement. Conclusions. Coexpression of PD-L1/PD-1 with CXCR3/CD36 in circulating lymphocytes and serum IL-19 levels contributes to poor prognosis and might be potential markers for extranodal involvement in lymphoma.
Shifting to Trauma-Informed Care in Inpatient Psychiatry: A Case Study of an Individual with Dissociative PTSD Undergoing EMDR Therapy
Authors: Winkler Olga , Burback Lisa , Greenshaw Andrew J. , Jin Jonathan
Published: January 2023

Caring for patients with personality disorders can be challenging due to risks associated with suicidal ideation, homicidal threats, splitting, and acting out with problematic behavior in psychiatric inpatient units. Limited resources on inpatient units further add to the stress and burden on staff. This case summarizes how trauma-informed care was implemented in an inpatient setting to produce marked improvement in a patient’s treatment outcomes as well as better staff engagement and satisfaction. This culture change in the approach to care was not an easy process, as effortful planning and resources were required for key elements such as ongoing coaching, education, and regular staff debriefings. This case report signals the need for service providers to enable health systems to examine rules and exceptions from a cultural perspective of considering equity, diversity, and inclusion (EDI)—to allow openness to rational exceptions, even if they are unconventional.
Colorimetry‐Based Phosphate Measurement for Polymerase Elongation
Authors: Yang Han , Ji Xiaoxin , Li Xiao , Feng Yunran , Zhang Ke , Guo Xuemin , Zhong Zhixiong , Mu Xin
Published: January 2023

DNA detection, which includes the measurement of variants in sequences or the presence of certain genes, is widely used in research and clinical diagnosis. Both require DNA‐dependent DNA polymerase‐catalyzed strand extension. Currently, these techniques rely heavily on the instruments used to visualize the results. This study introduced a simple and direct colorimetric method to measure polymerase‐directed elongation. First, pyrophosphate (PPi), a by‐product of strand extension, is converted into phosphate (Pi). Phosphate levels were measured using either Mo‐Sb or BIOMOL Green reagent. This study showed that this colorimetry can distinguish single‐base variants and detect PCR products in preset stringent conditions, implicating the potential value of this strategy to detect DNA.
Exosome-Associated Gene Signature for Predicting the Prognosis of Ovarian Cancer Patients
Authors: Zhu Zihan , Geng Rui , Zhang Yixin , Liu Jinhui , Bai Jianling
Published: January 2023

Background. The exosome is of vital importance throughout the entire progression of cancer. Because of the lack of effective biomarkers in ovarian cancer (OV), we intend to investigate the connection between exosomes and tumor immune microenvironment to verify that exosome-related genes (ERGs) can precisely forecast the prognosis of OV patients. Methods. First, 117 ERGs in The Cancer Genome Atlas (TCGA) dataset were recognized. Afterwards, the risk signature consisting of four ERGs with prognostic significance was built by univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. We also validated the risk signature by Kaplan-Meier analysis, receiver operating characteristic curve analysis and principal component analysis. Furthermore, gene set enrichment analysis was performed to compare the enrichment patterns between the two risk subgroups. The connections between the exosome-related gene risk score (ERGRS) and clinical features, immune infiltration, immune checkpoint-related genes, copy number variation, and drug sensitivity were explored. We also assessed the function of the ERGRS to forecast immunotherapeutic efficacy by immunophenoscore (IPS). Results. The high-risk group had a worse prognosis than the group with low risk. We verified that the established model possessed a relatively good prognostic value. Pathway enrichment analysis indicated that the genome-wide group with low risk was enriched in immune-related pathways. We discovered that resting dendritic cells and stromal scores were upregulated in patients with high risk in the TCGA and Gene Expression Omnibus (GEO) cohorts. Moreover, the expression of six common immune checkpoint inhibitor targets was assessed, which revealed that the expression levels of CD274 (PD-L1), PDCD1 (PD-1), and IDO1 in patients with high risk were lower than those in patients with low risk. Afterwards, the low-risk group had higher IPS across the four immunotherapies, implying that it had better effects of immunotherapies. Conclusion. Our study demonstrates that the exosome-related gene risk model is closely associated with immune infiltration. It can well forecast the prognosis of OV patients and guide the selection of immunotherapeutic strategies.
Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: January 2023

Purpose:

Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.

Experimental Design:

Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms.

Results:

Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance.

Conclusions:

CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1–NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors.
Considerations for Drug Development in Myelodysplastic Syndromes
Authors: Sekeres Mikkael A. , Kim Nina , DeZern Amy E. , Norsworthy Kelly J. , Garcia Jacqueline S. , de Claro R. Angelo , Theoret Marc R. , Jen Emily Y. , Ehrlich Lori A. , Zeidan Amer M. , Komrokji Rami S.
Published: January 2023

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients’ lives over existing therapies.
Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade
Authors: Pearce Hayden , Croft Wayne , Nicol Samantha M. , Margielewska-Davies Sandra , Powell Richard , Cornall Richard , Davis Simon J. , Marcon Francesca , Pugh Matthew R. , Fennell Éanna , Powell-Brett Sarah , Mahon Brinder S. , Brown Rachel M. , Middleton Gary , Roberts Keith , Moss Paul
Published: January 2023

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti–PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
Transition of Extremely Preterm Infants from Birth to Stable Breathing: A Secondary Analysis of the CORSAD Trial
Authors: Donaldsson Snorri , Palleri Elena , Jonsson Baldvin , Drevhammar Thomas
Published: January 2023

Objective: Exploratory secondary analysis of the CORSAD trial compared a new resuscitation system (rPAP) to the standard T-piece system. This analysis focused on the subgroup of infants who were not intubated in the delivery room. The aim was to compare the use of noninvasive positive pressure ventilation (PPV), oxygen saturation, and Apgar scores for the two resuscitation systems during the 30-min intervention period. Methods: This is secondary analysis of CORSAD trial using data from the intervention period in the delivery room. Infants in the original randomized system groups were divided into intubated and nonintubated groups. For nonintubated breathing infants, we compared demographics, the use of PPV, Apgar scores, and oxygen saturation at 5 and 10 min after birth. Generalized linear models were applied to calculate the risk difference and odds ratio with 95% CI between the two groups. Results: Among nonintubated infants, the use of PPV repeatedly (defined as PPV with at least 1 min of spontaneous breathing between PPV cycles) was less frequent in the rPAP group (26.8% vs. 43.3%, %RD −16.5, 95% CI [−31.7 to −1.1], p 0.04). The use of PPV after 5 min of age was also less common in the rPAP group (23.2% vs. 38.8%, %RD −15.6, 95% CI [−30.7 to −0.8], p 0.04). There were no statistically significant differences in Apgar scores or oxygen saturation levels between the groups. Conclusion: In the CORSAD trial, less PPV was needed to establish stable breathing in extremely preterm infants using the rPAP compared to using the standard T-piece without significant difference in Apgar scores or oxygenation.
Targeted Next-Generation Sequencing for the Diagnosis of Gene Variants in Patients with 46,XY Disorder of Sex Development
Authors: Guo Qiang , Zhong Wen Wen , Lai Hua Jian , Ye Lei , Zhang Yi Fei , Li Jun Tao , Qiu Jian Guang , Wang De Juan
Published: January 2023

Introduction: Disorders of sex development (DSDs) are congenital abnormalities in which chromosomal, gonadal, and anatomical sex development are atypical. One of these disorders, 46,XY DSD, is particularly difficult to diagnose and manage because its etiology and clinical phenotypes are highly heterogeneous. Methods: We used a gene panel containing 141 genes implicated in DSDs to perform targeted next-generation sequencing (NGS) in 50 patients with 46,XY DSD. Results: Gene variants were detected in 23 patients (46%). Among them, 13 patients had previously reported pathogenic or likely pathogenic variants, 9 patients had novel variants, and 1 patient had a previously reported variant of uncertain significance. Three of the novel variants were pathogenic, and the remaining were variants of uncertain significance; therefore, 16 patients had pathogenic or likely pathogenic variants according to ACMG guidelines, and the overall diagnostic rate of 46,XY DSD was 32%. The most common gene variants were SRD5A2 variants, followed by the AR variant. In addition, we analyzed the association between gene variants and clinical phenotypes. Most patients presented with multiple DSD phenotypes (i.e., two or more DSD phenotypes were observed, such as micropenis, hypospadias, and cryptorchidism), but the phenotype with the highest diagnostic rate was micropenis. Conclusion: Our results indicate that targeted NGS can effectively detect pathogenic gene variants in patients with 46,XY DSD.
Air versus Perfluoropropane Gas in Pars Plana Vitrectomy for Primary Rhegmatogenous Retinal Detachment: A 3-Year Retrospective Study
Authors: Qian Tianwei , Suo Yan , Ma Yingyan , Chen Chong , Liu Kun , Chen Feng'e , Fan Ying , Wang Weijun , Xu Xun
Published: January 2023

Introduction: This study aimed to compare anatomical outcomes of air and perfluoropropane gas (C3F8) tamponade in pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment (RRD). Methods: In this retrospective study, data were gathered from 578 patients (578 eyes) with RRD. The follow-up records of all 578 patients that underwent primary vitrectomy for RRD with air or C3F8 were examined and analyzed. Surgical outcomes of the two groups were compared. Results: A total of 342 eyes were treated with air and 236 with C3F8. The mean follow-up period was 37.65 ± 2.33 months. Baseline and preoperative clinical characteristics were similar between groups, but the period to intraocular bubble disappearance (p < 0.0001), intraocular pressure on the first postoperative day (p < 0.0001), number of cases with intraocular pressure >21 mm Hg within 3 days post-surgery (p < 0.0001), and the number with intraocular pressure >21 mm Hg during follow-up (p = 0.0002) differed significantly between groups. Primary reattachment rates for air and C3F8 groups were 95.03% and 95.34%, respectively. Clinical characteristics were similar in those with and without successful reattachment, and the frequency of new or unclosed breaks was similar between the two groups. There was no significant difference in two groups according to the presence or absence of inferior retinal breaks and inferior detached quadrants. Univariate and multivariate logistic regression identified no risk factor for surgical failure. Conclusions: Air showed equivalent effects to C3F8, with a shorter period to intraocular bubble disappearance, less risk of postoperative intraocular hypertension, and less expense.
Surgical Management and Mechanical Circulatory Support in High-Risk Pulmonary Embolisms: Historical Context, Current Status, and Future Directions: A Scientific Statement From the American Heart Association
Authors: Goldberg Joshua B. , Giri Jay , Kobayashi Taisei , Ruel Marc , Mittnacht Alexander J.C. , Rivera-Lebron Belinda , DeAnda Abe , Moriarty John M. , MacGillivray Thomas E. ,   on behalf of the American Heart Association Council on Cardiovascular Surgery and Anesthesia; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Published: January 2023

Acute pulmonary embolism is the third leading cause of cardiovascular death, with most pulmonary embolism–related mortality associated with acute right ventricular failure. Although there has recently been increased clinical attention to acute pulmonary embolism with the adoption of multidisciplinary pulmonary embolism response teams, mortality of patients with pulmonary embolism who present with hemodynamic compromise remains high when current guideline-directed therapy is followed. Because historical data and practice patterns affect current consensus treatment recommendations, surgical embolectomy has largely been relegated to patients who have contraindications to other treatments or when other treatment modalities fail. Despite a selection bias toward patients with greater illness, a growing body of literature describes the safety and efficacy of the surgical management of acute pulmonary embolism, especially in the hemodynamically compromised population. The purpose of this document is to describe modern techniques, strategies, and outcomes of surgical embolectomy and venoarterial extracorporeal membrane oxygenation and to suggest strategies to better understand the role of surgery in the management of pulmonary embolisms.
Abnormal Conduction Zone Detected by Isochronal Late Activation Mapping Accurately Identifies the Potential Atrial Substrate and Predicts the Atrial Fibrillation Ablation Outcome After Pulmonary Vein Isolation
Authors: Kuo Ming-Jen , Ton An Nu-Khanh , Lo Li-Wei , Lin Yenn-Jiang , Chang Shih-Lin , Hu Yu-Feng , Chung Fa-Po , Tuan Ta-Chuan , Chao Tze-Fan , Liao Jo-Nan , Chang Ting-Yung , Lin Chin-Yu , Kuo Ling , Wu Cheng-I , Liu Chih-Min , Cheng Wen-Han , Liu Shin-Huei , Chhay Chheng , Kao Pei-Heng , Chen Wei-Tso , Hsu Chu-Yu , Chen Shih-Ann
Published: January 2023

Background:

The presence of abnormal substrate of left atrium is a predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. We aimed to investigate the isochronal late activation mapping to access the abnormal conduction velocity for predicting AF ablation outcome.

Methods:

Forty-five paroxysmal AF patients (30 males, 57.8±8.7 years old) who underwent pulmonary vein isolation were enrolled. Isochronal late activation mapping was retrospectively constructed with 2 different windows of interest: from onset of P wave to onset of QRS wave on surface electrocardiography (W1) and 74 ms tracking back from the end of P wave (W2). Deceleration zone was defined as regions with 3 isochrones (DZa) or ≥4 isochrones (DZb) within a 1 cm radius on the isochronal late activation mapping, and the estimated conduction velocity (ECV) are 0.27 m/s and <0.20 m/s for DZa and DZb, respectively in W2. The distribution of deceleration zone was compared with the location of low-voltage zone (bipolar voltage ≤0.5 mV). Any recurrence of atrial arrhythmias was defined as the primary end point during follow ups after a 3-month blanking period.

Results:

Pulmonary vein isolation was performed in all patients, and there were 2 patients (4.4%) received additional extrapulmonary vein ablation. After a mean follow-up of 12.7±4.5 months, recurrence of AF occurred in 14 patients (31.1%). Patients with the presence of DZb in W2 had higher AF recurrence (Kaplan-Meier event rate estimates: HR, 9.41 [95% CI, 2.61–33.90]; log-rank
P
<0.0001). There were 52.6% of the DZb locations in W2 comparable to the distributions of low-voltage zone and 47.4% DZb were distributed in the area without low-voltage zone.

Conclusions:

Deceleration zone detected by isochronal late activation mapping represents a critical AF substrate, it accurately predicts the AF recurrence following ablation in patients with paroxysmal AF.
Validity of International Classification of Diseases (ICD)-10 Diagnosis Codes for Identification of Acute Heart Failure Hospitalization and Heart Failure with Reduced Versus Preserved Ejection Fraction in a National Medicare Sample
Authors: Bates Benjamin A. , Akhabue Ehimare , Nahass Meghan M. , Mukherjee Abhigyan , Hiltner Emily , Rock Joanna , Wilton Brandon , Mittal Garima , Visaria Aayush , Rua Melanie , Gandhi Poonam , Dave Chintan V. , Setoguchi Soko
Published: January 2023

Background:

Heart failure (HF) is a leading cause of hospitalization in older adults. Medicare data have been used to assess HF outcomes. However, the validity of ICD-10 diagnosis codes (used since 2015) to identify acute HF hospitalization or distinguish reduced (heart failure with reduced ejection fraction) versus preserved ejection fraction (HFpEF) is unknown in Medicare data.

Methods:

Using Medicare data (2015–2017), we randomly sampled 200 HF hospitalizations with ICD-10 diagnosis codes for HF in the first/second claim position in a 1:1:2 ratio for systolic HF (I50.2), diastolic HF (I50.3), and other HF (I50.X). The primary gold standards included recorded HF diagnosis by a treating physician for HF hospitalization, ejection fraction (EF)≤50 for heart failure with reduced ejection fraction, and EF>50 for HFpEF. If the quantitative EF was not present, then qualitative descriptions of EF were used for heart failure with reduced ejection fraction/HFpEF gold standards. Multiple secondary gold standards were also tested. Gold standard data were extracted from medical records using standardized forms and adjudicated by cardiology fellows/staff. We calculated positive predictive values with 95% CIs.

Results:

The 200-chart validation sample included 50 systolic, 50 diastolic, 47 combined dysfunction, and 53 unspecified HF patients. The positive predictive values of acute HF hospitalization was 98% [95% CI, 95–100] for first-position ICD-10 HF diagnosis and 66% [95% CI, 58–74] for first/second-position diagnosis. Quantitative EF was available for ≥80% of patients with systolic, diastolic, or combined dysfunction ICD-10 codes. The positive predictive value of systolic HF codes was 90% [95% CI, 82–98] for EFs≤50% and 72% [95% CI, 60–85] for EFs≤40%. The positive predictive value was 92% [95% CI, 85–100] for HFpEF for EFs>50%. The ICD-10 codes for combined or unspecified HF poorly predicted heart failure with reduced ejection fraction or HFpEF.

Conclusions:

ICD-10 principal diagnosis identified acute HF hospitalization with a high positive predictive value. Systolic and diastolic ICD-10 diagnoses reliably identified heart failure with reduced ejection fraction and HFpEF when EF 50% was used as the cutoff.
Effects of Ablation Versus Drug Therapy on Quality of Life by Sex in Atrial Fibrillation: Results From the CABANA Trial
Authors: Zeitler Emily P. , Li Yanhong , Silverstein Adam P. , Russo Andrea M. , Poole Jeanne E. , Daniels Melanie R. , Al‐Khalidi Hussein R. , Lee Kerry L. , Bahnson Tristram D. , Anstrom Kevin J. , Packer Douglas L. , Mark Daniel B. ,   for the CABANA Investigators
Published: January 2023

Background

Women with atrial fibrillation (AF) demonstrate more AF‐related symptoms and worse quality of life (QOL). Whether increased use of ablation in women reduces sex‐related QOL differences is unknown. Sex‐related outcomes for ablation versus drug therapy was a prespecified analysis in the CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial.

Methods and Results

Symptoms were assessed periodically over 60 months with the Mayo AF‐Specific Symptom Inventory (MAFSI) frequency score, and QOL was assessed with the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary and component scores. Women had lower baseline QOL scores than men (mean AFEQT scores 55.9 and 65.6, respectively). Ablation patients improved more than drug therapy patients with similar treatment effect by sex: AFEQT 12‐month mean adjusted treatment difference in women 6.1 points (95% CI, 3.5–8.6) and men 4.9 points (95% CI, 3.0–6.9). Participants with baseline AFEQT summary scores <70 had greater QOL improvement, with a mean treatment difference at 12 months of 7.6 points for women (95% CI, 4.3–10.9) and 6.4 points for men (95% CI, 3.3–9.4). The mean adjusted difference in MAFSI frequency score between women randomized to ablation versus drug therapy at 12 months was −2.5 (95% CI, −3.4 to −1.6); for men, the difference was −1.3 (95% CI, −2.0 to −0.6).

Conclusions

Compared with drug therapy for AF, ablation resulted in more QOL improvement in both sexes, primarily driven by improvements in those with lower baseline QOL. Ablation did not eliminate the AF‐related QOL gap between women and men.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00911508.