bluuebunny/crossref_metadata_2025 huggingface dataset:
How to be a GREAT mentor
Authors: Davis Jamaine S. , Sakwe Amos M. , Ramesh Aramandla , Lindsey Merry L. , Woods Letha
Published: June 2023

We provide here a framework to develop as a mentor, using the GREAT model. This includes giving opportunities and opening doors; reaching out to help students identify their strengths and reach their goals; encouraging them by serving as a positive example; advising each mentee as an individual; and training them for independent thinking.
Formative assessment and student understanding of structure-function
Authors: Carter Kelli P. , Prevost Luanna B.
Published: June 2023

Formative assessment provides feedback to both students and instructors about the process of learning. The core concept structure-function provides a foundation upon which many topics in anatomy and physiology can be built across all levels of organization. This study contributes to existing research about student conceptual understanding of the core concepts. Implications for practitioners include the design of formative assessments and a suite of questions to be used to gauge student understanding of structure-function.
Elevated renal afferent nerve activity in a rat model of endothelin B receptor deficiency
Authors: Becker Bryan K. , Grady Caroline M. , Markl Alexa E. , Torres Rodriguez Alfredo A. , Pollock David M.
Published: June 2023

Here, we found that endothelin B receptors are an important contributor to renal afferent nerve responsiveness to a high-salt diet. Rats lacking endothelin B receptors have increased afferent nerve activity that is not responsive to a high-salt diet.
Muscle fascicle and sarcomere adaptation in response to Achilles tendon elongation in an animal model
Authors: Hoeffner Rikke , Svensson Rene B. , Dietrich-Zagonel Franciele , Schefte Daniel , Kjær Michael , Eliasson Pernilla , Magnusson S. Peter
Published: June 2023

Following acute Achilles tendon rupture, patients are often left with functional deficits. The specific reason remains largely unknown. The shortened muscle leads to reduced fascicle length, in turn leading to adaptation by reduced serial sarcomere numbers. Surprisingly, this adaptation appears to “overshoot” and lead to increased sarcomere length. The present animal model advances understanding of how muscle sarcomeres, which are difficult to measure in humans, are affected when undue elongation takes place after tendon rupture.
Strength Improvement of Black Cotton Soil Using Plastic Bottles and Crushed Glass Wastes
Authors: Tsegaye Woldesenbet Tewodros
Published: June 2023

The aim of this study was to improve the strength of black cotton soil for its suitability for road subgrade construction using wastes from plastic bottles and glass waste powders. Currently, nondecomposable wastes from plastic and glasses have become threats to the human health and the environment. This study used the wastes to replace cement, since the cost of cement raised due to energy and raw material to use as stabilizer in weak soil. The glass powder (WGP) and the plastic chips were mixed with the soil sample with a percentage by dry weight of 6%, 12%, 18%, and 24% of WGP and 2%, 4%, 6%, and 8% of plastic chips, respectively. The glass waste can be prepared similar to the soil as the requirement of test standards and plastic wastes was used as reinforcement for the soil-glass-mix; hence, its purpose was geomechanical. Laboratory tests for soil-mix physical properties and strength parameters were conducted. Soil laboratory test results proved that the natural soils were classified to A-7-5 as per the AASHTO Soil Classification System and CH as per the Unified Soil Classification System (USCS). The Unconfined Compressive Strength (UCS) improved from 91.92 kPa to 688.83 kPa, and the California Bearing Ratio (CBR) improved from 2.64 to 17.5. The improvement of subgrade soil properties was increased with increased ratios of powder glass and plastic strips. The result indicated that the two stabilizers were very effective in improving strength parameters and index parameters.
Optimal Identification for Dynamic PV Cell Parameter Based on a Data-Extension-Driven Method
Authors: Long Yun , Lu Youfei , Wang Li , Bao Tao , Chen Chen
Published: June 2023

Affected by environmental factors, equipment aging, operating status, etc., the parameters of photovoltaic (PV) models will deviate from the original setting parameters. In order to accurately identify the dynamic parameters of photovoltaics under the general simulation model, traditional parameter identification methods mainly use heuristic intelligent optimization algorithms for direct solution. Due to the limited data collected and the strong randomness of the algorithm, it is easy to make the identification accuracy and stability of photovoltaic parameters difficult to meet the requirements. To this end, this paper proposes an optimal identification method for PV dynamic parameters driven by data expansion. Firstly, the PV external characteristic data is fitted and generalized, which used the generalized regression neural network (GRNN). Then, the extended high-quality data can be used for dynamic parameter identification for PV cell. To confirm the performance of the proposed algorithm in this paper, this paper expands based on the actual external characteristic data of different proportions and uses the general PV simulation model to conduct comparative tests on various commonly used algorithms. The case studies under different scenarios show that the proposed algorithm can provide a more reliable and well-represented fitness function to the metaheuristic algorithms. Therefore, the optimization accuracy and stability of the proposed algorithm for dynamic PV cell parameter identification can be significantly improved simultaneously.
A Battery Electric Vehicle Transportation Network Design Model with Bounded Rational Travelers
Authors: Xin Xu , Zhang Tao , Li Cui , Liu Yanran , Gao Lingyu , Du Yuchuan
Published: June 2023

With governments worldwide emphasizing environmental protection and the global focus on carbon reduction, the battery electric vehicle (BEV) industry has developed rapidly. An urban transportation network with BEVs as the main form of transportation will soon become mainstream. Motivated by the abovementioned background, a BEV transportation network design problem is investigated, and a network design model is established. The model aims to minimize the system travel time of BEV transportation networks and optimize the government’s lane expansion scheme (the location and number of lanes) under a limited budget. To consider the travel characteristics of BEV drivers, the charging time, range anxiety, and bounded rationality factors are simultaneously incorporated into the model. A heuristic algorithm is designed based on the active set algorithm to obtain the local optimal solution to the actual-scale problem. Moreover, a cutting-plane method is used to convert the original problem into a different form, and a column generation technique is embedded in the abovementioned algorithm to avoid the enumeration of paths. Sensitivity analyses of different levels of rationality of BEV drivers and government investment scales are performed. The experimental results demonstrate that the model and algorithm can effectively solve the problem and provide decision support for the government in formulating transportation infrastructure construction policies.
Eupatilin Alleviates Hyperlipidemia in Mice by Inhibiting HMG-CoA Reductase
Authors: Kim Kyung-Joo , Kang Nam E. , Oh Yoon Sin , Jang Se-Eun
Published: June 2023

Artemisia princeps (family Asteraceae) is a natural product broadly used as an antioxidative, hepatoprotective, antibacterial, and anti-inflammatory agent in East Asia. In the present study, eupatilin, the main constituent of Artemisia princeps, was investigated as an antihyperlipidemic agent. Eupatilin inhibited 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HCR), an enzyme that is a therapeutic target for hyperlipidemia, in an ex vivo assay using rat liver. In addition, oral administration of eupatilin significantly lowered the serum levels of total cholesterol (TC) and triglycerides (TG) in corn oil-induced and Triton WR-1339-induced hyperlipidemic mice. These results suggest that eupatilin can alleviate hyperlipidemia by inhibiting HCR.
The Effect of Sodium Reduction and Replacement on the Chemical, Microbial, and Sensory Quality of a Traditional South African Fresh Sausage
Authors: Rautenbach Anmeri , Cluff MacDonald , Bothma Carina , Hugo Celia , Roodt Eileen , van Wyngaard Barbara , Hugo Arno
Published: June 2023

Sodium (Na) reduction and replacement were evaluated in traditional South African sausages (boerewors). The Na levels were adjusted to contain the Na inclusion limits of South African regulations for 2017 and 2019, on its own and in combination with different replacers (KCl and K-lactate). The effect of these treatments was evaluated in terms of chemical (ash, NaCl, Na, and chloride contents, pH, water activity (

a

w

), lipid oxidative stability (TBARS), colour, and thaw and cooking losses), microbial (total viable count (TVC), coliform count, and yeast and mould count), and sensory (appearance, flavour, saltiness, and texture overall liking) characteristics. Lipid oxidative stability was comparable for all the treatments no longer than 6 days at 4°C. When the boerewors treatments were frozen for 180 days, the potassium-containing models with lowered levels of NaCl, indicated better secondary lipid oxidative stability than the models containing only Na. The red colour of the boerewors treatments was all negatively influenced by sodium. Higher concentrations of NaCl had a better effect on thaw, cooking, and total losses, which in turn will have a positive effect on texture and overall acceptability. The addition of NaCl better controlled the growth of the TVC until day 6 of storage at 4°C. However, KCl was a promising replacer regarding the control of coliforms. The Na levels and NaCl replacers assisted in inhibiting microbial growth. The sensory analysis indicated that consumers were only able to distinguish the negative control from the other treatments. A shelf life of between 3 and 6 days was recommended for boerewors with the treatments evaluated in this study.
A New Hybrid Forecasting Model Based on Dual Series Decomposition with Long‐Term Short‐Term Memory
Authors: Tang Hao , Bhatti Uzair Aslam , Li Jingbing , Marjan Shah , Baryalai Mehmood , Assam Muhammad , Ghadi Yazeed Yasin , Mohamed Heba G.
Published: June 2023

In recent years, ozone (O3) has gradually become the primary pollutant plaguing urban air quality. Accurate and efficient ozone prediction is of great significance to the prevention and control of ozone pollution. The air quality monitoring network provides multisource pollutant concentration monitoring data for ozone prediction, but ozone prediction based on multisource monitoring data still faces the challenges of each station’s series of data. Aiming at the problems of low prediction accuracy and low computational efficiency in traditional atmospheric ozone concentration prediction, ozone concentration prediction using dual series decomposition was proposed by variational mode decomposition (VMD), ensemble empirical mode decomposition (EEMD), and long short‐term memory (LSTM). First, the historical data series of Nanjing air quality monitoring stations is decomposed by VMD, and then the EEMD algorithm is applied to the residual of VMD to obtain several characteristic intrinsic mode function (IMF) components; each characteristic IMF component is trained by LSTM to obtain the prediction result of each component, and then the final result can be obtained by linear superposition. The proposed method achieved the best results with R2 = 99%, MSE = 5.38, MAE = 4.54, and MAPE = 3.12. Because LSTM has strong adaptive learning ability and good memory function, it has the learning advantage of long‐term memory for long‐term data, and the prediction results are more accurate. According to the data, the proposed method is superior to the baseline models in terms of statistical metrics. As a result, the proposed hybrid method can serve as a reliable model for ozone forecasting.
Antipruritic Effects of Doxepin Cream on Experimentally Induced Histaminergic and Nonhistaminergic Itch
Authors: Aliotta Giulia Erica , Lo Vecchio Silvia , Elberling Jesper , Arendt-Nielsen Lars
Published: June 2023

Background. Itch can be transmitted by two parallel pathways, histaminergic and nonhistaminergic. Histaminergic itch is transmitted by a subgroup of mechano‐insensitive C‐fibers, while nonhistaminergic itch by a subgroup of polymodal C‐fibers. Experimental models are used to study pruritus: histamine for the histaminergic itch by antagonizing the histamine H1‐receptors, and BAM8‐22 and cowhage for the nonhistaminergic by activating Mas‐related G protein‐coupled receptors and protease‐activated receptors, respectively. This study aims to evaluate the antipruritic effects of topical doxepin (H1‐receptor antagonistic effect) on histaminergic and nonhistaminergic itch induced by histamine, BAM8‐22, and cowhage. Methods. This study was conducted on 22 healthy subjects. Histamine, BAM8‐22, cowhage, and vehicle were applied to 4 areas on the forearms. After 7 days, the same substances were applied after 11/2 hour‐pretreatment with doxepin. After the application of pruritogens, itch and pain intensities were assessed for 9 minutes, followed by the measurement of superficial blood perfusion (SBP), mechanical and thermal sensitivities. Results. Application of histamine, BAM8‐22, and cowhage all induced itch as compared to a vehicle. The pretreatment with doxepin almost abolished the histamine‐induced itch and modestly reduced BAM8‐22‐ and cowhage‐induced itch. Histamine induced a higher SBP compared to the other conditions. Doxepin reduced SBP induced by each pruritogen, even though SBP of histamine remains the highest. Conclusion. Doxepin cream abolished histaminergic itch by antagonizing the peripheral H1‐histamine receptors. Moreover, doxepin reduced nonhistaminergic itch and related neurogenic inflammation. Further studies are needed to elucidate the molecular mechanisms underlying this peripheral modulation of nonhistaminergic itch by a topically applied H1‐antagonist. This trial is registered with NCT04588532.
Supplemental Materials from Wnt Signaling Stimulates Cooperation between GREB1 and HNF4α to Promote Proliferation in Hepatocellular Carcinoma
Authors: Matsumoto Shinji , Harada Akikazu , Seta Minami , Akita Masayuki , Gon Hidetoshi , Fukumoto Takumi , Kikuchi Akira
Published: June 2023

Supplemental Materials 1-3.
Validating Wave 1 (2014) Urinary Cotinine and TNE-2 Cut-points for Differentiating Wave 4 (2017) Cigarette Use from Non-use in the United States Using Data from the PATH Study
Authors: Edwards Kathryn C. , Khan Asia , Sharma Eva , Wang Lanqing , Feng June , Blount Benjamin C. , Sosnoff Connie S. , Smith Danielle M. , Goniewicz Maciej L. , Pearson Jennifer , Villanti Andrea C. , Delnevo Cristine D. , Bover-Manderski Michelle T. , Hatsukami Dorothy K. , Niaura Raymond , Everard Colm , Kimmel Heather L. , Duffy Kara , Rostron Brian L. , Del Valle-Pinero Arseima Y. , van Bemmel Dana M. , Stanton Cassandra A. , Hyland Andrew
Published: June 2023

Background:

Sex and racial/ethnic identity-specific cut-points for validating tobacco use using Wave 1 (W1) of the Population Assessment of Tobacco and Health (PATH) Study were published in 2020. The current study establishes predictive validity of the W1 (2014) urinary cotinine and total nicotine equivalents-2 (TNE-2) cut-points on estimating Wave 4 (W4; 2017) tobacco use.

Methods:

For exclusive and polytobacco cigarette use, weighted prevalence estimates based on W4 self-report alone and with exceeding the W1 cut-point were calculated to identify the percentage missed without biochemical verification. Sensitivity and specificity of W1 cut-points on W4 self-reported tobacco use status were examined. ROC curves were used to determine the optimal W4 cut-points to distinguish past 30-day users from non-users, and evaluate whether the cut-points significantly differed from W1.

Results:

Agreement between W4 self-reported use and exceeding the W1 cut-points was high overall and when stratified by demographic subgroups (0.7%–4.4% of use was missed if relying on self-report alone). The predictive validity of using the W1 cut-points to classify exclusive cigarette and polytobacco cigarette use at W4 was high (>90% sensitivity and specificity, except among polytobacco Hispanic smokers). Cut-points derived using W4 data did not significantly differ from the W1-derived cut-points [e.g., W1 exclusive = 40.5 ng/mL cotinine (95% confidence interval, CI: 26.1–62.8), W4 exclusive = 29.9 ng/mL cotinine (95% CI: 13.5–66.4)], among most demographic subgroups.

Conclusions:

The W1 cut-points remain valid for biochemical verification of self-reported tobacco use in W4.

Impact:

Findings from can be used in clinical and epidemiologic studies to reduce misclassification of cigarette smoking status.
Data from CD69 imposes tumor-specific CD8+ T-cell fate in tumor-draining lymph nodes
Authors: Koyama-Nasu Ryo , Kimura Motoko Y. , Kiuchi Masahiro , Aoki Ami , Wang Yangsong , Mita Yukiyoshi , Hasegawa Ichita , Endo Yukihiro , Onodera Atsushi , Hirahara Kiyoshi , Motohashi Shinichiro , Nakayama Toshinori
Published: June 2023

Abstract
Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to their cytotoxic progeny – Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLNs) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-PD-1 showed an efficient anti-tumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.
Data from CD69 Imposes Tumor-Specific CD8+ T-cell Fate in Tumor-Draining Lymph Nodes
Authors: Koyama-Nasu Ryo , Kimura Motoko Y. , Kiuchi Masahiro , Aoki Ami , Wang Yangsong , Mita Yukiyoshi , Hasegawa Ichita , Endo Yukihiro , Onodera Atsushi , Hirahara Kiyoshi , Motohashi Shinichiro , Nakayama Toshinori
Published: June 2023

Abstract
Tumor-specific CD8+ T cells play a pivotal role in antitumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stemlike CD8+ T cells give rise to their cytotoxic progeny—Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLN) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti–programmed cell death protein 1 (PD-1) showed an efficient antitumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.
Data from Systemic Alterations in Type-2 Conventional Dendritic Cells Leads to Impaired Tumor Immunity in Pancreatic Cancer
Authors: James C. Alston. , Baer John M. , Zuo Chong , Panni Usman Y. , Knolhoff Brett L. , Hogg Graham D. , Kingston Natalie L. , Kang Liang-I , Lander Varintra E. , Luo Jingqin , Tao Yu , Watson Mark A. , Aft Rebecca , Fields Ryan C. , Hawkins William G. , DeNardo David G.
Published: June 2023

Abstract
Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDACs) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 conventional DC (cDC2) development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from PDAC patients for changes in cDCs. We found circulating cDC2s and their progenitors were significantly decreased in the blood of PDAC patients, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in PDAC patents and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of PDAC patients showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.
Data from Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer
Authors: James C. Alston , Baer John M. , Zou Chong , Panni Usman Y. , Knolhoff Brett L. , Hogg Graham D. , Kingston Natalie L. , Kang Liang-I. , Lander Varintra E. , Luo Jingqin , Tao Yu , Watson Mark A. , Aft Rebecca , Fields Ryan C. , Hawkins William G. , DeNardo David G.
Published: June 2023

Abstract
Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)–mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.
CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer
Authors: Sozio Francesca , Schioppa Tiziana , Laffranchi Mattia , Salvi Valentina , Tamassia Nicola , Bianchetto-Aguilera Francisco M. , Tiberio Laura , Bonecchi Raffaella , Bosisio Daniela , Parmentier Marc , Bottazzi Barbara , Leone Roberto , Russo Eleonora , Bernardini Giovanni , Garofalo Stefano , Limatola Cristina , Gismondi Angela , Sciumè Giuseppe , Mantovani Alberto , Del Prete Annalisa , Sozzani Silvano
Published: June 2023

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of natural killer (NK) cells to the lung. C–C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27– CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2′-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell–mediated lung immune surveillance.
Figure S2 from Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer
Authors: Mehra Siddharth , Garrido Vanessa T. , Dosch Austin R , Lamichhane Purushottam , Srinivasan Supriya , Singh Samara P , Zhou Zhiqun , De Castro Silva Iago , Joshi Chandrashekar , Ban Yuguang , Datta Jashodeep , Gilboa Eli , Merchant Nipun B , Nagathihalli Nagaraj S
Published: June 2023

Raw uncropped images of Western blot
membranes for Figs. 2e, 2f, S3a and S3b.
Lenvatinib as Second-Line Treatment after Atezolizumab plus Bevacizumab for Unresectable Hepatocellular Carcinoma: Clinical Results Show Importance of Hepatic Reserve Function
Authors: Hiraoka Atsushi , Kumada Takashi , Tada Toshifumi , Hirooka Masashi , Kariyama Kazuya , Tani Joji , Atsukawa Masanori , Takaguchi Koichi , Itobayashi Ei , Fukunishi Shinya , Tsuji Kunihiko , Ishikawa Toru , Tajiri Kazuto , Ochi Hironori , Yasuda Satoshi , Toyoda Hidenori , Ogawa Chikara , Nishimura Takashi , Hatanaka Takeshi , Kakizaki Satoru , Shimada Noritomo , Kawata Kazuhito , Naganuma Atsushi , Kosaka Hisashi , Matono Tomomitsu , Kuroda Hidekatsu , Yata Yutaka , Ohama Hideko , Tada Fujimasa , Nouso Kazuhiro , Morishita Asahiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Okubo Tomomi , Arai Taeang , Yokohama Keisuke , Imai Michitaka , Koizumi Yohei , Nakamura Shinichiro , Iijima Hiroko , Kaibori Masaki , Hiasa Yoichi ,   on behalf of the Real-life Practice Experts for HCC (RELPEC) Study Group,   and HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan)
Published: June 2023

Introduction: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. Methods: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D = 1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. Results: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, p = 0.557) or OS (13.6 months, p = 0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD = 3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD = 1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3 = 2:15:10), general fatigue (21.8%) (grade 1:2:3 = 3:13:6), protein in urine (16.8%) (grade 1:2:3 = 0:4:13), and hypertension (13.9%) (grade 1:2:3 = 1:8:5). Conclusion: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment.
Elevating Omophoita octoguttata elytralis Bechyné, 1956 (Coleoptera: Chrysomelidae: Galerucinae: Alticini) to species
Authors: Begha Bruno Piotrovski , Santos Mateus Henrique , Prado Laura Rocha
Published: June 2023

An updated morphological description for Omophoita elytralis (Bechyné, 1956), stat. nov., is presented, including the first account of the genitalia for this species. The separation Omophoita elytralis from O. octoguttata (Fabricius, 1775) is supported by differences found in the median lobe of males, elytral tegument uniform in color (not patterned), and their allopatric geographical distribution.
A catalog of Pipunculidae of Chile (Diptera)
Authors: Rafael José Albertino , González Christian Raúl , Ale-Rocha Rosaly
Published: June 2023

An updated catalog of the Pipunculidae from Chile is provided. We present all valid names and synonyms for the 21 species belonging to six genera and three subfamilies distributed in the country. Information is given on name, author, year of publication, page number, type species, type depository, type locality, Chilean localities, and references. Tomosvaryella Aczél and Eudorylas Aczél are the richest genera in Chile, with eight species each, followed by Protonephrocerus Collin with two species, and Chalarus Walker, Neocephalosphaera De Meyer and Elmohardyia Rafael with one species each. The geographical distribution of the species was compiled from the literature and the retrieval of distributional data from collections.
Influence of Crestal Implant Position and a Smooth Collar on Marginal Bone Level: A 2-Year Retrospective Radiographic Analysis
Authors: Matar Roger , Naaman Nada , Mansour Safa , Karouni Michel , Fares Akl , Antoun Hadi
Published: June 2023

This retrospective study evaluated the survival rate and the clinical outcome of an endosseous implant system, as well as the marginal bone level (MBL) and the impact of the machined collar neck position on crestal bone level changes up to 2 years later. A total of 96 implants were placed in 57 patients and loaded with a final restoration after at least 3 months of healing: 15 implants were immediately placed into fresh extraction sockets, and 81 were placed in healed ridges. Marginal bone loss around implants was determined radiographically at 12 to 24 months postloading. The effects on marginal bone loss of the site (mandible vs maxilla), location (anterior vs posterior), immediate vs delayed implant, smoking habit, sex, implant length and diameter, prosthesis type (screw-retained/cemented), and the machined collar position were evaluated. The implant survival rate was 98.96% at 1 year. The mean MBL decreased significantly (0.238 mm) between baseline and loading (P < .001; post hoc test) and decreased by 0.154 mm between loading and 1 year, but this was not significant (P = .085; post hoc tests). After 2 years, the mean MBL decreased significantly (0.263 mm) between baseline and loading (P < .001) and decreased by 0.111 mm between loading and 1 year and by 0.199 mm between loading and 2 years, but these were not significant (P > .05; post hoc tests). The mean bone loss after 1 and 2 years was not significantly associated with implant type or site, smoking habit, or type of implant surgery (P = .792). However, the mean bone loss was significantly associated with the type of prosthesis and was significantly greater for cemented prostheses compared to screw-retained prostheses. A supracrestal position of the machined collar (tissue level) was associated with no bone loss, while placing the collar below the alveolar crest led to bone loss over 2 years. Of the factors evaluated, marginal bone loss after 1 and 2 years was significantly associated with prosthesis type and the machined collar position.
Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels
Authors: Mammadova-Bach Elmina , Gudermann Thomas , Braun Attila
Published: June 2023

Blood flow–induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the extracellular matrix and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress–induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.
Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition
Authors: Renna Stephanie A. , Zhao Xuefei , Kunapuli Satya P. , Ma Peisong , Holinstat Michael , Boxer Matthew B. , Maloney David J. , Michael James V. , McKenzie Steven E.
Published: June 2023

BACKGROUND:

Heparin-induced thrombocytopenia (HIT) is a major concern for all individuals that undergo cardiac bypass surgeries or require prolonged heparin exposure. HIT is a life- and limb-threatening adverse drug reaction with an immune response following the formation of ultra-large immune complexes that drive platelet activation through the receptor FcγRIIA. Thrombotic events remain high following the standard of care treatment with anticoagulants, while increasing risk of bleeding complications. This study sought to investigate a novel approach to treatment of HIT. Recent reports demonstrate increased procoagulant activity in HIT; however, these reports required analysis ex vivo, and relevance in vivo remains unclear.

METHODS:

Using human and mouse model systems, we investigated the cooperativity of PARs (protease-activated receptors) and FcγRIIA in HIT. We challenged humanized FcγRIIA transgenic mice with or without endogenous mouse Par4 (denoted as IIA-Par4
+/+
or IIA-Par4
−
/−
, respectively) with a well-established model IgG immune complex (anti [α]-CD9). Furthermore, we assessed the procoagulant phenotype and efficacy to treat HIT utilizing inhibitor of 12-LOX (12[S]-lipoxygenase), VLX-1005, previously reported to decrease platelet activation downstream of FcγRIIA and PAR4, using the triple allele HIT mouse model.

RESULTS:

IIA-Par4
+/+
mice given αCD9 were severely thrombocytopenic, with extensive platelet-fibrin deposition in the lung. In contrast, IIA-Par4
−/−
mice had negligible thrombocytopenia or pulmonary platelet-fibrin thrombi. We observed that pharmacological inhibition of 12-LOX resulted in a significant reduction in both platelet procoagulant phenotype ex vivo, and thrombocytopenia and thrombosis in our humanized mouse model of HIT in vivo.

CONCLUSIONS:

These data demonstrate for the first time the need for dual platelet receptor (PAR and FcγRIIA) stimulation for fibrin formation in HIT in vivo. These results extend our understanding of HIT pathophysiology and provide a scientific rationale for targeting the procoagulant phenotype as a possible therapeutic strategy in HIT.
TGF-β1/SMAD3 Regulates Programmed Cell Death 5 That Suppresses Cardiac Fibrosis Post–Myocardial Infarction by Inhibiting HDAC3
Authors: Weng Lin , Ye Jingjing , Yang Fenghe , Jia Shi , Leng Minghong , Jia Bo , Xu Chunling , Zhao Yang , Liu Ruxia , Xiong Yufei , Zhou Yiqing , Zhao Junhui , Zheng Ming
Published: June 2023

BACKGROUND:

Progressive cardiac fibrosis leads to ventricular wall stiffness, cardiac dysfunction, and eventually heart failure, but the underlying mechanism remains unexplored. PDCD5 (programmed cell death 5) ubiquitously expresses in tissues, including the heart; however, the role of PDCD5 in cardiac fibrosis is largely unknown. Therefore, this study aims at exploring the possible role and underlying mechanisms of PDCD5 in the pathogenesis of cardiac fibrosis.

METHODS AND RESULTS:

PDCD5 levels were found to be elevated in the serum obtained from patients with cardiac fibrosis, in fibrotic mice heart tissues after myocardial infarction, and in cardiac fibroblasts stimulated by Ang II (angiotensin II)- or TGF-β1 (transforming growth factor-β1). Overexpression of PDCD5 in cardiac fibroblasts or treatment with PDCD5 protein reduced the expression of profibrogenic proteins in response to TGF-β1 stimulation, while knockdown of PDCD5 increased fibrotic responses. It has been demonstrated that SMAD3, a protein that is also known as mothers against decapentaplegic homolog 3, directly upregulated PDCD5 during cardiac fibrosis. Subsequently, the increased PDCD5 promoted HDAC3 (histone deacetylase 3) ubiquitination, thus, inhibiting HDAC3 to reduce fibrotic responses. Fibroblast-specific knock-in of PDCD5 in mice ameliorated cardiac fibrosis after myocardial infarction and enhanced cardiac function, and these protective effects were eliminated by AAV9-mediated HDAC3 overexpression.

CONCLUSIONS:

The findings of this study demonstrated that PDCD5 is upregulated by SMAD3 during cardiac fibrosis, which subsequently ameliorated progressive fibrosis and cardiac dysfunction through HDAC3 inhibition. Thus, this study suggests that PDCD5 functions as a negative feedback factor on fibrotic signaling pathways and might serve as a potential therapeutic target to suppress the progression of fibrotic responses.
Cross‐Sectional Validation of a Novel Computed Tomography‐Based Carotid Mean Calcium Density Measurement
Authors: Cahalane Rachel , Akyildiz Ali , Kavousi Maryam , Vernooij Meike W. , Ikram M. Kamran , Gijsen Frank , Bos Daniel
Published: June 2023

Background

The purpose of this study was to validate a technique for measuring mean calcium density and to determine associations of cardiovascular risk factors with carotid calcium density.

Methods and Results

We performed a cross‐sectional study in a random sample of 100 stroke‐free participants from the population‐based Rotterdam Study. The mean calcium density of the combined left and right carotid bifurcations was quantified with a threshold of 130 Hounsfield Units (HU) using a novel density technique. To validate the methodology, carotid calcium volumes acquired using the technique in the current study were compared with measurements computed using dedicated clinical software (semiautomatic technique based on a threshold of ≥130 HU). Next, we investigated the associations of participant demographics, total calcium volume, and known cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking status) with the newly derived mean carotid calcium density measurement using linear regression analyses. Calcium volumes obtained with the 2 methods showed a high agreement (intraclass correlation coefficient=0.99,
P
<0.001), underlining the validity of the density technique. The total calcium volume was statistically significantly associated with the mean calcium density (cardiovascular risk factors adjusted model (B: 0.48 [95% CI, 0.30–0.66],
P
<0.001). We also found an association between hypercholesterolemia and mean calcium density (0.46 [0.09–0.83],
P
=0.017). No other significant associations were found between participant demographics or cardiovascular risk factors and mean carotid calcium density.

Conclusions

We demonstrated the feasibility of a carotid calcium density measurement technique. The data warrant a subsequent longitudinal study to determine the association between carotid calcium density and the risk of cerebrovascular events.
Variation in Risk‐Standardized Acute Admission Rates Among Patients With Heart Failure in Accountable Care Organizations: Implications for Quality Measurement
Authors: Chuzi Sarah , Lindenauer Peter K. , Faridi Kamal , Priya Aruna , Pekow Penelope S. , D'Aunno Thomas , Mazor Kathleen M. , Stefan Mihaela S. , Spatz Erica S. , Gilstrap Lauren , Werner Rachel M. , Lagu Tara
Published: June 2023

Background

Accountable care organizations (ACOs) aim to improve health care quality and reduce costs, including among patients with heart failure (HF). However, variation across ACOs in admission rates for patients with HF and associated factors are not well described.

Methods and Results

We identified Medicare fee‐for‐service beneficiaries with HF who were assigned to a Medicare Shared Savings Program ACO in 2017 and survived ≥30 days into 2018. We calculated risk‐standardized acute admission rates across ACOs, assigned ACOs to 1 of 3 performance categories, and examined associations between ACO characteristics and performance categories. Among 1 232 222 beneficiaries with HF, 283 795 (mean age, 81 years; 54% women; 86% White; 78% urban) were assigned to 1 of 467 Medicare Shared Savings Program ACOs. Across ACOs, the median risk‐standardized acute admission rate was 87 admissions per 100 people, ranging from 61 (minimum) to 109 (maximum) admissions per 100 beneficiaries. Compared to the overall average, 13% of ACOs performed better on risk‐standardized acute admission rates, 72% were no different, and 14% performed worse. Most ACOs with better performance had fewer Black beneficiaries and were not hospital affiliated. Most ACOs that performed worse than average were large, located in the Northeast, had a hospital affiliation, and had a lower proportion of primary care providers.

Conclusions

Admissions are common among beneficiaries with HF in ACOs, and there is variation in risk‐standardized acute admission rates across ACOs. ACO performance was associated with certain ACO characteristics. Future studies should attempt to elucidate the relationship between ACO structure and characteristics and admission risk.
Improvement in the Prediction of Cerebrovascular Events With White Matter Hyperintensity
Authors: de Havenon Adam , Smith Eric E. , Sharma Richa , Falcone Guido J. , Bangad Aaron , Prabhakaran Shyam , Sheth Kevin N.
Published: June 2023

Background

It remains unclear if white matter hyperintensity (WMH) on magnetic resonance imaging adds relevant cerebrovascular prognostic information beyond vascular risk factors and demographics alone.

Methods and Results

We performed a post hoc analysis of hypertensive individuals in SPRINT‐MIND (Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension). The primary outcome was incident stroke or cognitive impairment (mild cognitive impairment or dementia). We fit logistic regression models with the predictors of Atherosclerotic Cardiovascular Disease Risk Score, age, sex, race, education, current cigarette smoking, and the SPRINT‐MIND randomization arm. WMH was subsequently included in the model to determine if it improved area under the receiver operating curve using the DeLong test. We used a structural equation model to determine the indirect effect on the primary outcome mediated through WMH. We included 727 individuals (mean age at baseline 67.7±8.4 years, 61.1% were men, 62.6% were non‐Hispanic White, and mean years of follow‐up was 3.6±0.9). Of the 727 individuals, 67 (9.2%) developed incident stroke or cognitive decline. The area under the receiver operating curve of the baseline model (without WMH) was 0.75 (95% CI, 0.70–0.81), and after the addition of WMH it increased to 0.81 (95% CI, 0.76–0.86) (
P
=0.004 for difference). The mediation analysis showed that 26.3% of the vascular risk's effect on the primary outcome is indirectly mediated through WMH.

Conclusions

In adult hypertensive individuals, we found that the addition of WMH to models predicting incident stroke or cognitive impairment improved the prognostic ability above vascular risk and demographics alone to a level consistent with excellent prediction.

Registration Information

REGISTRATION:
URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01206062.
Age‐Related Trends in the Predictive Value of Carotid Intima‐Media Thickness for Cardiovascular Death: A Prospective Population‐Based Cohort Study
Authors: Ge Jinzhuo , Jing Fuyu , Ji Runqing , Tian Aoxi , Su Xiaoming , Li Wei , He Guangda , Pu Boxuan , Lei Lubi , Lu Jiapeng , Li Jing
Published: June 2023

Background

The age‐related trends in the predictive ability of carotid intima‐media thickness (CIMT) for cardiovascular risk remain unclear. We aimed to identify the age‐related trends in the predictive value of CIMT for cardiovascular death.

Methods and Results

In a prospective cohort of adults aged 35 to 75 years without history of cardiovascular disease who were enrolled between 2014 and 2020, we measured CIMT at baseline and collected the vital status and cause of death. We divided the study population into 4 age groups (35–44, 45–54, 55–64, and 65–75 years). Competing risk models were fitted to estimate the associations between CIMT and cardiovascular death. The added values of CIMT in prediction were assessed by the differences of the Harrell's concordance index and the net reclassification improvement index. We included 369 478 adults and followed them for a median of 4.7 years. A total of 4723 (1.28%) cardiovascular deaths occurred. After adjusting for the traditional risk factors, the hazard ratios for CIMT
mean
per SD decreased with age, from 1.27 (95% CI, 1.17–1.37) in the 35 to 44 years age group to 1.14 (95% CI, 1.10–1.19) in the 65 to 75 years age group (
P
for interaction <0.01). Meanwhile, the net reclassification improvement indexes for CIMT
mean
were attenuated with age, from 22.60% (95% CI, 15.56%–29.64%) in the 35 to 44 years age group to 7.00% (95% CI, −6.82% to 20.83%) in the 65 to 75 years age group. Similar results were found for maximum CIMT in all age groups.

Conclusions

CIMT may improve cardiovascular risk prediction in the young and middle‐aged populations, rather than those aged ≥55 years.