bluuebunny/crossref_metadata_2025 huggingface dataset:
Data 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

Abstract
Wnt signaling is known to maintain two cell states, hepatocyte differentiation and proliferation, in hepatocellular carcinoma (HCC). On the other hand, activation of Wnt signaling in colon cancer promotes uncontrollable stereotypic proliferation, whereas cells remain undifferentiated. To elucidate the unique mode of Wnt signaling in HCC, we comprehensively investigated HCC-specific Wnt pathway target genes and identified GREB1. Wnt signaling induced expression of GREB1 coupled with HNF4α and FOXA2, master transcription factors that maintain hepatic differentiation. Moreover, GREB1 was enriched at the regulatory region of atypical HNF4α target genes, including progrowth genes, thereby stimulating HCC proliferation. Therefore, GREB1 acts as a unique mediator of versatile Wnt signaling in HCC progression, bridging the roles of the Wnt pathway in differentiation and proliferation.
Significance:
GREB1 is a liver cancer-specific Wnt signaling target gene that induces an oncogenic shift of HNF4α, a putative tumor suppressor, and may represent a therapeutic target in Wnt-activated hepatocellular carcinoma.
Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype
Authors: Kim Jihye , Yuan Chen , Amundadottir Laufey T. , Wolpin Brian M. ,   for the Pancreatic Cancer Cohort Consortium (PanScan), Klein Alison P. ,   for the Pancreatic Cancer Case–Control Consortium (PanC4), Risch Harvey A. , Kraft Peter
Published: June 2023

Background:

In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC.

Methods:

We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually.

Results:

We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15–1.42) and 1.17 (95% CI, 1.03–1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens.

Conclusions:

Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status.

Impact:

Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.
Supplemental Figure 2 from Trimodality Therapy Improves Disease Control in Radiation-Associated Angiosarcoma of the Breast
Authors: Degnim Amy C. , Siontis Brittany L. , Ahmed Safia K. , Hoskin Tanya L. , Hieken Tina J. , Jakub James W. , Baum Christian L. , Day Courtney , Schrup Sarah E. , Smith Lauren , Carter Jodi M. , Sae Kho Tiffany M. , Glazebrook Katrina N. , Vijayasekaran Aparna , Okuno Scott H. , Petersen Ivy A.
Published: June 2023

Supplemental Figure 2. Kaplan Meier survival curve of local recurrence free survival (LRFS).
Supplemental Figure 1 from Trimodality Therapy Improves Disease Control in Radiation-Associated Angiosarcoma of the Breast
Authors: Degnim Amy C. , Siontis Brittany L. , Ahmed Safia K. , Hoskin Tanya L. , Hieken Tina J. , Jakub James W. , Baum Christian L. , Day Courtney , Schrup Sarah E. , Smith Lauren , Carter Jodi M. , Sae Kho Tiffany M. , Glazebrook Katrina N. , Vijayasekaran Aparna , Okuno Scott H. , Petersen Ivy A.
Published: June 2023

Supplemental Figure 1. Clinical response in one representative patient treated with trimodality therapy who experienced a pathologic complete response to preoperative chemoradiation; a) baseline photograph at time of diagnosis/Pre-treatment, b) photograph after induction chemotherapy, c) photograph after completion of chemoradiation, prior to surgery.
Data from Trimodality Therapy Improves Disease Control in Radiation-Associated Angiosarcoma of the Breast
Authors: Degnim Amy C. , Siontis Brittany L. , Ahmed Safia K. , Hoskin Tanya L. , Hieken Tina J. , Jakub James W. , Baum Christian L. , Day Courtney , Schrup Sarah E. , Smith Lauren , Carter Jodi M. , Sae-Kho Tiffany M. , Glazebrook Katrina N. , Vijayasekaran Aparna , Okuno Scott H. , Petersen Ivy A.
Published: June 2023

Abstract
Purpose: To evaluate the impact of trimodality treatment versus mono- or dual-therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment. Experimental Design: With IRB approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included 1) taxane induction, 2) concurrent taxane/radiation, and then 3) surgical resection with wide margins. Results: 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 mono/dual-therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared to 48% of mono/dual-therapy patients (p<0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the mono/dual-therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year RFS (93.8% vs 42.9%, p=0.004, HR 7.6 (95% CI: 1.3-44.2)). Combining all RAASB patients regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR 9.0, p=0.002); distant recurrence developed in 3/28 (11%) patients without local recurrence compared to 6/10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing. Conclusions: Trimodality therapy for RAASB was more toxic but is promising with a high rate of pCR, durable local control, and improved RFS.
Data from Trimodality Therapy Improves Disease Control in Radiation-Associated Angiosarcoma of the Breast
Authors: Degnim Amy C. , Siontis Brittany L. , Ahmed Safia K. , Hoskin Tanya L. , Hieken Tina J. , Jakub James W. , Baum Christian L. , Day Courtney , Schrup Sarah E. , Smith Lauren , Carter Jodi M. , Sae Kho Tiffany M. , Glazebrook Katrina N. , Vijayasekaran Aparna , Okuno Scott H. , Petersen Ivy A.
Published: June 2023

AbstractPurpose:
To evaluate the impact of trimodality treatment versus monotherapy or dual therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment.
Experimental Design:
With Institutional Review Board approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included (i) taxane induction, (ii) concurrent taxane/radiation, and then (iii) surgical resection with wide margins.
Results:
A total of 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 monotherapy/dual therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared with 48% of monotherapy/dual therapy patients (P < 0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the monotherapy/dual therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year recurrence-free survival [RFS; 93.8% vs. 42.9%; P = 0.004; HR, 7.6 (95% confidence interval, CI: 1.3–44.2)]. Combining all patients with RAASB regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR, 9.0; P = 0.002); distant recurrence developed in 3 of 28 (11%) patients without local recurrence compared with 6 of 10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing.
Conclusions:
Trimodality therapy for RAASB was more toxic but is promising, with a high rate of pCR, durable local control, and improved RFS.
Supplementary Figure 4 from Granulocyte–Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade
Authors: Li Xiaoyu , Li Jingjing , Zheng Yue , Lee Sandra J. , Zhou Jun , Giobbie-Hurder Anita , Butterfield Lisa H. , Dranoff Glenn , Hodi F. Stephen
Published: June 2023

Supplementary figure 4
Supplementary Table 3 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

Supplementary Table 3
Supplementary Figure 3 from Granulocyte–Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade
Authors: Li Xiaoyu , Li Jingjing , Zheng Yue , Lee Sandra J. , Zhou Jun , Giobbie-Hurder Anita , Butterfield Lisa H. , Dranoff Glenn , Hodi F. Stephen
Published: June 2023

Supplementary figure 3
Supplementary Table 1 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

Supplementary Table 1
Supplementary Figure 1 from Granulocyte–Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade
Authors: Li Xiaoyu , Li Jingjing , Zheng Yue , Lee Sandra J. , Zhou Jun , Giobbie-Hurder Anita , Butterfield Lisa H. , Dranoff Glenn , Hodi F. Stephen
Published: June 2023

Supplementary Figure 1
Supplementary Figures 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

Supplemental Figures and Legends
Figure S4 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

Tumor weight, mouse weight and
cytokine profiling of Uro A treatment in PKT mice.
TABLE 2 from A Mendelian Randomization Analysis of 55 Genetically Predicted Metabolic Traits with Breast Cancer Survival Outcomes in the Pathways Study
Authors: Fiorica Peter N. , Sheng Haiyang , Zhu Qianqian , Roh Janise M. , Laurent Cecile A. , Ergas Isaac J. , Delmerico Jennifer , Kwan Marilyn L. , Kushi Lawrence H. , Ambrosone Christine B. , Yao Song
Published: June 2023

Survival events in the Pathways Study (n = 3,902)
VISTA Approach in Conjunction with Enamel Matrix Derivative, Corticocancellous Bone, and Connective Tissue Graft for Periodontal Defect Surgery: A Case Series
Authors: Pohl Snjezana , Buljan Mia
Published: June 2023

The biggest challenge during periodontal regeneration in the anterior region is the prevention of soft tissue recession. Minimally invasive surgeries, particularly papilla preservation techniques and soft tissue augmentation, may significantly reduce such postoperative soft tissue recession. This article presents the vestibular incision subperiosteal tunnel access (VISTA) approach for periodontal regeneration in the anterior region. A subperiosteal tunnel prepared from a single vertical vestibular incision adjacent to the defect is used for debridement, application of enamel matrix derivative, defect grafting with corticocancellous tuberosity bone, and insertion of the connective tissue graft. Evaluation of six cases with up to 6 years of follow-up showed improvements in all clinical parameters. The probing pocket depth improved from 8.2 ± 0.75 mm initially to 2.7 ± 0.52 mm at follow-up, clinical attachment level improved from 8.5 ± 0.83 mm initially to 2.7 ± 0.52 mm at follow-up, and midfacial gingival recession of 1 mm at two sites was corrected. The papillae were stable at all sites, with an average distance of 4.8 mm from the incisal edge to the papilla tip. This technique seems to be a promising approach for achieving both esthetic and functional goals of periodontal regenerative surgery. However, experience in performing microsurgeries and harvesting tuberosity tissues may be a limitation.
Alveolar Ridge Preservation Procedures Performed with a Freeze-Dried Bone Allograft: Histologic Outcomes in a Cohort Study
Authors: Iezzi Giovanna , Valente Nicola Alberto , Velasco-Ortega Eugenio , Piattelli Adriano , Perez Alexandre , D'amico Emira , Barone Antonio
Published: June 2023

The primary aim of this study was to assess the histomorphometric outcomes of extraction sockets grafted with freeze-dried bone allograft (FDBA) and sealed with a collagen membrane after 3 months of healing in specific region of interest (ROI) areas. The secondary aims were to analyze the biomaterial resorption rate, the bone-to-biomaterial contact (BBC), and the area and perimeter of grafted particles compared with commercially available FDBA particles. Fifteen patients underwent tooth extractions and ridge preservation procedures performed with FDBA and a collagen membrane. Bone biopsy samples were harvested after 3 months at the time of implant placement for histologic and histomorphometric analysis. Two areas of concern (ROI1 and ROI2) with different histologic features were identified within the biopsy samples; ROI1, ROI2, and commercially available particles were analyzed and compared. The following parameters were analyzed: newly formed bone, marrow space, residual graft particles, perimeter and area of FDBA particles, and BBC. The histomorphometric analysis showed 35.22% ± 10.79% newly formed bone, 52.55% ± 16.06% marrow spaces, and 12.41% ± 7.87% residual graft particles. Moreover, the histologic data from ROI1 and ROI2 showed that (1) the mean percentage of BBC was 64.61% ± 27.14%; (2) the newly formed bone was significantly higher in ROI1 than in ROI2; (3) the marrow space was significantly lower in ROI1 than in ROI2; and (4) the FDBA particles in ROI1 sites showed significantly lower area and perimeter when compared to commercially available FDBA particles. This latter data led to the hypothesis that FDBA particles embedded in newly formed bone undergo a resorption/remodeling process.
The New Generation of Subperiosteal Implants for Patient-Specific Treatment of Atrophic Dental Arches: Literature Review and Two Case Reports
Authors: Vatteroni Ernesto , Covani Ugo , Menchini Fabris Giovanni B
Published: June 2023

Subperiosteal implants were first introduced in the early 1940s for the treatment of edentulous maxillary and mandibular arches with severe bone atrophy. After achieving widespread popularity in the 80s and 90s, this denture therapy was progressively abandoned due to significant technique limitations, including high rates of infection and the complications and difficulties with positioning implants and obtaining sufficiently extensive bone impressions. In the last two decades, digital technology has dramatically changed the world of implant dentistry. In particular, modern diagnostic imaging, digital technology, and direct metal laser sintering now allow for the projection of implants with the proper extension, leading to the fabrication of custom-made titanium meshes that perfectly fit the specific anatomical requirements of patients. With modern production methods, subperiosteal implants have been digitally reinterpreted, and interest in them is being renewed for the treatment of edentulous patients with atrophic arches. This article describes the evolution of subperiosteal implants in recent years and presents two clinical cases involving the placement of new generation (NG) subperiosteal implants with the clinical and radiographic findings at the 1-year follow-up.
Functional Exploration of Conserved Sequences in the Distal Face of Angiotensinogen—Brief Report
Authors: Amioka Naofumi , Wu Chia-Hua , Sawada Hisashi , Ito Sohei , Pettey Alex C. , Wu Congqing , Moorleghen Jessica J. , Howatt Deborah A. , Graf Gregory A. , Vander Kooi Craig W. , Daugherty Alan , Lu Hong S.
Published: June 2023

BACKGROUND:

Angiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and β-sheet regions among species; however, their functions have not been studied.

METHODS:

Adeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), β-sheet (AAV.βsheet-Mut), or both regions (AAV.loop/βsheet-Mut) was injected into male hepatocyte-specific AGT-deficient (hepAGT
−/−
) mice in an LDL (low-density lipoprotein) receptor–deficient background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a western diet for 12 weeks. To determine how AGT secretion is regulated in hepatocytes, AAVs containing the above mutations were transducted into HepG2 cells.

RESULTS:

In hepAGT
−/−
mice infected with AAV.loop-Mut or βsheet-Mut, plasma AGT concentrations, systolic blood pressure, and atherosclerosis were comparable to those in AAV.mAGT-infected mice. Interestingly, plasma AGT concentrations, systolic blood pressure, and atherosclerotic lesion size in hepAGT
−/−
mice infected with AAV.loop/βsheet-Mut were not different from mice infected with AAV.null. In contrast, hepatic
Agt
mRNA abundance was elevated to a comparable magnitude as AAV.mAGT-infected mice. Immunostaining showed that AGT protein was accumulated in hepatocytes of mice infected with AAV.loop/βsheet-Mut or HepG2 cells transducted with AAV.loop/βsheet-Mut. Accumulated AGT was not located in the endoplasmic reticulum.

CONCLUSIONS:

The conserved sequences in either the loop or β-sheet region individually have no effect on AGT regulation, but the conserved sequences in both regions synergistically contribute to the secretion of AGT from hepatocytes.
Dedifferentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development in Mice
Authors: Arolkar Gauri , Kumar Sneha K. , Wang Hanjay , Gonzalez Karen M. , Kumar Suraj , Bishnoi Bhavnesh , Rios Coronado Pamela E. , Woo Y. Joseph , Red-Horse Kristy , Das Soumyashree
Published: June 2023

Background:

Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries is dictated by their ability to dedifferentiate.

Methods:

Single-cell RNA sequencing of coronary endothelial cells was performed to identify differences in molecular profiles of neonatal and adult endothelial cells in mice. Findings from this in silico analyses were confirmed with in vivo experiments using genetic lineage tracing, whole organ immunostaining, confocal imaging, and cardiac functional assays in mice.

Results:

Upon coronary occlusion, neonates showed a significant increase in actively cycling artery cells and expressed prominent dedifferentiation markers. Data from in silico pathway analyses and in vivo experiments suggested that upon myocardial infarction, cell cycle reentry of preexisting neonatal artery cells, the subsequent collateral artery formation, and recovery of cardiac function are dependent on arterial VegfR2 (vascular endothelial growth factor receptor-2). This subpopulation of dedifferentiated and proliferating artery cells was absent in nonregenerative postnatal day 7 or adult hearts.

Conclusions:

These data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to dedifferentiate and proliferate.
Outcomes With Peripheral Venoarterial Extracorporeal Membrane Oxygenation for Suspected Acute Myocarditis: 10-Year Experience From the Extracorporeal Life Support Organization Registry
Authors: Nunez Jose I. , Grandin E. Wilson , Reyes-Castro Tiago , Sabe Marwa , Quintero Pablo , Motiwala Shweta , Fleming Lisa M. , Sriwattanakomen Roy , Ho Jennifer E. , Kennedy Kevin , Tonna Joseph E. , Garan A. Reshad
Published: June 2023

BACKGROUND:

Acute myocarditis can result in severe hemodynamic compromise requiring venoarterial extracorporeal membrane oxygenation (VA-ECMO). Outcomes and factors associated with mortality among myocarditis patients are not well described in the modern ECMO era.

METHODS:

We queried the Extracorporeal Life Support Organization registry from 2011 to 2020 for adults with suspected acute myocarditis undergoing peripheral VA-ECMO support. The primary outcome was in-hospital mortality and was compared to all-comers receiving VA-ECMO in the registry over the same period. Secondary outcomes were rates of bridging to advanced therapies and ECMO complications. We used multivariable logistic regression to examine factors associated with in-hospital mortality.

RESULTS:

Among 850 patients with suspected acute myocarditis receiving peripheral VA-ECMO, the mean age was 41 years, 52% were men, 39% Asian race, and 14.8% underwent extracorporeal cardiopulmonary resuscitation. During the study period, in-hospital mortality steadily declined and was 58.3% for all all-comers receiving VA-ECMO compared with 34.9% for patients with myocarditis (
P
<0.001). After multivariable modeling, risk factors for mortality were earlier year of support, older age, higher weight, Asian race, need for extracorporeal cardiopulmonary resuscitation, sepsis, and lower mean arterial pressure and pH prior to ECMO initiation. ECMO complications including bleeding, limb ischemia, infections and ischemic stroke were more common among nonsurvivors and significantly declined during the study period.

CONCLUSIONS:

Compared with all-comers supported with VA-ECMO, in-hospital mortality for patients with acute myocarditis is significantly lower, with nearly two-thirds of patients surviving to discharge. Major modifiable risk factors for mortality were ongoing cardiopulmonary resuscitation requiring ECMO and markers of illness severity prior to ECMO.
Ventilatory Efficiency Is Reduced in People With Hypertension During Exercise
Authors: Hope Katrina , Chant Ben , Hinton Thomas , Kendrick Adrian H. , Nightingale Angus K. , Paton Julian F. R. , Hart Emma C.
Published: June 2023

Background

An elevated ventilatory efficiency slope during exercise (minute ventilation/volume of expired CO
2
; V
E
/VCO
2
slope) is a strong prognostic indicator in heart failure. It is elevated in people with heart failure with preserved ejection, many of whom have hypertension. However, whether the V
E
/VCO
2
slope is also elevated in people with primary hypertension versus normotensive individuals is unknown. We hypothesize that there is a spectrum of ventilatory inefficiency in cardiovascular disease, reflecting an increasingly abnormal physiological response to exercise. The aim of this study was to evaluate the V
E
/VCO
2
slope in patients with hypertension compared with age‐, peak oxygen consumption–, and sex‐matched healthy subjects.

Methods and Results

Ramped cardiovascular pulmonary exercise tests to peak oxygen consumption were completed on a bike ergometer in 55 patients with primary hypertension and 24 normotensive controls. The V
E
/VCO
2
slope was assessed from the onset of exercise to peak oxygen consumption. Data were compared using unpaired Student
t
test. Age (mean±SD, 66±6 versus 64±6 years;
P
=0.18), body mass index (25.4±3.5 versus 24±2.4 kg/m
2
;
P
=0.13), and peak oxygen consumption (23.2±6.6 versus 24±7.3 mL/min per kg;
P
=0.64) were similar between groups. The V
E
/VCO
2
slope was elevated in the hypertensive group versus controls (31.8±4.5 versus 28.4±3.4;
P
=0.002). Only 27% of the hypertensive group were classified as having a normal V
E
/VCO
2
slope (20–30) versus 71% in the control group.

Conclusions

Ventilatory efficiency is impaired people with hypertension without a diagnosis of heart failure versus normotensive individuals. Future research needs to establish whether those patients with hypertension with elevated V
E
/VCO
2
slopes are at risk of developing future heart failure.
Trends in Short‐, Intermediate‐, and Long‐Term Mortality Following Hospitalization for Myocardial Infarction Among Medicare Beneficiaries, 2008 to 2018
Authors: Kini Vinay , Magid David J. , Luo Qian , Masoudi Frederick A. , Black Bernard , Moghtaderi Ali
Published: June 2023

Background

Advances in technology and care quality have transformed the care of acute myocardial infarction (AMI), but little is known about trends in mortality rates across separate time periods after hospitalization.

Methods and Results

We identified all Medicare fee‐for‐service beneficiaries hospitalized with incident AMI from 2008 to 2018. We calculated unadjusted mortality rates by dividing the number of all‐cause deaths by the number of patients with incident AMI for the following time periods: acute (in hospital), post acute (0–30 days after hospital discharge), short term (31 days to 1 year after discharge), intermediate term (1–2 years after discharge), and long term (2–3 years after discharge). Each period was considered separately (ie, patients who died during one period were not counted in subsequent periods). Using logistic regression to account for differences in patient characteristics, we calculated annual risk standardized mortality ratios defined as observed over expected mortality based on 2008 rates. Among 768 084 patients with incident AMI (mean age 81 years, 48% male, 87% White), declines in observed‐to‐expected mortality ratios were observed for each time period: acute (0.68 [95% CI, 0.66–0.71]), postacute (0.72 [95% CI, 0.71–0.75]), short term (0.77 [95% CI, 0.75–0.78]), intermediate term (0.79 [95% CI, 0.77–0.81]), and long term (0.77 [95% CI, 0.75–0.79]). Declines were observed both for patients with and without ST‐segment–elevation AMI.

Conclusions

For patients with incident AMI, there have been improvements in mortality rates across periods spanning the hospital stay through 3 years after discharge, reflecting advances in AMI care from hospitalization through long‐term outpatient follow‐up.
Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis
Authors: Srinivas Balaji K. , Bourdi Aya , O'Regan Jacob D. , Malavalli Kumar D. , Rhaleb Nour‐Eddine , Belmadani Souad , Matrougui Khalid
Published: June 2023

Background

Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood.

Methods and Results

C57/Bl6J and interleukin‐1β
−/−
male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin‐1β
−/−
mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin‐1β
−/−
mice were fed a high‐fat diet with N[w]‐nitro‐l‐arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high‐fat diet and N[w]‐nitro‐l‐arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin‐1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms.

Conclusions

Our data suggest that interleukin‐1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.
Sex Differences in Murray Law‐Based Quantitative Flow Ratio Among Patients With Intermediate Coronary Lesions
Authors: Zuo Wenjie , Sun Renhua , Ji Zhenjun , Zuo Pengfei , Zhang Xiaoguo , Huang Rong , Tao Zaixiao , Tu Shengxian , Li Yongjun , Ma Genshan
Published: June 2023

Background

The Murray law‐based quantitative flow ratio (μQFR) is a novel technique that simulates fractional flow reserve (FFR) from a single angiographic view. However, the impact of sex differences on the diagnostic performance of μQFR has not been investigated.

Methods and Results

In this study, FFR and μQFR were assessed in 497 intermediate stenoses (30%–70% by visual estimation) from 460 patients (34.3% female). Physiological significance was defined as FFR ≤0.80 or μQFR ≤0.80. After adjusting for potential confounders, female sex was independently associated with higher FFR (
P
=0.048 and 0.026, respectively) and μQFR (
P
=0.001 for both) in both fully adjusted and stepwise backward models. μQFR provided superior diagnostic accuracy compared with angiography alone for detecting FFR ≤0.80 in both women (area under the curve, 0.93 [95% CI, 0.88–0.97] versus 0.80 [95% CI, 0.73–0.86];
P
=0.001) and men (area under the curve, 0.88 [95% CI, 0.84–0.92] versus 0.73 [95% CI, 0.68–0.78];
P
<0.001), with comparable performance between the sexes (
P
=0.175). In the multivariable analysis, sex was not a significant factor contributing to the overall disagreement between FFR and μQFR.

Conclusions

Regardless of angiographic stenosis severity, women tend to have higher FFR and μQFR values than men. Furthermore, μQFR performs similarly well in both sexes and offers improved diagnostic accuracy over angiography alone, indicating its potential as a reliable, wire‐free tool to identify functional ischemia.
Metabolic Signatures of Cardiac Dysfunction, Multimorbidity, and Post–Transcatheter Aortic Valve Implantation Death
Authors: Perry Andrew S. , Zhao Shilin , Murthy Venkatesh , Gupta Deepak K. , Fearon William F. , Kim Juyong B. , Kapadia Samir , Kumbhani Dharam J. , Gillam Linda , Whisenant Brian , Quader Nishath , Zajarias Alan , Mallugari Ravinder R. , Clark Daniel E. , Patel Jay N. , Gonzales Holly , Welt Frederick G. , Bavry Anthony A. , Coylewright Megan , Piana Robert N. , Vatterott Anna , Jackson Natalie , Gerszten Robert E. , Lindman Brian R. , Shah Ravi , Elmariah Sammy
Published: June 2023

Background

Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long‐term follow‐up and characterization currently exist.

Methods and Results

Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre–transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post–transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25–1.90];
P
<0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis.

Conclusions

Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post–transcatheter aortic valve implantation recovery, rehabilitation, and survival.
Social Determinants of Health and Cerebral Small Vessel Disease: Is Epigenetics a Key Mediator?
Authors: Parodi Livia , Mayerhofer Ernst , Narasimhalu Kaavya , Yechoor Nirupama , Comeau Mary E. , Rosand Jonathan , Langefeld Carl D. , Anderson Christopher D.
Published: June 2023

Cerebral small vessel disease is highly prevalent, particularly in marginalized communities, and its incidence is expected to increase given the aging global population. Cerebral small vessel disease contributes to risk for stroke, vascular cognitive impairment and dementia, late‐life depression, and gait disorders. A growing body of evidence suggests that adverse outcomes, including cerebral small vessel disease, caused by traditional cardiovascular risk factors are at least partly mediated by epigenetic changes, some of them already beginning during fetal development. Societal and health care access inequities, summarized under the umbrella term social determinants of health, put a higher burden of cardiovascular risk factors on marginalized populations and expose them to an increased risk for adverse outcomes. Social epigenetics has begun to deliver solid evidence that social determinants of health lead to distinct epigenetic signatures that potentially mediate the biological effect of environmental exposures on cardiovascular risk factors. Here, we provide a review of the most recent advances in the epigenetics of cerebral small vessel disease risk factors and social determinants of health and call for research efforts combining insights from both fields to reach a deeper understanding of the causal pathways, ultimately facilitating discovery of new treatment targets for a disease whose burden is magnified by existing health disparities.
Virtue Discounting: Observability Reduces Moral Actors’ Perceived Virtue
Authors: Kraft-Todd Gordon T. , Kleiman-Weiner Max , Young Liane
Published: June 2023

Performing prosociality in public presents a paradox: only by doing so can people demonstrate their virtue and also influence others through their example, yet observers may derogate actors’ behavior as mere “virtue signaling.” Here we investigate the role of observability of actors’ behavior as one reason that people engage in such “virtue discounting.” Further, we investigate observers’ motivational inferences as a mechanism of this effect, using the comparison of generosity and fairness as a case study among virtues. Across 14 studies (7 preregistered, total N = 9,360), we show that public actors are perceived as less virtuous than private actors, and that this effect is stronger for generosity compared to fairness (i.e., differential virtue discounting). Exploratory factor analysis suggests that three types of motives—principled, reputation-signaling, and norm-signaling—affect virtue discounting. Using structural equation modeling, we show that observability’s effect on actors’ trait virtue ratings is largely explained by inferences that actors have less principled motivations. Further, we leverage experimental evidence to provide stronger causal evidence of these effects. We discuss theoretical and practical implications of our findings, as well as future directions for research on the social perception of virtue.
How to Conceive Virtual Entities: Peirce’s Proposal
Authors: Steinle Friedrich
Published: June 2023

The term “virtual entities” has a long tradition and a variety of meanings. My short article focuses on one particular meaning, as clearly defined by Charles Sanders Peirce in 1902. I will discuss the definition he provided and touch on the wide resonance it had and still has in science.
The Eye Stays in the Picture: Virtual Images in Early Modern and Modern Optics
Authors: Borrelli Arianna
Published: June 2023

In optics, real images can be projected onto a screen, while virtual ones always remain behind mirrors. This apparently straightforward distinction is based on complex premises which emerged in the Early Modern period, and its development went hand in hand with a transformation of the notion of image, which became detached from sensual perception. In this article I will outline this historical process, and argue that the distinction between a real and virtual image still implies a reference to visual perception which makes it problematic, yet useful for didactic purposes.
Virtuality in Modern Physics in the 1920s and 1930s: Meaning(s) of an Emerging Notion
Authors: Martinez Jean-Philippe
Published: June 2023

This article discusses the meaning of the notion of virtuality in modern physics. To this end, it develops considerations on the introduction and establishment in nuclear physics of two independent concepts at the turn of the 1920s and 1930s: that of the virtual state, used in the context of neutron scattering studies, and that of the virtual transition, useful for the theoretical understanding of strong nuclear forces, which forms the basis of what are now called virtual particles. Their comparative analysis highlights the theoretical nature of virtual entities and processes in modern physics. It also shows how the virtual has been associated with various purely physical attributes, leading to a form of polysemy of the term, from the beginning of the application of these concepts.
Understanding, Virtually: How Does the Synthetic Cell Matter?
Authors: Broeks Daphne , Knuuttila Tarja , de Regt Henk
Published: June 2023

This paper examines how scientific understanding is enhanced by virtual entities, focusing on the case of the synthetic cell. Comparing it to other virtual entities and environments in science, we argue that the synthetic cell has a virtual dimension, in that it is functionally similar to living cells, though it does not mimic any particular naturally evolved cell (nor is it constructed to do so). In being cell-like at most, the synthetic cell is akin to many other virtual objects as it is selective and only partially implemented. However, there is one important difference: it is constructed by using the same materials and, to some extent, the same kind of processes as its natural counterparts. In contrast to virtual reality, especially to that of digital entities and environments, the details of its implementation is what matters for the scientific understanding generated by the synthetic cell. We conclude by arguing for the close connection between the virtual and the artifactual.
Nonverbal Communication in Immersive Virtual Reality through the Lens of Presence: A Critical Review
Authors: Xenakis Ioannis , Gavalas Damianos , Kasapakis Vlasios , Dzardanova Elena , Vosinakis Spyros
Published: June 2023

The emergence of metaverse signifies the transformation of virtual reality (VR) from an isolated digital experience into a social medium, which facilitates new contexts of information exchange and communication. In fact, VR comprises the first-ever computer-mediated communication paradigm that enables the transfer of a broad range of nonverbal cues, including some unique cues which are not even known from face-to-face social encounters. This highlights the urgency to theoretically and experimentally investigate aspects of nonverbal communication (NVC) in immersive virtual environments (IVEs). We provide a critical outlook on empirical studies aiming at widening the discussion on how presence, as a core social factor, is affected by the perception of nonverbal signals and how NVC may be effectively utilized to facilitate social interactions in immersive environments. Our review proposes a classification of the most fundamental cues and modalities of NVC, which we associate with conceptualizations of presence that are more relevant to interpersonal communication. We also investigate the NVC-related aspects that are essential to construct an “active” virtual self-concept and highlight associations among NVC-related aspects through forming a complex web of research topics coming from the field of IVEs. We establish that the key research challenge is to go beyond simply studying nonverbal cues and technological settings in isolation.
Reasoning One’s Way Back into Skepticism
Authors: Satta Mark
Published: June 2023

Susanna Rinard aims to show that it is possible to rationally persuade an external world skeptic to reject external world skepticism. She offers an argument meant to convince a skeptic who accepts her views on “several orthogonal issues in epistemology” to give up their external world skepticism. While I agree with Rinard that it is possible to reason with a skeptic, I argue that Rinard overlooks a variety of good epistemic grounds a skeptic could appeal to in rejecting her argument and its conclusion. More specifically, I argue that the external world skeptic can resist Rinard’s conclusion by (1) distinguishing between skepticism about knowledge and skepticism about justification, (2) by prioritizing obtaining accurate beliefs (maximizing true beliefs and minimizing false beliefs) over being rational, or (3) by treating suspension of judgment as the default rational doxastic attitude.
Design Thinking from Multiple Perspectives
Authors: Tan Aik Ling
Published: June 2023

Design thinking is interpreted and implemented in various ways as detailed by the five articles in this special issue. Besides offering a summary of the five articles, this editorial commentary advocates for the need to view design thinking more holistically by considering the larger system in which the solution resides and also giving thought to the end-point of design thinking cycles.
A new species of planthopper in the genus Shellenius (Hemiptera: Fulgoroidea: Derbidae) from palms in Costa Rica
Authors: BAHDER BRIAN W. , ECHAVARRIA MARCO A. ZUMBADO , BARRANTES EDWIN A. BARRANTES , HELMICK ERICKA E. , BARTLETT CHARLES R.
Published: June 2023

The genus Shellenius is a small taxon of planthoppers in the family Derbidae (Otiocerinae: Otiocerini) found in the eastern United States and Mesoamerica. A new species of Shellenius associated with palms is herein described from Costa Rica. Molecular data for the barcoding region cytochrome c oxidase subunit I (COI) and 18S rRNA gene is provided to produce a preliminary phylogenetic tree for related taxa and support placement of the novel taxon in Shellenius. A review of Fowler type material suggests that Otiocerus interruptus Fowler is a Shellenius species and is here transferred to that genus as Shellenius interruptus new combination.
Towards a US-led Networked Interregional Architecture for the Indo-Pacific?
Authors: Calabrese John
Published: June 2023

The Biden administration’s approach to the Indo-Pacific strategy represents the latest and most ambitious incarnation of the ‘new multilateralism’—an institutional redesign that seeks to respond to unprecedented changes in and challenges to the US-led international order. This article sheds light on the conceptual underpinnings, structural features, and development of the strategy. It shows how ‘entrepreneurial’ Japanese diplomacy, US coalition-building, Transatlantic policy convergences, and the galvanizing effects of the Russian invasion of Ukraine have combined to shape the contours of the strategy and endow it with a sense of common purpose. It brings into sharp focus the US strategy’s reliance on the creation, strengthening, and leveraging of informal institutional configurations of power and cooperation. And it highlights some of the factors that might result in this approach ultimately proving to be more of a triumph of structure and process than of concrete substance and accomplishment.
Floral nectar reabsorption and a sugar concentration gradient in two long-spurred Habenaria species (Orchidaceae)
Authors: Zhang Hai-Ping , Wen Shi-Jia , Wang Hong , Ren Zong-Xin
Published: June 2023

Background

Floral nectar is the most common reward flowers offered to pollinators. The quality and quantity of nectar produced by a plant species provide a key to understanding its interactions with pollinators and predicting rates of reproductive success. However, nectar secretion is a dynamic process with a production period accompanied or followed by reabsorption and reabsorption remains an understudied topic. In this study, we compared nectar volume and sugar concentration in the flowers of two long-spurred orchid species,Habenaria limprichtiiandH. davidii(Orchidaceae). We also compared sugar concentration gradients within their spurs and rates of reabsorption of water and sugars.

Results

Both species produced diluted nectar with sugar concentrations from 17 to 24%. Analyses of nectar production dynamics showed that as flowers of both species wilted almost all sugar was reabsorbed while the original water was retained in their spurs. We established a nectar sugar concentration gradient for both species, with differences in sugar concentrations at their spur’s terminus and at their spur’s entrance (sinus). Sugar concentration gradient levels were 1.1% inH. limprichtiiand 2.8% inH. davidii, both decreasing as flowers aged.

Conclusion

We provided evidence for the reabsorption of sugars but not water occurred in wilted flowers of bothHabenariaspecies. Their sugar concentration gradients vanished as flowers aged suggesting a slow process of sugar diffusion from the nectary at the spur’s terminus where the nectar gland is located. The processes of nectar secretion/reabsorption in conjunction with the dilution and hydration of sugar rewards for moth pollinators warrant further study.