bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO-086: Exploring therapeutic strategies against pancreatic ductal adenocarcinoma (PDAC)
Authors: Liaki Vasiliki
Published: November 2021

Studies of our group have previously assessed the therapeutic efficacy in a PDAC mouse model of the combined genetic elimination of EGFR and RAF1, two main targets of the KRAS molecular pathway. Specifically, our results illustrated that, PDACs are composed of at least two distinct tumor cell populations based on their response (regression or non-response) to the combined elimination of EGFR and c-Raf both in vivo and in vitro that can be distinguished by a different expression profile (Blasco et al., Cancer Cell, 2019). We have further studied the nature of this heterogeneity that interferes with the efficacy of this therapeutic strategy by OMICs and we have identified targetable molecular pathways as promising therapeutic approaches that we are currently validating.

Citation Format: Vasiliki Liaki. Exploring therapeutic strategies against pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-086.
Abstract PO-090: TGF-β induced EMT gene expression is associated with promoter demethylation in pancreatic cancer
Authors: Rana Manjul , Elahi Abul , Ajidahun Abidemi O. , Kansal Rita G. , Berglund Anders E. , Shibata David , Glazer Evan S.
Published: November 2021

INTRODUCTION: Transforming growth factor-β (TGF-β), a ubiquitous molecule in pancreatic ductal adenocarcinoma (PDA) tumors, acts as a potent inducer of tumor invasion by regulating proteins involved in metastasis and driving epithelial-mesenchymal transition (EMT). We hypothesized that TGF-β signaling-induced EMT is regulated by DNA methylation. To evaluate this, we investigated the association between EMT gene promoter methylation status and gene expression in the TCGA PDA dataset. We also investigated vimentin gene (a mesenchymal marker)-specific changes in DNA methylation due to TGF-β treatment in PDA cells. METHODS: The methylation status of EMT-related genes (ZEB2, CDH2, Vimentin) was interrogated in the TCGA PDA data set. β-values (proportion of methylated gene probes in a location) were compared to gene expression levels. Next, a PDA cell line (Panc-1) was treated with TGF-β (10ng/ml), vehicle control, DNA methyltransferase inhibitor (5-azacytidine, AZA, 10mM), or TGF-β plus AZA to evaluate the effects on the DNA methylation status of the vimentin gene with methylation-specific PCR (MSP) against the promoter region of vimentin. Unmethylation and methylation levels at the vimentin promoter region were then compared. RESULTS: We found that β values of promotor regions of ZEB2, CDH2, and Vimentin were moderately negatively correlated with gene expression (Pearson r varies from 0.45 to 0.63) in the PDA TCGA data set. In Panc-1 cells, vimentin gene expression was increased following treatment with AZA compared to controls suggesting that DNA demethylation increases vimentin gene expression. MSP demonstrated that TGF-β treatment increased unmethylated vimentin gene levels compared to vehicle control treatment. TGF-β treatment increased unmethylated vimentin gene levels more so than methylated gene levels. CONCLUSIONS: These results demonstrate that gene expression of EMT-related genes may be at least partially regulated by DNA methylation. We demonstrate that TGF-β treatment leads to increased Vimentin promotor demethylation (lower β value) and increased gene expression in Panc-1 cells. This observation is consistent with our findings in the TCGA data set that lower β-values are associated with increased expression of mesenchymal genes, indicative of EMT. Further studies are underway to investigate the relationship between DNA methylation and TGF-β-induced EMT in general.

Citation Format: Manjul Rana, Abul Elahi, Abidemi O. Ajidahun, Rita G. Kansal, Anders E. Berglund, David Shibata, Evan S. Glazer. TGF-β induced EMT gene expression is associated with promoter demethylation in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-090.
Abstract PO-091: Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors
Authors: Salmeron Cristina , Sriram Krishna , Javadi-Paydar Mehrak , Insel Paul A.
Published: November 2021

A recent study reported that patients taking HRH1 antihistamines have decreased progression of various tumors, including PDAC; the authors inferred that this was an immune effect (Fritz et al., PMID: 33550204). We have initiated studies to test an alternative hypothesis: HRH1 expressed by PDAC cells may contribute to the malignant phenotype and if so, FDA-approved HRH1 antihistamines might be therapeutics to treat or perhaps prevent PDAC. We have undertaken bioinformatic and experimental approaches to test this hypothesis. Our bioinformatic analysis revealed that PDAC tumors in The Cancer Genome Atlas (TCGA) have >30-fold higher HRH1 expression than in normal pancreas (GTEx database) and is highly expressed in PDAC cell lines in the Cancer Cell Line Encyclopedia (CCLE). HRH1 expression was selectively associated with markers of PDAC cells and not with markers of other cell types in the tumor microenvironment. Higher expression of HRH1 in TCGA-PDAC tumors negatively impacts on patient survival. Our experimental studies indicate that human and mouse PDAC cells express HRH1 mRNA, protein and signaling and that HRH1 is present on the surface of PDAC cells. We found that histamine prominently increases calcium [Ca2+] in multiple human PDAC cell lines with EC50 values comparable to that in other cell types. The histamine-stimulated increase in [Ca2+] occurs via a Gq/11 (heterotrimeric GTP binding protein)-dependent mechanism and is blocked by multiple FDA-approved HRH1 antihistamines (with pKi values similar to those of HRH1 inhibition of other cell types). HRH1 activation by histamine increases PDAC cell migration. Histamine also increases the production of numerous cytokines (including VEGF) from PDAC cells, and in preliminary studies, stimulates growth of multiple PDAC cell lines at low concentrations (1-10 nM). Together with published data indicating that mast cells (which synthesize and release histamine) in PDAC tumors are associated with PDAC cell growth/invasion, angiogenesis and worse prognosis, our findings suggest that independent of immune cells, a "mast cell-histamine-PDAC cell HRH1 axis" may contribute to the malignant phenotype of PDAC tumors. Importantly, HRH1 on PDAC cells could be targeted by repurposing approved HRH1 antihistamines as a novel therapeutic approach for PDAC tumors. Supported by grants from the University of California Cancer Research Coordinating Committee and Tobacco-Related Disease Research Program.

Citation Format: Cristina Salmeron, Krishna Sriram, Mehrak Javadi-Paydar, Paul A. Insel. Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-091.
Abstract PO-104: Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer
Authors: Du Wenting , Menjivar Rosa E. , Donahue Katelyn , Velez-Delgado Ashley , Pasca di Magliano Marina
Published: November 2021

WNT ligand expression and activation of the WNT signaling have been associated with pancreatic ductal adenocarcinoma (PDA). Using a mouse model that recapitulates the stepwise progression of PDA, we previously showed that epithelial WNT signaling is required for PDA initiation and progression. Through single cell RNA sequencing, we discovered that, in addition to epithelial cells, infiltrating immune cells and in particular T cells express the WNT signaling machinery, including receptors, downstream effectors and target genes. In particular, T cells express high levels of Tcf7, encoding the transcription factor TCF1. TCF1 is important for T cell development, but its role in adult T cells and specifically in the setting of pancreatic cancer remained unknown. To address this, we generated mice that allow deletion of Tcf7 specifically in CD4+ T cells in an inducible manner. We then implanted orthotopic syngeneic tumors in control mice or in mice lacking Tcf7 in CD4+ T cells, and observed reduced tumor growth in the latter. Analysis of the tumors revealed an increase in apoptotic cells; while the prevalence of infiltrating T cells did not change, we observed an increase in cytotoxic marker expression, such as Granzyme B, consistent with increased T cell activation. We observed decreased regulatory T cells, possibly indicating less immune suppression. However, we also observed a compensatory infiltration of increased granulocytic myeloid derived suppressor cells. Deletion of Tcf7 in CD4+ T cells also re-polarized the immunosuppressive macrophages into pro-inflammatory macrophages, and alterations of inflammatory cytokines secreted by cancer associated fibroblasts. Taken together, this study reveals an important role of WNT signaling in CD4+ T cells in the PDA microenvironment. We are currently evaluating ways to exploit changes in the immune microenvironment upon inactivation of Tcf7 in CD4+ T cells in combination therapy approaches.

Citation Format: Wenting Du, Rosa E. Menjivar, Katelyn Donahue, Ashley Velez-Delgado, Marina Pasca di Magliano. Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-104.
Abstract PO-123: Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer
Authors: Pahlavan Mahsa , Xiao Weikun , Eun Flora , Hwang Chang-Il , Hill Reginald
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the United States with a 5-year survival rate of only 7%. Early diagnosis is very difficult and thus 53% of PDAC patients are diagnosed after metastasis has already occurred with liver being the most frequently affected site. Therefore, it is urgent to understand the mechanism that leads to PDAC metastasis in liver in order to develop potential therapeutics. Research shows that environment that comprises the metastatic niche has unique features that facilitate tumor growth and chemoresistance. Differences between the tumor microenvironment (TME) of the primary site and the metastatic site may be a key reason why metastatic tumors are highly resistant to standard treatment. However, most current models only recreate the primary tumor environment, while a proper model which recapitulates the key features of the metastatic niche to study liver metastasis (LM) is still missing. To address this problem, we aim to design a biomimetic model that specifically recapitulates the liver premetastatic niche (PMN). Our 3D model accomplishes this by using 1) a collagen rich extracellular matrix (ECM) that mimics the metastatic site, 2) LM-derived fibroblasts, 3) and LM organoids derived from a mouse model of PDAC. Our preliminary results showed that primary PDAC organoids require CAFs derived from primary PDACs to exhibit chemoresistance. In contrast, LM organoids did not require primary CAFs to exhibit the same level of chemoresistance. This suggests that there are cell intrinsic factors that promote chemoresistance in LM organoid in addition to possible cell extrinsic factors from the PMN. In this research we investigate the role of LM-derived CAFs and PDAC-derived exosomes in liver PMN development and study their effect on growth and chemoresistance of LM organoids. Results of this research will help us to develop strategies specifically tailored to overcome the factors which promote chemoresistance in the PMN.

Citation Format: Mahsa Pahlavan, Weikun Xiao, Flora Eun, Chang-Il Hwang, Reginald Hill. Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-123.
Patterns of Prescribing Sodium-Glucose Cotransporter-2 Inhibitors for Medicare Beneficiaries in the United States
Authors: Sangha Veer , Lipska Kasia , Lin Zhenqiu , Inzucchi Silvio E. , McGuire Darren K. , Krumholz Harlan M. , Khera Rohan
Published: November 2021

Background:

Evidence from large randomized clinical trials supports the benefit of SGLT2i (sodium-glucose cotransporter-2 inhibitors) to improve cardiovascular and kidney outcomes in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease or chronic kidney disease. Considering this evidence, which has been expanding since the product label indication for empagliflozin to reduce risk of cardiovascular death in 2016, clinician-level variation in the prescription of SGLT2i among US Medicare beneficiaries was evaluated.

Methods:

Antihyperglycemic medication prescribers were identified as those physicians and advanced practice providers prescribing metformin in Medicare part D prescriber data. In this cross-sectional study, the proportion prescribing SGLT2i was assessed overall and across specialties in 2018, with changes assessed from 2014 to 2018. SGLT2i use was compared with other second-line antihyperglycemic medication classes, sulfonylureas and DPP4is (dipeptidyl peptidase-4 inhibitors).

Results:

Among 232 523 unique clinicians who prescribed metformin for Medicare beneficiaries in 2018 (diabetes-treating clinicians), 45 255 (19.5%) prescribed SGLT2i. There was substantial variation across specialties—from 72% of endocrinologists to 14% of cardiologists who prescribed metformin also prescribed SGLT2i. Between 2014 and 2018, the number prescribing SGLT2i increased 5-fold from 9048 in 2014 to 45 255 in 2018. Among clinicians who prescribed both sulfonylureas and SGLT2i in 2018, SGLT2i was prescribed to a median 33 beneficiaries for every 100 prescribed sulfonylureas (interquartile range, 18–67). SGLT2i use relative to sulfonylureas increased from 19 (interquartile range, 11–34) per 100 in 2014 to 33 (interquartile range, 18–67) per 100 in 2018 (
P
trend
<0.001).

Conclusions:

Eighty percent of clinicians prescribing metformin to Medicare beneficiaries did not prescribe SGLT2i in 2018. Moreover, sulfonylureas prescriptions were 3 times more frequent than those of SGLT2is, although a pattern of increasing uptake may portend future trends. These findings highlight a baseline opportunity to improve care and outcomes for patients with type 2 diabetes.
Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review
Authors: Asatryan Babken , Asimaki Angeliki , Landstrom Andrew P. , Khanji Mohammed Y. , Odening Katja E. , Cooper Leslie T. , Marchlinski Francis E. , Gelzer Anna R. , Semsarian Christopher , Reichlin Tobias , Owens Anjali T. , Chahal C. Anwar A.
Published: November 2021

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.
Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial
Authors: Butler Javed , Filippatos Gerasimos , Jamal Siddiqi Tariq , Brueckmann Martina , Böhm Michael , Chopra Vijay K. , Pedro Ferreira João , Januzzi James L. , Kaul Sanjay , Piña Ileana L. , Ponikowski Piotr , Shah Sanjiv J. , Senni Michele , Vedin Ola , Verma Subodh , Peil Barbara , Pocock Stuart J. , Zannad Faiez , Packer Milton , Anker Stefan D.
Published: November 2021

Background:

Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.

Methods:

Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.

Results:

The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69–1.00], 0.70 [95% CI, 0.55–0.88], and 0.82 [95% CI, 0.62–1.08] for scores <62.5, 62.5–83.3, and ≥83.3, respectively;
P
trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively;
P
<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10–1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03–1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02–1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75–0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.

Conclusions:

In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03057951.
Twenty-Four–Hour Central (Aortic) Systolic Blood Pressure: Reference Values and Dipping Patterns in Untreated Individuals
Authors: Weber Thomas , Protogerou Athanase D. , Agharazii Mohsen , Argyris Antonis , Aoun Bahous Sola , Banegas Jose R. , Binder Ronald K. , Blacher Jacques , Araujo Brandao Andréa , Cruz Juan J. , Danninger Kathrin , Giannatasio Cristina , Graciani Auxiliadora , Hametner Bernhard , Jankowski Piotr , Li Yan , Maloberti Alessandro , Mayer Christopher C. , McDonnell Barry J. , McEniery Carmel M. , Antonio Mota Gomes Marco , Machado Gomes Annelise , Lorenza Muiesan Maria , Nemcsik Janos , Paini Anna , Rodilla Enrique , Schutte Aletta E. , Sfikakis Petros P. , Terentes-Printzios Dimitrios , Vallée Alexandre , Vlachopoulos Charalambos , Ware Lisa , Wilkinson Ian , Zweiker Robert , Sharman James E. , Wassertheurer Siegfried ,   International Academic 24-Hour Ambulatory Aortic Blood Pressure Consortium (i24abc.org)
Published: November 2021

Central (aortic) systolic blood pressure (cSBP) is the pressure seen by the heart, the brain, and the kidneys. If properly measured, cSBP is closer associated with hypertension-mediated organ damage and prognosis, as compared with brachial SBP (bSBP). We investigated 24-hour profiles of bSBP and cSBP, measured simultaneously using Mobilograph devices, in 2423 untreated adults (1275 women; age, 18–94 years), free from overt cardiovascular disease, aiming to develop reference values and to analyze daytime-nighttime variability. Central SBP was assessed, using brachial waveforms, calibrated with mean arterial pressure (MAP)/diastolic BP (cSBP
MAP/DBPcal
), or bSBP/diastolic blood pressure (cSBP
SBP/DBPcal
), and a validated transfer function, resulting in 144 509 valid brachial and 130 804 valid central measurements. Averaged 24-hour, daytime, and nighttime brachial BP across all individuals was 124/79, 126/81, and 116/72 mm Hg, respectively. Averaged 24-hour, daytime, and nighttime values for cSBP
MAP/DBPcal
were 128, 128, and 125 mm Hg and 115, 117, and 107 mm Hg for cSBP
SBP/DBPcal
, respectively. We pragmatically propose as upper normal limit for 24-hour cSBP
MAP/DBPcal
135 mm Hg and for 24-hour cSBP
SBP/DBPcal
120 mm Hg. bSBP dipping (nighttime-daytime/daytime SBP) was −10.6 % in young participants and decreased with increasing age. Central SBP
SBP/DBPcal
dipping was less pronounced (−8.7% in young participants). In contrast, cSBP
MAP/DBPcal
dipping was completely absent in the youngest age group and less pronounced in all other participants. These data may serve for comparison in various diseases and have potential implications for refining hypertension diagnosis and management. The different dipping behavior of bSBP versus cSBP requires further investigation.
Ischemic ST‐Segment Depression Maximal in V1–V4 (Versus V5–V6) of Any Amplitude Is Specific for Occlusion Myocardial Infarction (Versus Nonocclusive Ischemia)
Authors: Meyers H. Pendell , Bracey Alexander , Lee Daniel , Lichtenheld Andrew , Li Wei J. , Singer Daniel D. , Rollins Zach , Kane Jesse A. , Dodd Kenneth W. , Meyers Kristen E. , Shroff Gautam R. , Singer Adam J. , Smith Stephen W.
Published: November 2021

Background

Occlusion myocardial infarctions (OMIs) of the posterolateral walls are commonly missed by ST‐segment–elevation myocardial infarction (STEMI) criteria, with >50% of patients with circumflex occlusion not receiving emergent reperfusion and experiencing increased mortality. ST‐segment depression maximal in leads V1–V4 (STDmaxV1–4) has been suggested as an indicator of posterior OMI.

Methods and Results

We retrospectively reviewed a high‐risk population with acute coronary syndrome. OMI was defined from prior studies as a culprit lesion with TIMI (Thrombolysis in Myocardial Infarction) 0 to 2 flow or TIMI 3 flow plus peak troponin T >1.0 ng/mL or troponin I >10 ng/mL. STEMI was defined by the Fourth Universal Definition of Myocardial Infarction. ECGs were interpreted blinded to outcomes. Among 808 patients, there were 265 OMIs, 108 (41%) meeting STEMI criteria. A total of 118 (15%) patients had “suspected ischemic” STDmaxV1–4, of whom 106 (90%) had an acute culprit lesion, 99 (84%) had OMI, and 95 (81%) underwent percutaneous coronary intervention. Suspected ischemic STDmaxV1–4 had 97% specificity and 37% sensitivity for OMI. Of the 99 OMIs detected by STDmaxV1–4, 34% had <1 mm ST‐segment depression, and only 47 (47%) had accompanying STEMI criteria, of which 17 (36%) were identified a median 1.00 hour earlier by STDmaxV1–4 than STEMI criteria. Despite similar infarct size, TIMI flow, and coronary interventions, patients with STEMI(−) OMI and STDmaxV1–4 were less likely than STEMI(+) patients to undergo catheterization within 90 minutes (46% versus 68%;
P
=0.028).

Conclusions

Among patients with high‐risk acute coronary syndrome, the specificity of ischemic STDmaxV1–4 was 97% for OMI and 96% for OMI requiring emergent percutaneous coronary intervention. STEMI criteria missed half of OMIs detected by STDmaxV1–4. Ischemic STDmaxV1–V4 in acute coronary syndrome should be considered OMI until proven otherwise.
Chronic Rhinosinusitis Outcomes of Patients With Aspirin-Exacerbated Respiratory Disease Treated With Budesonide Irrigations: A Case Series
Authors: Talat Rehab , Gengler Isabelle , Phillips Katie M. , Caradonna David S. , Gray Stacey T. , Sedaghat Ahmad R.
Published: November 2021

Background:

Pathophysiology-targeting treatments exist for aspirin-exacerbated respiratory disease (AERD) through aspirin desensitization and biologics, such as dupilumab. With increasing attention paid to these treatments, which may be associated with significant side effects and/or cost, there is little description of chronic rhinosinusitis with nasal polyps (CRSwNP) response to treatment with intranasal corticosteroids and saline irrigations in AERD.

Objective:

To determine the effect of intranasal budesonide irrigations for the treatment of CRSwNP in AERD.

Methods:

This is an observational study of 14 AERD patients presenting to a rhinology clinic for CRS who were treated with twice daily high volume, low pressure irrigations with 240 mL of saline to which a 0.5 mg/2 mL respule of budesonide was added. All participants completed a 22-item Sinonasal Outcome Test (SNOT-22) at enrollment and at follow up 1 to 6 months later. Polyp scores were also calculated at each time point.

Results:

SNOT-22 scores ranged from 26 to 98 (median: 40.5) at enrollment and 3 to 85 (median: 38.5) at follow-up. Polyp scores ranged from 2 to 6 (median: 4) at enrollment at 0 to 6 (median: 2) at follow-up. Over the treatment period, change in SNOT-22 score ranged from −38 to 16 (median: −18) and change in polyp score ranged from −2 to 0 (median: −0.5). Approximately 57% of participants experienced at least 1 minimal clinically important difference in SNOT-22 score and 21% of participants had a SNOT-22 score <20 at follow-up.

Conclusion:

Medical management with intranasal corticosteroids and saline irrigations alone leads to significant improvement in sinonasal symptomatology in a subset of AERD.
The Limits of Possibilities of Religious Politics: The Case of the Tehreek-i-Labbaik in Pakistani Punjab
Authors: Javid Hassan
Published: November 2021

Historically, despite the tremendous influence exerted by Islam on public life, religious parties and organisations have historically failed to do well at the ballot box, receiving an average of only 6% of votes cast in elections since the 1980s. Focusing on the case of the Tehreek-i-Labbaik Pakistan (TLP), a new Barelvi political party and social movement that has campaigned on the emotive issue of blasphemy since being formed in 2015, this article argues that the clientelistic, patronage-based nature of democratic politics in Punjab, coupled with factionalism and competition within the religious right, continues to play a role in limiting the electoral prospects of religious parties. Nonetheless, as was seen in the General Elections of 2018 in which the TLP outperformed expectations, there are particular circumstances in which the religious parties are able to make electoral breakthroughs. While the TLP was able to make effective use of populist rhetoric to garner some genuine support for itself, this article argues that the organisations sustained campaign of protests over the issue of blasphemy fed into broader efforts by the military establishment and opposition political parties to destabilise and weaken the government of the PML-N prior to the 2018 elections.
A multi-function textile with pH-induced switch wettability transition for controllable oil−water separation
Authors: Feng Long , Hou Yimiao , Hao Qingqing , Chen Mingxing , Wang Shuo , Hu Xuemin , Yang Wenxiu
Published: November 2021

The deterioration of water ecology caused by the discharge of oil spill wastewater, industrial sewage, and municipal sewage has attracted wide attention worldwide. Thus, it is significant to design a simple, environmentally friendly approach to separate oil–water mixtures. In this work, three different fabrics with pH-induced wettability transition were prepared by a dip-coating process for oil and water separation. The dip-coating fabrics had the advantages of oil–water separation, photocatalytic degradation, and recycling. Polyethylene terephthalate/polyamide nonwoven fabric was used as the substrate materials of the fabric. The carboxylic acid-modified TiO2 endowed the fabric with hydrophilicity–hydrophobicity and photocatalytic properties. The Fe3O4 nanoparticles obtained by the coprecipitation method provided magnetism for the fabric, facilitating the recycling of the fabric and improving the hydrophobicity of the fabric. The fabrics coated with dipping solutions were superhydrophobic in a neutral environment and hydrophilic in an alkaline environment. Among the three coated fabrics, the fabric coated with stearic acid/TiO2-Fe3O4 (FST) had the most satisfying oil–water separation performance and durability. Under the neutral condition, the contact angle of the FST was 151° and the separation efficiency was 98%. Under the alkaline condition, the underwater oil contact angle of the FST was 150° and the separation efficiency was 95%. After 15 cycles, the oil–water separation rate of the FST was still higher than 90%. Due to the presence of TiO2, the coated fabric had an exceptional performance in the photodegradation of organic pollutants (69.9%). In addition, the fabrics can be quickly recovered due to magnetism.
Economies and employment in growing and declining urban peripheries in South Africa
Authors: Todes Alison , Houghton Jennifer
Published: November 2021

Urban peripheral growth takes diverse forms, including the development of new economic centralities, raising questions about access to employment for residents, especially in contexts where unemployment is high and economies are shifting towards more skilled and service-related employment. This article explores two case studies of residents’ experience of access to employment close to economic centralities on the urban edge in South Africa: the growing northern eThekwini area (Durban), which has developed major retail and office complexes since the 1990s and more recently a new airport and industrial spaces, and a declining industrial decentralisation point established in the 1980s on the eastern edge of the City of Tshwane (Pretoria). It shows the severe impact of industrial decline in the Tshwane case, but while unemployment is less in northern eThekwini, access to employment for low-income residents in these areas is still very limited and constrained. Experiences are however differentiated, suggesting a complexity of outcomes. The cases point to the vulnerability of these economic centralities to economic change and the limits of new developments on the urban periphery to addressing unemployment. These findings have implications for the current advocacy of ‘new cities’ in economic contexts such as South Africa.
White matter damage due to pulsatile versus steady blood pressure differs by vascular territory: A cross-sectional analysis of the UK Biobank cohort study
Authors: Wartolowska Karolina A , Webb Alastair JS
Published: November 2021

Small vessel disease is associated with age, mean blood pressure (MAP) and blood pressure pulsatility (PP). We used data from the UK Biobank cohort study to determine the relative importance of MAP versus PP driving white matter injury within individual white matter tracts, particularly in the anterior and posterior vascular territory. The associations between blood pressure and diffusion indices in 27 major tracts were analysed using unadjusted and fully-adjusted general linear models and mixed-effect linear models. Blood pressure and neuroimaging data were available for 37,041 participants (mean age 64+/−7.5 years, 53% female). In unadjusted analyses, MAP and PP were similarly associated with diffusion indices in the anterior circulation. In the posterior circulation, the associations were weaker, particularly for MAP. In fully-adjusted analyses, MAP remained associated with all diffusion indices in the anterior circulation, independently of age. In the posterior circulation, the effect of MAP became protective. PP remained associated with greater mean diffusivity and extracellular free water diffusion in the anterior circulation and all diffusion indices in the posterior circulation. There was a significant interaction between PP and age. This implies discordant mechanisms for chronic white matter injury in different brain regions and potentially in the associated stroke risks.
Vladimir’s Bakarić’s Idea of a Socialist (Croatian) Nation: From Communist Historicism to Depoliticization
Authors: Đurašković Stevo
Published: November 2021

This article examines how the long-serving Croatian communist leader Vladimir Bakarić conceptualized the Croatian self-managing nation from a set of ideas that involved decentralization, the depoliticization of national identity, and the forging of a classless self-managing nation. As the centralism of the 1950s, originally envisioned to serve the progress of socialism, eventually brought about the gradual rise of inter-national antagonisms between republics in Yugoslavia, Bakarić assumed that empowering the authorities of the republics and the autonomous provinces should serve as the necessary precondition to prevent national identity from being the source of any potential future conflicts. Subsequently, Bakarić conceptualized decentralization as a means that would eventually lead to the depoliticization of national identity, which was necessary to unleash the building of a classless self-management society accompanied by the withering away of state. This article will show how Bakarić’s concept of the nation suffered from two serious shortcomings. The first one stemmed from the 1960 purge of socialist Yugoslavism of any notion of ethnicity, since any idea of Yugoslav ethnic identity had been linked to the Greater-Serbian legacy of the pre-war Yugoslav Royal Dictatorship. The second one stemmed from the fact that ethnic nationalism was latently maintained by the deployment of historical narratives of the communists as the heirs of the true national traditions and the best guardians of the national interest.
The Influence of Human Capital on Re-entry Intention of Indian Micro and Small Enterprise Owners: An Empirical Investigation
Authors: Socrates Kalai , B. V. Gopalakrishna
Published: November 2021

Entrepreneurial exit is an important phase of the entrepreneurial process that has a significant impact on enterprises and the economy. Extant research in developed countries has shown that personal and business motives of entrepreneurs trigger exit intentions, which, in turn, affect their choice of exit strategy. Though all-India census indicates that most of the closed enterprises are micro and small enterprises (MSE), the factors influencing the exit decision of the Indian MSE owners still remain largely unexplored due to their unorganised nature. Since the majority of Indian MSEs are owned by individuals, and human capital represents the assets of each individual, this article aims to understand the influence of entrepreneurs’ human capital on exit intention for re-entry using the theory of planned behaviour. This study employs a questionnaire-based survey approach and uses a sample size of 150 MSE owners of working enterprises in industrial estates of Mangalore and Udupi districts for hypotheses testing. Empirical analysis is performed using SPSS software, and the results indicate that entrepreneurs with good health and inherited experience have exit intentions and subsequent entrepreneurial re-entry. This knowledge may be useful for stakeholders to understand serial entrepreneurship with a proper exit mechanism.
‘Team ethnography visual maps’: Methods for identifying the ethnographic object in multiple sites of fieldwork
Authors: Parkin Stephen , Locock Louise , Montgomery Catherine , Chisholm Alison
Published: November 2021

Team ethnography is becoming more popular in research. However, there is currently limited understanding of how multiple ethnographers working together actually share their experiences of conducting team ethnography. There is also an associated lack of explanation regarding how evidence and conclusions are drawn from such collective endeavour. This article attempts to address this absence of detail regarding the practice and conduct of team ethnography. In the following account, the authors present details of the design, development and application of ‘team ethnography visual maps’ and the collaborative reflexivity that took place within ‘team ethnography data sessions’ that were each embedded within a mixed methods study of frontline services located in six different National Health Service Trusts throughout England (UK). After a presentation of the ethnographic methods and analyses that occurred as part of team ethnography, they are then discussed in terms of their applied and academic value from a methodological perspective.
Systematic Video Analysis of Anterior Cruciate Ligament Injuries in Professional Male Rugby Players: Pattern, Injury Mechanism, and Biomechanics in 57 Consecutive Cases
Authors: Della Villa Francesco , Tosarelli Filippo , Ferrari Rocco , Grassi Alberto , Ciampone Luca , Nanni Gianni , Zaffagnini Stefano , Buckthorpe Matthew
Published: November 2021

Background:

Anterior cruciate ligament (ACL) injuries represent a significant burden to rugby players. Improving our understanding of the patterns and biomechanics that result in ACL injury may aid in the design of effective prevention programs.

Purpose:

To describe, using video analysis, the mechanisms, situational patterns, and biomechanics of ACL injuries in professional rugby matches. Further aims were to document injuries according to pitch location and timing within the match.

Study Design:

Case series; Level of evidence, 4.

Methods:

A total of 62 ACL injuries were identified in players of the 4 most important rugby leagues across 4 consecutive seasons. We analyzed 57 (92%) injury videos for injury mechanism and situational patterns; biomechanical analysis was performed on indirect and noncontact ACL injuries only (38 cases available). Three reviewers independently evaluated each video.

Results:

More injuries occurred while attacking than defending (41 [72%] vs 16 [28%]; P < .01). Regarding mechanism, 18 (32%) injuries were direct contact; 15 (26%), indirect contact; and 24 (42%), noncontact. Most direct contact injuries involved being tackled directly to the knee (n = 10). Three situational patterns were identified for players who had a noncontact or indirect contact injury: offensive change of direction (COD) (n = 18), being tackled (n = 10), and pressing/tackling (n = 8). Injuries generally involved a knee-loading strategy in the sagittal plane, which was accompanied by knee valgus loading in most cases (94%). Overall, 73% of injuries occurred during the first 40 minutes of effective playing time.

Conclusion:

Most ACL injuries in professional male rugby players happened through a noncontact or indirect contact mechanism (68%). Three situational patterns were described, including offensive change of direction, being tackled, and pressing/tackling. Biomechanical analysis confirmed a multiplanar mechanism, with a knee-loading pattern in the sagittal plane accompanied by dynamic valgus. As most injuries occurred in the first 40 minutes, accumulated fatigue appears not to be a major risk factor for ACL injury.
Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy
Authors: Chiesa Robert , Boelens Jaap Jan , Duncan Christine N. , Kühl Jörn-Sven , Sevin Caroline , Kapoor Neena , Prasad Vinod K. , Lindemans Caroline A. , Jones Simon A. , Amartino Hernan M. , Algeri Mattia , Bunin Nancy , Diaz-de-Heredia Cristina , Loes Daniel J. , Shamir Esther , Timm Alison , McNeil Elizabeth , Dietz Andrew C. , Orchard Paul J.
Published: November 2021

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy can stabilize neurologic function and improve survival but has associated risks including transplant-related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n = 16) with Loes score >9 or neurological function score (NFS) >1 and 2 early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n = 24] and ED2 [Loes >4-9 and NFS ≤1; n = 13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) vs AD (41%) cohort (P = .015) and comparable between ED1 and ED2 cohorts (P = .991). The stabilization of neurologic function posttransplant was greater in the ED vs AD cohort, with a median change from baseline at 24 months after allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n = 13), 0.5 and 0 in ED2 (n = 6), and 2.5 and 3.0 (n = 4) in AD cohort. TRM was lower in the ED (7%) compared with the AD (22%) cohort; however, the difference was not significant (P = .094). Transplant-related safety outcomes were also affected by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts vs matched related donors (P = .039), and acute GVHD and graft failure incidences varied by conditioning regimen. This study was registered at www://clinicaltrials.gov as #NCT02204904.
Cost-effectiveness of eltrombopag vs intravenous immunoglobulin for the perioperative management of immune thrombocytopenia
Authors: Kaur Manraj N. , Arnold Donald M. , Heddle Nancy M. , Cook Richard J. , Hsia Cyrus , Blostein Mark , Jamula Erin , Sholzberg Michelle , Lin Yulia , Kassis Jeannine , Larratt Loree , Tinmouth Alan , Carruthers Julie , Li Na , Liu Yang , Xie Feng
Published: November 2021

Eltrombopag has been shown to be noninferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50 mg daily starting dose, with IVIG 1 or 2 g/kg (according to local practice) from a Canadian public health care payer’s perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n = 38; IVIG, n = 36), and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using nonparametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian per patient. Compared with IVIG, the probability of eltrombopag being cost effective was 70% even with no willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2 g/kg), eltrombopag saved $2,714 per patient, whereas with the lower dose of IVIG (1 g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated noninferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.
Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia
Authors: Morimoto Yuki , Chonabayashi Kazuhisa , Kawabata Hiroshi , Okubo Chikako , Yamasaki-Morita Makiko , Nishikawa Misato , Narita Megumi , Inagaki Azusa , Nakanishi Kayoko , Nagao Miki , Takaori-Kondo Akifumi , Yoshida Yoshinori
Published: November 2021

X-linked sideroblastic anemia (XLSA) is associated with mutations in the erythroid-specific δ-aminolevulinic acid synthase (ALAS2) gene. Treatment of XLSA is mainly supportive, except in patients who are pyridoxine responsive. Female XLSA often represents a late onset of severe anemia, mostly related to the acquired skewing of X chromosome inactivation. In this study, we successfully generated active wild-type and mutant ALAS2-induced pluripotent stem cell (iPSC) lines from the peripheral blood cells of an affected mother and 2 daughters in a family with pyridoxine-resistant XLSA related to a heterozygous ALAS2 missense mutation (R227C). The erythroid differentiation potential was severely impaired in active mutant iPSC lines compared with that in active wild-type iPSC lines. Most of the active mutant iPSC-derived erythroblasts revealed an immature morphological phenotype, and some showed dysplasia and perinuclear iron deposits. In addition, globin and HO-1 expression and heme biosynthesis in active mutant erythroblasts were severely impaired compared with that in active wild-type erythroblasts. Furthermore, genes associated with erythroblast maturation and karyopyknosis showed significantly reduced expression in active mutant erythroblasts, recapitulating the maturation defects. Notably, the erythroid differentiation ability and hemoglobin expression of active mutant iPSC-derived hematopoietic progenitor cells (HPCs) were improved by the administration of δ-aminolevulinic acid, verifying the suitability of the cells for drug testing. Administration of a DNA demethylating agent, azacitidine, reactivated the silent, wild-type ALAS2 allele in active mutant HPCs and ameliorated the erythroid differentiation defects, suggesting that azacitidine is a potential novel therapeutic drug for female XLSA. Our patient-specific iPSC platform provides novel biological and therapeutic insights for XLSA.