bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C045: CA19-9-mediated remodeling of the pancreatic tumor microenvironment
Authors: Hsu Jasper , Chung Sejin , Rock Angelica E. , Okhovat Shira R. , Engle Dannielle D.
Published: November 2022

Pancreatic ductal adenocarcinoma (PDA) is an intractable common malignancy with a pro-tumorigenic and immunosuppressive microenvironment (ME) that often limits treatment efficacy. The glycan CA19-9 is used to follow treatment response in PDA patients, but its functional role in PDA remained unknown until recently because rodents lack this carbohydrate. CA19-9 elevation in a KRAS-mutant background promotes rapid progression to invasive carcinoma and induces ME remodeling in mice. The tumor ME includes cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) that contribute to desmoplasia, immunosuppression, and therapeutic resistance. All prior work investigating the tumor ME in PDA mouse models was performed in a CA19-9 negative context, potentially missing a key element of PDA biology. Elevation of CA19-9 in mice caused expansion of both CAFs and TAMs, but the mechanisms by which CA19-9 contributes to ME remodeling remains largely unknown. We aim to uncover the direct and indirect mechanisms of CA19-9-mediated ME remodeling. We identified CA19-9 modified ligands by immunoprecipitation and mass spectrometry that may contribute to reprogramming of the PDA ME. In addition to exploring changes in abundance, localization, and protein interactions, we will functionally characterize these candidate effectors via CRISPR ablation and antibody blockade using a novel Macrophage, Organoid, and Fibroblast (MOrF) co-culture platform. MOrF co-cultures can be sustained for at least 10 days in defined media conditions and enable compartment specific delineation of paracrine and juxtacrine signals. While CA19-9 modification may play a direct role in stromal remodeling, we also investigate effectors that are altered in response to CA19-9 elevation. CA19-9 induction in KRAS-mutant organoid mono-cultures increased gene expression of IL1α, CSF1,and TGFβ. In addition, CA19-9 expression increased gene set enrichment of inflammatory programs inorganoid mono-culture and led to increased expression of CAF and TAM differentiation programs in MOrF co-culture. These results are being validated as discussed above as well as by evaluation in vivo in CA19-9 positive and negative syngeneic orthotopic transplantation and autochthonous genetically engineered mouse models using scRNA-seq, pharmacologic and genetic perturbation, as well as other approaches. Using these orthogonal approaches, we will identify the mechanisms by which CA19-9 directly and indirectly contributes to PDA ME remodeling and ultimately, contributes to treatment response in the future.

Citation Format: Jasper Hsu, Sejin Chung, Angelica E. Rock, Shira R. Okhovat, Dannielle D. Engle. CA19-9-mediated remodeling of the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C045.
Abstract C046: Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment
Authors: Kim Rina , Hashimoto Ayumi , Markosyan Nune , Tyurin Vladimir A. , Tyurina Yulia Y. , Fu Shuyu , Sehgal Mohit , Garcia-Gerique Laura , Kar Gozde , Kossenkov Andrew , Gebregziabher Bereket A. , Tobias John W. , Hicks Kristin , Deng Hui , Donthireddy Laxminarasimha , Greenberg Andrew , Nam Brian , Nefedova Yulia , Kagan Valerian E. , Vonderheide Robert H. , Gabrilovich Dmitry
Published: November 2022

Myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) function as an immunosuppressive shield that protects the tumor from the host’s immune system and considered a barrier to effective immunotherapy. Here, we focused on polymorphonuclear (PMN)-MDSCs, the most prevalent MDSCs in the TME, to identify mechanisms regulating their maintenance, turnover, and accumulation. Using four mouse models of cancer including autochthonous pancreatic adenocarcinoma from KPC genetically engineered mice (KrasG12D/p53R172H, PdxCre), we found that PMN-MDSCs spontaneously die by ferroptosis, a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Only PMN-MDSCs within the TME were observed to spontaneously undergo ferroptosis. In mice, ferroptosis-related gene expression in CD11b+L6ClowLy6G+ PMN-MDSC isolated from bone marrow, spleen, and tumor demonstrated tumor-specific ferroptosis across tumor models. In humans, whole transcriptomic analysis of PMN-MDSC sorted from tumors and matched blood of lung cancer patients vs blood of healthy donors revealed up-regulation of genes involved in the regulation of ferroptosis in tumor PMN-MDSC. Ferroptosis gene signatures correlated with the PMN-MDSC signatures in pancreatic cancer patients and was associated with worse overall survival. Thus, ferroptosis is an unappreciated, prominent pathway of cell death of PMN-MDSCs in cancer linked to clinical outcome in patients with pancreatic cancer.

Citation Format: Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Gozde Kar, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Yulia Nefedova, Valerian E. Kagan, Robert H. Vonderheide, Dmitry Gabrilovich. Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C046.
Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment
Authors: Cornwell Abigail C. , Alahmari Abdulrahman A. , Tisdale Arwen A. , Maraszek Kathryn , Venkat Swati , Feigin Michael E.
Published: November 2022

Benzodiazepines (BZDs) are a class of drugs commonly prescribed to pancreatic ductal adenocarcinoma (PDAC) patients to treat anxiety, anticipatory nausea prior to chemotherapy, and insomnia. We discovered that approximately 1 in 4 pancreatic cancer patients are prescribed BZDs and that significant differences in survival outcomes are associated with the type of BZD prescribed. Lorazepam is associated with poorer recurrence-free survival (HR 3.83 (1.53,9.57)) while alprazolam is associated with improved recurrence-free survival (HR 0.38 (0.16,0.92)). We hypothesize that these differences in survival result from off-target activation of the proton-sensing GPCR, GPR68, by n-unsubstituted BZDs, such as lorazepam. GPR68 is preferentially expressed in PDAC cancer-associated fibroblasts (CAFs). We found that n-unsubstituted BZDs commonly prescribed to PDAC patients potentiate activation of GPR68 in the presence of acidity, subsequently promoting secretion of IL-6 by CAFs in a GPR68-dependent manner. Conversely, we found that n-substituted BZDs, such as alprazolam, decrease IL-6 secretion by CAFs in a GPR68-independent manner. Using a syngeneic KPC transplant model, we found that tumors from mice treated with lorazepam had increased expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Histologically, lorazepam-treated tumors had increased levels of collagen, alpha-smooth muscle actin staining, and high levels of ischemic necrosis in the centers of the tumors. Overall, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, which may subsequently impact chemotherapeutic efficacy and patient survival.

Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C048.
Abstract C069: Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment
Authors: Kemp Samantha B. , Georgescu Andrei , Pitarresi Jason , Katsuda Takeshi , Kim Il-Kyu , Racca Dora , Tobias John , Huh Dan , Stanger Ben
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is overwhelmingly resistant to therapy. PDAC tumors are characterized by an immunosuppressive fibroinflammatory stroma and can be broadly classified into those with an abundance of T cells or a paucity of T cells. Our lab has previously identified several tumor cell intrinsic factors that regulate the degree of T cell infiltration and response to immunotherapy, but it remains unknown how these factors influence T cell trafficking through the vasculature to the tumor. We used in vivo models and a cancer-on-a-chip platform to examine immune-vascular crosstalk in the pancreatic tumor microenvironment (TME). We first sought to characterize the vascular landscape in PDAC. Following up from previous work in the lab, we used bulk RNA sequencing appraoches to identify a subset of hyper-vascular murine PDAC lines. Using an in vivo dextran assay, we determined that endothelial-high tumors have increased vascular perfusion. We next utilized an in vitro tube formation assay to assess if the defects seen in tumor vasculature are from tumor-cell derived factors. Endothelial cells cultured in conditioned media from endothelial-low tumors had defects in tubule formation. We further identified endothelial-low tumors have a defect in pericyte coverage of the vessel. We next utilized organ-on-a-chip devices to assess angiogenesis in PDAC. Endothelial cells and fibroblasts self-assemble into a 3D vascular network when incorporated into the microdevices. In the absence of tumor cells, mature vascular networks formed on day 4 of culture. Interestingly, vascular networks formed faster in the presence of PDAC tumor cells, suggesting a tumor derived factor enhanced angiogenesis. The cancer-on-a-chip devices are perfusable and allow for the incorporation of other TME components. Future directions, include incorporation of myeloid cells and perfusing fluorescently labeled T cells into the vascular networks and using live imaging to monitor T cell trafficking in different PDAC TME settings. Further, we will use immune checkpoint blockade and CAR T cells to identify methods to enhance tumoral T cell infiltration.

Citation Format: Samantha B. Kemp, Andrei Georgescu, Jason Pitarresi, Takeshi Katsuda, Il-Kyu Kim, Dora Racca, John Tobias, Dan Huh, Ben Stanger. Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C069.
Abstract C076: Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival
Authors: Attebury Holly B.
Published: November 2022

Bacterial dysbiosis is emerging as an accomplice to carcinogenesis and is associated with pancreatic cancer progression and poorer survival. We found that gut bacteria can directly access the pancreas, and pancreatic tumors harbor a unique microbiome that differs from that of the healthy pancreas. We have also found that the tumor-associated microbiome regulates pancreatic cancer progression by skewing tumor-infiltrating immune cells towards an immunosuppressive phenotype. However, the exact mechanisms via which bacteria regulate immune cell function is still unknown. Inflammatory signaling by cancer cells and stromal cells in the tumor microenvironment has been shown to effectively regulate immune cell infiltration and differentiation. Our data suggests that pathogenic bacteria in the pancreatic tumor microenvironment can directly engage with pancreatic epithelial cells inducing proliferation and an inflammatory response. Specifically, the dominant Proteobacteria in the pancreatic tumor microenvironment induces the production of many pro-tumorigenic cytokines, such as IL-8 and IL-6, from cancer cells and pancreatic epithelial cells. Furthermore, we have found that pancreatic tumor- associated bacteria skews fibroblast differentiation towards an inflammatory, tumor-promoting phenotype. These findings show that pathogenetic tumor-associated bacteria can modulate the epithelial and stromal compartments in the pancreatic tumor microenvironment, thereby serving as mediators of tumorigenesis. Our results delineate the mechanisms via which microbes interface with the non-immune cell compartment in the tumor microenvironment and provide insight into therapeutic strategies for gut microbial modulation in treating pancreatic cancer.

Citation Format: Holly B. Attebury. Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C076.
Abstract IA008: The origins and function of copy number alterations in pancreas cancer
Authors: Lowe Scott W.
Published: November 2022

Pancreas ductal adenocarcinoma is a devastating disease that lacks effective treatment options. Often considered genetically homogenous, it is initiated by activation of oncogenic Kras and often sustains inactivating mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes. However, additionally, advanced full blown PDAC often has a large degree of somatic copy number alterations (CNA) whose significance to disease etiology are poorly understood. Interestingly, gene mutations and copy number events may be interconnected, as TP53 mutations are strongly associated with the emergence of tumors harboring large number of CNAs, detectable chromothripsis, extensive intratumoral heterogeneity, and are often polyploid. Using new mouse modeling and genetic engineering approachs, we have begun to explore the emergence and functionality of copy number alterations in human PDAC. The current presentation will focus on the evolution of highly rearranged tumors that arise in Kras mutant pancreatic epithelial cells that sporadically inactivate p53, as well as the cell extrinsic functions of so-called CDKN2A deletions. The work highlights the fundamental importance of copy number events in PDAC.

Citation Format: Scott W. Lowe. The origins and function of copy number alterations in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA008.
Abstract IA017: The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma
Authors: Perez Kimberly
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration. In this talk, I will review our understanding of the role of the VDR in PDAC, including the proposed mechanisms of growth inhibition, transcriptional profile changes in VDR agonist-treated tumors, and the impact on the immune tumor environment in VDR agonist-treated tumors. I will present the preliminary results of the safety run-in of a two-stage randomized phase 2 study (NCT03520790) evaluating the clinical impact of paricalcitol, a synthetic VDR agonist, when given with standard systemic chemotherapy of gemcitabine and nab-paclitaxel in previously untreated patients with metastatic PDAC. In the run-in stage, 36 patients were randomized 1:1:1 to gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) given 3 weeks on and 1 week off in addition to: paricalcitol 75 mcg IV weekly, paricalcitol 16 mg oral daily, or placebo oral daily. Lastly, I will present the preliminary analysis of the pre-treatment and on-treatment (after 6-8 weeks of therapy) tissue biopsies taken from patients participating in this study, highlighting the results of whole transcriptome sequencing and multiplex spatial analyses used to characterize VDR signaling activity and the tumor microenvironment.

Citation Format: Kimberly Perez. The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA017.
BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation
Authors: Chen Haobin , Gesumaria Lisa , Park Young-Kwon , Oliver Trudy G. , Singer Dinah S. , Ge Kai , Schrump David S.
Published: November 2022

Small-cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promising targets in SCLC-N subtype tumors.

Implications:

Our findings suggest that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.
Sex Determination and Ovarian Development in Reptiles and Amphibians: From Genetic Pathways to Environmental Influences
Authors: Smaga Christopher R. , Bock Samantha L. , Johnson Josiah M. , Parrott Benjamin B.
Published: November 2022

Background: Reptiles and amphibians provide untapped potential for discovering how a diversity of genetic pathways and environmental conditions are incorporated into developmental processes that can lead to similar functional outcomes. These groups display a multitude of reproductive strategies, and whereas many attributes are conserved within groups and even across vertebrates, several aspects of sexual development show considerable variation. Summary: In this review, we focus our attention on the development of the reptilian and amphibian ovary. First, we review and describe the events leading to ovarian development, including sex determination and ovarian maturation, through a comparative lens. We then describe how these events are influenced by environmental factors, focusing on temperature and exposure to anthropogenic chemicals. Lastly, we identify critical knowledge gaps and future research directions that will be crucial to moving forward in our understanding of ovarian development and the influences of the environment in reptiles and amphibians. Key Messages: Reptiles and amphibians provide excellent models for understanding the diversity of sex determination strategies and reproductive development. However, a greater understanding of the basic biology of these systems is necessary for deciphering the adaptive and potentially disruptive implications of embryo-by-environment interactions in a rapidly changing world.
Selective Fetoscopic Laser Photocoagulation or Expectant Management for Stage I Twin-Twin Transfusion: A Cost-Effectiveness Analysis
Authors: Stone Jordan S. , Shaaban Aimen F. , Grobman William A. , Premkumar Ashish
Published: November 2022

Background: Selective fetoscopic laser photocoagulation (SFLP) is the preferred intervention for stage II-IV twin-twin transfusion syndrome (TTTS); however, there is no consensus on whether SFLP or expectant management (EM) is the preferred strategy to manage Quintero stage I TTTS. Objective: The objective of this study is to estimate whether SFLP or EM is the cost-effective strategy for management of Quintero stage I TTTS. Study Design: A decision-analysis (DA) model compared SFLP to EM for 1,000 pregnant people with monochorionic-diamniotic twins affected by stage I TTTS. All subjects were assumed to be appropriate candidates for either SFLP or EM. Probabilities, costs, and utilities were derived from the literature. The DA was conducted from a healthcare payor perspective, and the analytic horizon was over the course of an offspring’s lifetime, with primary outcomes of survivorship (i.e., no intrauterine fetal demise or neonatal death) and long-term neurodevelopmental impairment. The model incorporated Markov processes with 4-week cycles throughout pregnancy. Incremental cost-effectiveness ratios (ICER) for each strategy were calculated and compared to estimate marginal cost effectiveness. An ICER of USD 100,000 per quality-adjusted life year was used to define the cost-effectiveness threshold. One-way sensitivity and Monte Carlo analyses (MCA), as well as microsimulations, were performed. Results: For base-case estimates, SFLP was found to be cost-effective compared to EM in the management of stage I TTTS. In one-way sensitivity analysis, varying each variable along pre-specified ranges did not result in changes in the conclusion. MCA projects SFLP as the cost-effective strategy in 100% of runs. Conclusions: With base-case estimates, SFLP is estimated to be the cost-effective strategy for the treatment of Quintero stage I TTTS when compared with EM. This remained true across a wide range of inputs.
Anemia in Celiac Disease: Multiple Aspects of the Same Coin
Authors: Kokoris Styliani , Gavriilaki Eleni , Vrigκou Eleni , Triantafyllou Konstantinos , Roumelioti Anna , Kyriakou Elias , Lada Evangelia , Gialeraki Argyri , Kalantzis Dimitrios , Grouzi Elisavet
Published: November 2022

Extraintestinal manifestations of celiac disease (CD) are an integral part of the disease’s clinical profile and, frequently, appear as the presenting feature. Given that anemia in CD may be multifactorial, increased awareness is needed on the part of treating physicians, and especially hematologists, to screen for CD. In this study, we highlight anemia as the presenting feature of CD which has remained undiagnosed for several years. In patients with a positive antibody testing or high suspicion of CD, endoscopy with a biopsy of the small intestine is performed, as it is considered the “gold standard” for diagnosing CD. Since most of the manifestations of CD are preventable or treatable with a gluten-free diet, an early diagnosis is vital for the prevention of serious and potentially lethal complications.
Changes in Management Preference of Deep Carious Lesions and Exposed Pulps: Questionnaire Studies with a 10-Year Interval among Dentists in Lithuania
Authors: Stangvaltaite-Mouhat Lina , Stankeviciene Indre , Brukiene Vilma , Puriene Alina , Drachev Sergei N.
Published: November 2022

We aimed to investigate changes in management preferences for deep carious lesions and pulps exposed during carious tissue removal that occurred during the last 10 years and identify associated dentists’ background factors. The data were collected among dentists registered with the Lithuanian Dental Chamber at two time points using a similar questionnaire. In 2011, 400 randomly selected dentists received a questionnaire by mail, and 153 (38.3%) responded. In 2021, an electronic invitation to an online questionnaire was sent to all members of the Lithuanian Dental Chamber, and 213 (8.9%) dentists responded. The questionnaire included the definitions of management options, a radiograph, and a clinical picture of a deep carious lesion reaching to the inner fourth of dentine in a mature permanent tooth, asked management preferences in four different scenarios, as well as participants’ background characteristics, reasons for management, and procedural preferences. Data were analyzed using bivariate and multivariable analyses. Compared to 2011, participants in 2021 had 60% lower odds of preferring nonselective versus selective caries removal (OR 0.4, 95% CI 0.2–0.7) and endodontic treatment versus nonselective and selective caries removal (OR 0.4, 95% CI 0.2–0.6) in the scenario of asymptomatic and symptomatic (indicating reversible pulpitis at most) deep lesions, respectively. For exposed pulp, participants in 2021 had lower odds than in 2011 of preferring endodontic treatment versus vital pulp therapy (direct pulp capping and pulpotomies) for both scenarios without symptoms (OR 0.4, 95% CI 0.2–0.7) and with symptoms (OR 0.2, 95% CI 0.1–0.4). A higher proportion of respondents in 2021 reported using rubber dam (44% vs. 17% in 2011, p < 0.001) and hydraulic calcium silicate cements as a capping material (68% vs. 40% in 2011, p < 0.001). The management preferences were associated with the university of graduation and the number of years in dental practice, indicating “recommended in textbooks” and “recommended in scientific publications” as reasons for management preferences. To conclude, a change toward less invasive management options was observed. To a certain extent, dentists have implemented evidence-based recommendations in dental practice. To ensure further adoption of scientific evidence, dentists should be encouraged to update themselves on the newest evidence-based practices.
Integrating Genomics into the Care of People with Palliative Needs: A Global Scoping Review of Policy Recommendations
Authors: White Stephanie , McErlean Gemma , Virdun Claudia , Phillips Jane L. , Jacobs Chris
Published: November 2022

Background: Genomics has growing relevance to palliative care, where testing largely benefits relatives. Integrating genomics into palliative care has not received the critical attention it requires. Health professionals report a lack of policy guidance to support them to overcome practice barriers to identify palliative patients who are eligible for genetic testing, provide genetic counselling, and facilitate genetic testing or DNA storage. Summary: To identify policy recommendations related to (1) integrating genomics into the care of patients with palliative care needs and their families and (2) care of the family unit, we performed a scoping review of palliative care and genomic policies. Two of 78 policies recommended integrating genomics into palliative care. Six palliative care policies mentioned genomics in background information but were without relevant recommendations. No genomic policies mentioned palliative care in the background information. Across all policies, “delivering family centred care” was the most frequent recommendation related to care of the family unit (n = 62/78, 79.5%). Key Messages: We identified a policy gap related to integrating genomics into palliative care. Without policy guidance, health services are less likely to commit funding towards supporting health professionals. Without funding, delivering the benefits of genomics to patients and relatives is more difficult for health professionals. Framing recommendations about genomics as family centred care may resonate with genomic and palliative care stakeholders. These findings highlight an opportunity to improve the policy landscape and access to genomic information for patients with palliative care needs. We call for incorporation of appropriate recommendations into palliative care and genomic policy.
Clinical and Socioeconomic Determinants of Angiotensin Receptor-Neprilysin Inhibitor Prescription at Hospital Discharge in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Tran Jeffrey S. , Loveland Macklin G. , Alamer Ahmad , Piña Ileana L. , Sweitzer Nancy K.
Published: November 2022

Background:

Angiotensin receptor-neprilysin inhibitor (ARNI) prescription in the United States remains suboptimal despite strong evidence for efficacy and value in heart failure with reduced ejection fraction. Factors responsible for under prescription are not completely understood. Economic limitations may play a disproportionate role in reduced access for some patients.

Methods:

This is an analysis of the Get With The Guidelines-Heart Failure registry, supplemented with data from the Distressed Community Index. Data were fit to a mixed-effects regression model to investigate clinical and socioeconomic factors associated with ARNI prescription at hospital discharge. Missing data were handled by multilevel multiple imputation.

Results:

Of the 136 144 patients included in analysis, 12.6% were prescribed an ARNI at discharge. The dominant determinants of ARNI prescription were ARNI use while inpatient (odds ratio [OR], 72 [95% CI, 58–89];
P
<0.001) and taking an ARNI before hospitalization (OR 9 [95% CI, 7–13];
P
<0.001). Having an ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB)/ARNI contraindication was associated with lower likelihood of ARNI prescription at discharge (OR, 0.11 [95% CI, 0.10–0.12];
P
<0.001). Socioeconomic factors associated with lower likelihood of ARNI prescription included having no insurance (OR, 0.60 [95% CI, 0.50–0.72];
P
<0.001) and living in a ZIP Code identified as distressed (OR, 0.81 [95% CI, 0.70–0.93];
P
=0.010). The rate of ARNI prescription is increasing with time (OR, 2 [95% CI, 1.8–2.3];
P
<0.001 for patients discharged in 2020 as opposed to 2017), but the disparity in prescription rates between distressed and prosperous communities appears to be increasing.

Conclusions:

Multiple medical and socioeconomic factors contribute to low rates of ARNI prescription at hospital discharge. Potential targets for improving ARNI prescription rates include initiating ARNIs during hospitalization and aggressively addressing patients’ access barriers with the support of inpatient social services and pharmacists.
Improving Fairness in the Prediction of Heart Failure Length of Stay and Mortality by Integrating Social Determinants of Health
Authors: Li Yikuan , Wang Hanyin , Luo Yuan
Published: November 2022

Background:

Machine learning (ML) approaches have been broadly applied to the prediction of length of stay and mortality in hospitalized patients. ML may also reduce societal health burdens, assist in health resources planning and improve health outcomes. However, the fairness of these ML models across ethnoracial or socioeconomic subgroups is rarely assessed or discussed. In this study, we aim (1) to quantify the algorithmic bias of ML models when predicting the probability of long-term hospitalization or in-hospital mortality for different heart failure (HF) subpopulations, and (2) to propose a novel method that can improve the fairness of our models without compromising predictive power.

Methods:

We built 5 ML classifiers to predict the composite outcome of hospitalization length-of-stay and in-hospital mortality for 210 368 HF patients extracted from the Get With The Guidelines-Heart Failure registry data set. We integrated 15 social determinants of health variables, including the Social Deprivation Index and the Area Deprivation Index, into the feature space of ML models based on patients’ geographies to mitigate the algorithmic bias.

Results:

The best-performing random forest model demonstrated modest predictive power but selectively underdiagnosed underserved subpopulations, for example, female, Black, and socioeconomically disadvantaged patients. The integration of social determinants of health variables can significantly improve fairness without compromising model performance.

Conclusions:

We quantified algorithmic bias against underserved subpopulations in the prediction of the composite outcome for HF patients. We provide a potential direction to reduce disparities of ML-based predictive models by integrating social determinants of health variables. We urge fellow researchers to strongly consider ML fairness when developing predictive models for HF patients.
Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants
Authors: Di Maria Michael V. , Goldberg David J. , Zak Victor , Hu Chenwei , Lubert Adam M. , Dragulescu Andreea , Mackie Andrew S. , McCrary Andrew , Weingarten Angela , Parthiban Anitha , Goot Benjamin , Goldstein Bryan H. , Taylor Carolyn , Lindblade Christopher , Petit Christopher J. , Spurney Christopher , Harrild David M. , Urbina Elaine M. , Schuchardt Eleanor , Beom Kim Gi , Kyoung Yoon Ja , Colombo Jamie N. , Files Matthew D. , Schoessling Megan , Ermis Peter , Wong Pierre C. , Garg Ruchira , Swanson Sara K. , Menon Shaji C. , Srivastava Shubhika , Thorsson Thor , Johnson Tiffanie R. , Krishnan Usha S. , Paridon Stephen M. , Frommelt Peter C. ,   for the Pediatric Heart Network
Published: November 2022

Background:

The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied.

Methods:

The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value.

Results:

The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (
P
=0.03, adjusted mean difference [SE] of changes between groups −0.03[0.01]), atrioventricular valve inflow peak E (
P
=0.009, 3.95 [1.50]), and A velocities (
P
=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e′ velocity (
P
=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e′ ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s′ and e′ velocity).

Conclusions:

FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort.

Registration:

URL:
https://clinicaltrials.gov
; Unique Identifier: NCT02741115.
Decision-Making During Percutaneous Coronary Intervention Guided by Optical Coherence Tomography: Insights From the LightLab Initiative
Authors: Bergmark Brian , Dallan Luis A.P. , Pereira Gabriel T.R. , Kuder Julia F. , Murphy Sabina A. , Buccola Jana , Wollmuth Jason , Lopez John , Spinelli Joia , Meinen Jennifer , West Nick E.J. , Croce Kevin ,   on behalf of the LightLab Initiative Investigators
Published: November 2022

BACKGROUND:

Use of intracoronary imaging is associated with improved outcomes in patients undergoing percutaneous coronary intervention (PCI). Yet, the impact of intracoronary imaging on real-time physician decision-making during PCI is not fully known.

METHODS:

The LightLab Initiative is a multicenter, prospective, observational study designed to characterize the use of a standardized optical coherence tomography (OCT) workflow during PCI. Participating physicians performed pre-PCI and post-PCI OCT in accordance with this workflow and operator assessments of lesion characteristics and treatment plan were recorded for each lesion based on angiography alone and following OCT. Physicians were categorized as having low (n=15), intermediate (n=13), or high (n=14) OCT use in the year preceding participation.

RESULTS:

Among 925 patients with 1328 lesions undergoing PCI, the prescribed OCT workflow was followed in 773 (84%) of patients with 836 lesions. Operator lesion assessment and decision-making during PCI changed with OCT use in 86% (721/836) of lesions. Pre-PCI OCT use changed operator decision-making in 80% of lesions, including lesion assessment (45%), vessel preparation strategy (27%), stent diameter (37%), and stent length (36%). Post-PCI OCT changed stent optimization decision-making in 31% of lesions. These findings were consistent across strata of physician prior OCT experience.

CONCLUSIONS:

A standardized OCT workflow impacted PCI decision-making in 86% of lesions, with a predominant effect on pre-PCI lesion assessment and planning of treatment strategy. This finding was consistent regardless of operator experience level and provides insight into mechanisms by which intravascular imaging might improve PCI outcomes.
Improvements and Maintenance of Clinical and Functional Measures Among Rural Women: Strong Hearts, Healthy Communities-2.0 Cluster Randomized Trial
Authors: Seguin-Fowler Rebecca A. , Eldridge Galen D. , Rethorst Chad D. , Graham Meredith L. , Demment Margaret , Strogatz David , Folta Sara C. , Maddock Jay E. , Nelson Miriam E. , Ha Seungyeon
Published: November 2022

Background:

Cardiovascular disease is the leading cause of death in the United States; however, women and rural residents face notable health disparities compared with male and urban counterparts. Community-engaged programs hold promise to help address disparities through health behavior change and maintenance, the latter of which is critical to achieving clinical improvements and public health impact.

Methods:

A cluster-randomized controlled trial of Strong Hearts, Healthy Communities-2.0 conducted in medically underserved rural communities examined health outcomes and maintenance among women aged ≥40 years, who had a body mass index >30 or body mass index 25 to 30 and also sedentary. The multilevel intervention provided 24 weeks of twice-weekly classes with strength training, aerobic exercise, and skill-based nutrition education (individual and social levels), and civic engagement components related to healthy food and physical activity environments (community, environment, and policy levels). The primary outcome was change in weight; additional clinical and functional fitness measures were secondary outcomes. Mixed linear models were used to compare between-group changes at intervention end (24 weeks); subgroup analyses among women aged ≥60 years were also conducted. Following a 24-week no-contact period, data were collected among intervention participants only to evaluate maintenance.

Results:

Five communities were randomized to the intervention and 6 to the control (87 and 95 women, respectively). Significant improvements were observed for intervention versus controls in body weight (mean difference: −3.15 kg [95% CI, −4.98 to −1.32];
P
=0.008) and several secondary clinical (eg, waist circumference: −3.02 cm [−5.31 to −0.73],
P
=0.010; systolic blood pressure: −6.64 mmHg [−12.67 to −0.62],
P
=0.031; percent body fat: −2.32% [−3.40 to −1.24];
P
<0.001) and functional fitness outcomes; results were similar for women aged ≥60 years. The within-group analysis strongly suggests maintenance or further improvement in outcomes at 48 weeks.

Conclusions:

This cardiovascular disease prevention intervention demonstrated significant, clinically meaningful improvements and maintenance among rural, at-risk older women.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03059472.
Experiences Implementing a Suite of Decision Aids for Implantable Cardioverter Defibrillators: Qualitative Insights From the DECIDE-ICD Trial
Authors: Knoepke Christopher E. , Wallace Bryan C. , Allen Larry A. , Lewis Carmen L. , Gupta Sanjaya K. , Peterson Pamela N. , Kramer Daniel B. , Brancato Scott C. , Varosy Paul D. , Mandrola John M. , Tzou Wendy S. , Matlock Daniel D.
Published: November 2022

Background:

Shared decision making (SDM) is gaining importance in cardiology, including Centers for Medicare & Medicaid Services (CMS) reimbursement policies requiring documented SDM for patients considering primary prevention implantable cardioverter defibrillators. The DECIDE-ICD Trial (Decision Support Intervention for Patients offered implantable Cardioverter-Defibrillators) assessed the implementation and effectiveness of patient decision aids (DAs) using a stepped-wedge design at 7 sites. The purpose of this subanalysis was to qualitatively describe electrophysiology clinicians’ experience implementing and using the DAs.

Methods:

This included semi-structured individual interviews with electrophysiology clinicians at participating sites across the US, at least 6 months following conversion into the implementation phase of the trial (from June 2020 through February 2022). The interview guide was structured according to the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance [implementation evaluation model]) framework, assessing clinician experiences, which can impact implementation domains, and was qualitatively assessed using a mixed inductive/deductive method.

Results:

We completed 22 interviews post-implementation across all 7 sites. Participants included both physicians (n=16) and other clinicians who counsel patients regarding treatment options (n=6). While perception of SDM and the DA were positive, participants highlighted reasons for uneven delivery of DAs to appropriate patients. The CMS mandate for SDM was not universally viewed as associating with patients receiving DA’s, but rather (1) logistics of DA delivery, (2) perceived effectiveness in improving patient decision-making, and (3) match of DA content to current patient populations. Remaining tensions include the specific trial data used in DAs and reconciling timing of delivery with when patients are actively making decisions.

Conclusions:

Clinicians charged with delivering DAs to patients considering primary prevention implantable cardioverter defibrillators were generally supportive of the tenets of SDM, and of the DA tools themselves, but noted several opportunities to improve the reach and continued use of them in routine care.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT03374891.
Case in Wholesale Late Merger: Evidence from Mongolian Scrambling
Authors: Gong Zhiyu Mia
Published: November 2022

Takahashi and Hulsey (2009) suggest that wholesale late merger is controlled by case. This article presents novel evidence for this idea from Condition C reconstruction effects in Mongolian local and long-distance scrambling. Departing from previous accounts, I argue that the complexity of the phenomenon reveals that Condition C connectivity is related neither to the position of underlying binders nor to A/Ā-properties—scrambling bleeds Condition C, so long as the case requirement of the late-merged NP can be satisfied. Crucially, I motivate a hybrid case system for Mongolian in which accusative case is assigned as a dependent case. I show that this is both necessary and independently motivated, thereby introducing a fine-grained view of case into the wholesale-late-merger mechanism.
Beyond Oral and Written Prophecy
Authors: Stell Elizabeth
Published: November 2022

This article examines performance as part of the prophetic and revelatory in ancient Jewish literature. The body of the article centres on the so-called “prophetic actions” within the biblical corpus. Scholarship’s use of this category has highlighted nonverbal performance as a part of prophecy but raises questions regarding the efficacy of these varied actions as well as their distinction from written or spoken prophecy. Here I reapply J.L. Austin’s speech act theory to further examine their function. Isaiah 20:1–6 and Jeremiah 51:59–64, my central case studies, demonstrate not only the variety among these performances but also how interwoven they are with prophetic biography, writing, and speech. Exploring such phenomena through this more flexible lens further illuminates the continued significance of performance and prophecy in the Second Temple period, which the article demonstrates using 11QPsalmsa and the Exagoge of Ezekiel.
On the identity of Cryptocoryne pygmaea (Araceae) from Western Mindanao and the description of a new species from the islands of Palawan and Busuanga
Authors: NAIVE MARK ARCEBAL K. , BASTMEIJER JAN D. , JACOBSEN NIELS
Published: November 2022

Recent fieldwork in Zamboanga del Norte resulted in the recollection of the poorly known aquatic aroid, Cryptocoryne pygmaea. In this study, we have clarified the identity of C. pygmaea as well as provided a detailed morphological description based on our recently collected material, updated its geographical distribution information, ecology, phenology, and a proposed conservation status. Through this recollection, it was revealed that plants previously identified as C. pygmaea in Palawan and Busuanga are different, thus we describe them here as C. palawanensis, a species new to science and the eighth representative of the genus for the Philippine archipelago.
Two new species of Acantholaimus (Nematoda, Chromadoridae) from the deep southeastern Atlantic (Santos Basin)
Authors: MANOEL ALEX , ESTEVES ANDRÉ MORGADO , NERES PATRÍCIA FERNANDES
Published: November 2022

Two new species of the genus Acantholaimus (Nematoda, Chromadoridae) are described from the South Atlantic, in the Santos Basin off the slope of southeastern Brazil. Acantholaimus pugious sp. n. is characterized by a narrow and elongated anterior end; teeth that are thin and long stylet-like (two in number), amphidial fovea located far from the anterior end and occupying most of the corresponding body diameter. Acantholaimus bidentatus sp. n. is characterized by a narrow anterior end, cuticle with more evident dots on both body extremities (up to amphidial fovea and tail); two long, protractible thin teeth (similar to stylet), with curved proximal part. The two species are similar in the shape of the teeth. The teeth morphology may be correlated to the process of adaptive convergence of these species. An emended diagnosis of the genus is provided.