bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Road Microsimulation Software within BIM Environments: A Preliminary Assessment
Authors: Botte Marilisa , Zampi Amedeo , Oreto Cristina , D’Acierno Luca
Published: August 2021

The use of Building Information Modelling (BIM) is becoming increasingly adopted worldwide to support the creation and management of digital environments in which physical and functional features of a facility are modelled. Due to its characteristic flexibility and interoperability, it rapidly extends beyond the boundaries of applications for which it was originally conceived, thus being implemented in other contexts such as the infrastructure sector. Indeed, during each phase of the construction process for building a linear infrastructure, a suitable design of a traffic control plan to optimising traffic flows proves crucial, both for drivers and builders. In this context, there arises the need to perform a comprehensive analysis, combining infrastructure design and building issues with transportation theory principles. For this purpose, the paper proposes a comparative analysis of two different approaches relying on BIM-based tools, namely integrated (i.e., BIM environments with an in-built module for transport simulation tasks) and an interfaceable solution (i.e., BIM environments offering a customised interface for external mobility simulation software). Specifically, after an overview of the issues involved, the two solutions analysed are customised according to the software packages adopted, and a numerical application is carried out. The goal of the paper is to perform a preliminary analysis on the potential of such frameworks by means of comparative evaluation aimed at identifying pros and cons of the two approaches, as well as the best field of application, according to the effort required from the designer, the degree of flexibility offered, and the target pursued.
Effect of Entecavir Combined with Adefovir Dipivoxil on Clinical Efficacy and TNF-α and IL-6 Levels in Patients with Hepatitis B Cirrhosis
Authors: Yu Yonghuan , Cui Xinfeng , Zhao Jingjing , Jia Ting , Ren Baofeng , Zhang Xiaoyan
Published: August 2021

Objective. The purpose of the study was to investigate the effect of entecavir combined with adefovir dipivoxil on clinical efficacy and TNF-α and IL-6 levels in patients with hepatitis B cirrhosis. Methods. A total of 100 patients with hepatitis B cirrhosis admitted to our hospital between January 2018 and June 2019 were randomly selected and divided into the control group (n = 50) and experimental group (n = 50) according to the order of admission. Among them, the control group patients were treated with entecavir, while the patients in the experimental group received entecavir combined with adefovir dipivoxil. After that, the effective rate of treatment, the incidence of adverse reactions, liver function indexes, liver fibrosis condition, and TNF-α and IL-6 expression levels were all compared between the two groups. Results. The effective rate of treatment in the experimental group was significantly higher than that in the control group, with statistical significance (

p
<
0.001

); the incidence of adverse reactions of the patients in the experimental group was significantly lower than that in the control group, with statistical significance (

p
<
0.001

); the liver function indexes in the experimental group were significantly better than those in the control group, with statistical significance (

p
<
0.001

); the number of patients with liver fibrosis in the experimental group was significantly less than that in the control group, with statistical significance (

p
<
0.001

); the TNF-α and IL-6 expression levels in the experimental group were significantly lower than those in the control group, with statistical significance (

p
<
0.001

). Conclusion. Entecavir combined with adefovir dipivoxil in the treatment of hepatitis B cirrhosis can effectively improve the therapeutic effect and reduce the serum inflammatory factor levels, with high safety, which is worthy of application and popularization.
Effectiveness of Transcutaneous Electrical Nerve Stimulation with Taping for Stroke Rehabilitation
Authors: In Tae-Sung , Jung Jin-Hwa , Jung Kyoung-Sim , Cho Hwi-Young
Published: August 2021

Background. Spasticity is a factor that impairs the independent functional ability of stroke patients, and noninvasive methods such as electrical stimulation or taping have been reported to have antispastic effects. The purpose of this study was to investigate the effects of transcutaneous electrical nerve stimulation (TENS) combined with taping on spasticity, muscle strength, and gait ability in stroke patients. Methods. From July to October 2020, 46 stroke patients with moderate spasticity in the plantar flexors participated and were randomly assigned to the TENS group (n = 23) and the TENS+taping group (n = 23). All subjects performed a total of 30 sessions of functional training for 30 min/session, 5 days/week, for 6 weeks. For therapeutic exercise, sit‐to‐standing, indoor walking, and stair walking were performed for 10 min each. In addition, all participants in both groups received TENS stimulation around the peroneal nerve for 30 min before performing functional training. In the TENS+taping group, taping was additionally applied to the feet, ankles, and shin area after TENS, and the taping was replaced once a day. The composite spasticity score and handheld dynamometer measurements were used to assess the intensity of spasticity and muscle strength, respectively. Gait ability was measured using a 10 m walk test. Results. The spasticity score and muscle strength were significantly improved in the TENS+taping group compared to those in the TENS group (p < 0.05). A significant improvement in gait speed was observed in the TENS+taping group relative to that in the TENS group (p < 0.05). Conclusions. Thus, TENS combined with taping may be useful in improving spasticity, muscle strength, and gait ability in stroke patients. Based on these results, an additional application of taping could be used to enhance the antispastic effect of TENS or other electrical stimulation treatments in the clinic. A long‐term follow‐up study is needed to determine whether the spasticity relieving effect persists after taping is removed.
Dose Correlation of Panax ginseng and Atractylodes macrocephala Koidz. Drug Pairs in the Chinese Medicine Prescription Based on the Copula Function
Authors: Lin Wei , Zheng Mingyue , Chen Yunhui , He Qian , Khoja Adeel , Long Mingyue , Fan Jiaxin , Hao Yiwen , Fu Chaomei , Hu Peng , Wang Ke , Jiang Jianhua , Zhao Xuan
Published: August 2021

Objective. Panax ginseng and Atractylodes macrocephala Koidz. (AMK) are widely used in treating various diseases; however, research is insufficient on measuring the relationship that exists by combining this drug pair using the copula function. Methods. In this study, 279 traditional Chinese medicine prescriptions containing the Panax ginseng and AMK drug pair were extracted from the prescription database for three types of screened indications, namely, diabetes mellitus, diarrhea, and insomnia. Following the principle of dose conversion, each dynasty unit was uniformly converted into a modern unit. Then, the kernel density distribution of Panax ginseng and AMK was fitted with their empirical distribution functions. Finally, the optimal copula function was selected from the copula function family as a t-copula function. Results. The empirical distribution and probability density functions of Panax ginseng and AMK were obtained. From the results, their Kendall rank correlation coefficients with indications of diabetes mellitus, insomnia, and diarrhea were 0.8689, 0.7858, and 0.7403, whereas their Spearman rank correlation coefficients were 0.9563, 0.9276, and 0.8958. Results also indicated that the use of the t-copula function can better reflect the correlation between Panax ginseng and AMK doses. Conclusion. From the three indications, the dose between Panax ginseng and AMK was positively correlated. This study, therefore, confirms the medicinal principle of Chinese medicine “combining” from the perspective of mathematical statistics. Results from this study are practical to evaluate the correlation between the drug pair doses, Panax ginseng and AMK, using the copula function model, which provides a new model for the scientific explanation of compatibility for Chinese medicines. This study also provides a methodological basis for more drug measurement studies and clinical medications.
Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in aTP53-Dependent Manner
Authors: McDonald James I. , Diab Noor , Arthofer Elisa , Hadley Melissa , Kanholm Tomas , Rentia Uzma , Gomez Stephanie , Yu Angela , Grundy Erin E. , Cox Olivia , Topper Michael J. , Xing Xiaoyun , Strissel Pamela L. , Strick Reiner , Wang Ting , Baylin Stephen B. , Chiappinelli Katherine B.
Published: August 2021

Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response. To understand which REs are affected by epigenetic therapies in ovarian carcinoma, we assessed the effect of DNMTi and HDACi on ovarian carcinoma cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild-type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53-mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild-type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in ovarian carcinoma after epigenetic treatment and implicate p53 in RE transcriptional regulation.

Significance:

This study identifies the repetitive element targets of epigenetic therapies in ovarian carcinoma and indicates a role for p53 in this process.

See interview with Katherine B. Chiappinelli, PhD, recipient of the 2022 Cancer Research Early Career Award: https://vimeo.com/720726570
TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas
Authors: Gonzalez-Buendia Edgar , Zhao Junfei , Wang Lu , Mukherjee Subhas , Zhang Daniel , Arrieta Víctor A. , Feldstein Eric , Kane J. Robert , Kang Seong Jae , Lee-Chang Catalina , Mahajan Aayushi , Chen Li , Realubit Ronald , Karan Charles , Magnuson Lisa , Horbinski Craig , Marshall Stacy A. , Sarkaria Jann N. , Mohyeldin Ahmed , Nakano Ichiro , Bansal Mukesh , James Charles D. , Brat Daniel J. , Ahmed Atique , Canoll Peter , Rabadan Raul , Shilatifard Ali , Sonabend Adam M.
Published: August 2021

Purpose:

The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors.

Experimental Design:

To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes.

Results:

We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA.

Conclusions:

Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.
Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
Authors: Even Caroline , Wang Hung-Ming , Li Shau-Hsuan , Ngan Roger K-C , Dechaphunkul Arunee , Zhang Li , Yen Chia-Jui , Chan Po Chung , Chakrabandhu Somvilai , Ma Brigette B.Y. , Tanasanvimon Suebpong , Lee Victor H.F. , Lou Pei-Jen , Li Zujun , Spira Alexander I. , Sukari Ammar , Guigay Joël , McCune Steven , Gonzalez-Maffe Juan , Szpakowski Sebastian , Yao Yao , Liang Hongzi , Mataraza Jennifer , Séchaud Romain , Manenti Luigi , Lim Darren W-T.
Published: August 2021

Purpose:

No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.

Patients and Methods:

Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice.

Results:

Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression.

Conclusions:

Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.
A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe
Published: August 2021

Purpose:

Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study.

Patients and Methods:

A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200–900 mg/day; arm B, LSZ102 200–600 mg/day plus ribociclib 300–600 mg/day; arm C, LSZ102 300–450 mg/day plus alpelisib 200–300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1).

Results:

The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0–7.0); arm B, 16.9% (9.3–27.1); and arm C, 7.0% (1.5–19.1), and clinical benefit rates 7.8% (2.9–16.2), 35.1% (24.5–46.8), and 20.9% (10.0–36.0), respectively.

Conclusions:

LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.
NEI-01-Induced Arginine Deprivation Has Potent Activity Against Acute Myeloid Leukemia Cells BothIn VitroandIn Vivo
Authors: Cai Yijun , Chow Jeremy P.H. , Leung Yu-On , Lu Xiaoxu , Yuen Chak-Ho , Lee Wing Lun , Chau Ka-Chun , Yang Liz L. , Wong Raymond M.H. , Lam Justin Y.T. , Chow Daniel T.L. , Chung Steven H.K. , Kwok Sui-Yi , Leung Yun-chung
Published: August 2021

Recent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo. NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell-cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft, mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft. This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.
Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages
Authors: Smith Bryan D. , Kaufman Michael D. , Wise Scott C. , Ahn Yu Mi , Caldwell Timothy M. , Leary Cynthia B. , Lu Wei-Ping , Tan Gege , Vogeti Lakshminarayana , Vogeti Subha , Wilky Breelyn A. , Davis Lara E. , Sharma Maitreyi , Ruiz-Soto Rodrigo , Flynn Daniel L.
Published: August 2021

Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.
Gut Microbiota Profiles in Early- and Late-Onset Colorectal Cancer: A Potential Diagnostic Biomarker in the Future
Authors: Abdullah Murdani , Sukartini Ninik , Nursyirwan Saskia Aziza , Pribadi Rabbinu Rangga , Maulahela Hasan , Utari Amanda Pitarini , Muzellina Virly Nanda , Wiraatmadja Agustinus , Renaldi Kaka
Published: August 2021

Background: Researchers believe the role of gut microbiota dysbiosis in the raised incidence of early-onset colorectal cancer (EOCRC). The development of EOCRC may be associated with microbiota dysbiosis either dependently or independently (combined with other risk factors). Summary: Recently, the rising of incidence and mortality of EOCRC have been noted. Some researchers are looking for risk factors influencing this fact. They hypothesize that it may be because of microbiota dysbiosis. Microbiota dysbiosis has been known to promote cancer development through immunity dysregulation and chronic inflammation. Microbiomes profile in late-onset colorectal cancer (LOCRC) among older patients has been documented, but there is still lack of data about microbial profiles among younger colorectal cancer (CRC) patients. This review tries to explain microbial profiles differences between EOCRC and LOCRC as a potential diagnostic biomarker in the future, and whether microbiota can have a role in EOCRC genesis. Key Messages: Microbiota does vary with age, and EOCRC may be associated with colonization of some specific bacteria. Further studies about gut microbiota profiles in EOCRC and LOCRC may provide a new insight on diagnostic biomarker of CRC.
Cardiac Metastasis from Medullary Thyroid Cancers with Long-Term Survival under Vandetanib
Authors: Buffet Camille , Leboulleux Sophie , Kraeber-Bodéré Françoise , Bodet-Milin Caroline , Cabanes Laure , Dohan Anthony , Leprince Pascal , Schlumberger Martin , Huillard Olivier , Groussin Lionel
Published: August 2021

Background: Cardiac metastases from thyroid cancers are uncommon with a poor prognosis. There is a lack of long-term follow-up studies. Cases: We report 2 cases of cardiac metastasis from medullary thyroid cancer (MTC). Both patients presented limited metastatic disease apart from a cardiac metastasis. The initial diagnosis was challenging and was facilitated by functional imaging with an immuno-PET-CT using an anti-CEA bispecific antibody and a 68Ga-labeled peptide. Both patients were treated with the multitarget kinase inhibitor vandetanib with prolonged stability. The first patient was alive at the last follow-up, 14 years after the diagnosis of cardiac metastasis. The second patient required surgical excision of the cardiac mass because of disease progression under vandetanib. Conclusion: These cases illustrate long-term survival and effectiveness of clinical management of 2 patients who developed cardiac metastases from MTC, in the current era of personalized medicine with targeted therapy.
Do SARS-CoV-2 Infection (COVID-19) and the Medications Administered for Its Treatment Impair Testicular Functions?
Authors: Gul Abdullah , Zengin Salim , Dundar Gokce , Ozturk Murat
Published: August 2021

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted primarily via respiratory droplets and enters host cells through angiotensin-converting enzyme 2 (ACE-2) receptors. ACE-2 receptors have been identified in many tissues including testes. The aim of the study has been to investigate the long-term effects of SARS-CoV-2 infection (COVID-19) and its relative treatment on male reproductive health. Methods: Cross-sectional analysis has been performed on 49 recovered COVID-19 patients who had semen analysis prior to the COVID-19 pandemic. Those who had a recovery time lag of at least 3 months have been re-examined, and 29 eligible patients with no andrological problems have been enrolled in the study. Following a detailed physical examination and retrieval of medical history, the values of semen analysis and serum sex hormone parameters have been collected and compared before and after COVID-19 infection. The p value of <0.05 has been considered significant. Results: The average age of the 29 patients has been 31.21 ± 5.48 (range: 18–41) years. Favipiravir has been co-administered with hydroxychloroquine in 17 patients, while the remaining 12 received favipiravir treatment without hydroxychloroquine. The average time between clinical recovery from COVID-19 and collection of semen has been 4.52 ± 1.36 (range: 3–8) months. Before and after COVID-19, serum follicle-stimulating hormone, luteinizing hormone, total testosterone, and prolactin levels, as well as all semen parameters, have been comparable. Conclusion: Our study demonstrated that COVID-19 and its treatment with favipiravir and hydroxychloroquine did not affect spermatogenesis and serum androgen levels in the long-term period. Further clinical studies with larger sample size are needed to confirm and support our findings.
The Association between Baseline and 3-Month Albuminuria and 1-Year Prognosis of Ischemic Stroke
Authors: Wang Dongxue , Pan Yuesong , Li Hao , Yan Hongyi , Meng Xia , Lin Jinxi , Wang Hong , Matsushita Kunihiro , Shlipak Michael G. , Zhou Yilun , Wang Yongjun
Published: August 2021

Introduction: The association between the changes in albuminuria levels and the clinical prognosis of stroke is unknown. The present study aimed to explore the relationships between changes in albuminuria and the risk of adverse stroke outcomes. Methods: The patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry (CNSR-III) who had the urinary albumin-to-creatinine ratio (ACR) detected at baseline and 3-month were recruited. They were classified into 4 groups according to baseline and 3-month ACR and followed up for 1 year. Results: A total of 5,311 patients were finally included in the study. There were 3,738 (70.4%), 483 (9.1%), 451 (8.5%), and 639 (12.0%) patients with no albuminuria, baseline albuminuria, 3-month albuminuria, and persistent albuminuria, respectively. After adjustment for confounding variables, persistent albuminuria was independently associated with all-cause death (hazard ratio [HR], 2.23; 95% CI, 1.17–4.25; p = 0.02), stroke recurrence (HR, 1.55; 95% CI, 1.02–2.36; p = 0.04), and poor functional outcome (OR, 2.22; 95% CI, 1.66–2.96; p < 0.001). Baseline albuminuria was independently associated with poor functional outcome (OR, 1.65; 95% CI, 1.19–2.28; p = 0.003), while 3-month albuminuria was independently associated with stroke recurrence (HR, 1.68; 95% CI, 1.06–2.65; p = 0.03). Conclusions: Changes in albuminuria can predict adverse 1-year outcomes in Chinese ischemic stroke patients. In particular, persistent albuminuria was independently associated with 1-year all-cause death, stroke recurrence, and poor functional outcome.
Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19
Authors: Yeaman Michael R.
Published: August 2021

Background: Glomerular diseases (GD) are chronic conditions that often involve immune dysfunction and require immunosuppressive therapy (IST) to control underlying pathogenesis. Unfortunately, such diseases appear to heighten risks of severe outcomes in COVID-19 and predispose to other infections that may be life-threatening. Thus, averting preventable infections is imperative in GD patients. Summary: The advent of vaccines demonstrated to be safe and efficacious against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has favorably impacted the COVID-19 pandemic epidemiology. However, patients on ISTs were excluded from initial vaccine clinical trials. Thus, only limited and incomplete data are available currently regarding the potential impact of immunosuppression on immune response to or efficacy of the SARS-CoV-2 vaccines. However, new insights are emerging from SARS-CoV-2 vaccine studies, and impacts of ISTs on conventional vaccines are useful to consider. Mechanisms of immunosuppressive agents commonly used in the treatment of GD are reviewed with respect to implications for immune responses induced by SARS-CoV-2 vaccines. ISTs discussed include corticosteroids; alkylating agents; antimetabolites; calcineurin or mammalian target of rapamycin inhibitors; CD38+, CD20+, or CD19+ cell depletion; and complement protein C5 inhibition. Key Messages: Many immunosuppressive therapies may potentially attenuate or impair protective immunity of the SARS-CoV-2 vaccines. However, as vaccines currently in use employ mRNA or nonreplicative viral vectors, they appear to be safe in patients on immunosuppression, further favoring vaccination. Moreover, predominant SARS-CoV-2 vaccines are likely to afford at least partial protective immunity through one or more immune mechanisms even in patients on IST. Guidelines and emerging strategies are also considered to optimize vaccine protection from COVID-19.
Evaluation of Racial and Ethnic Disparities in Cardiac Transplantation
Authors: Chouairi Fouad , Fuery Michael , Clark Katherine A. , Mullan Clancy W. , Stewart James , Caraballo Cesar , Clarke John‐Ross D. , Sen Sounok , Guha Avirup , Ibrahim Nasrien E. , Cole Robert T. , Holaday Louisa , Anwer Muhammed , Geirsson Arnar , Rogers Joseph G. , Velazquez Eric J. , Desai Nihar R. , Ahmad Tariq , Miller P. Elliott
Published: August 2021

Background

Racial and ethnic disparities contribute to differences in access and outcomes for patients undergoing heart transplantation. We evaluated contemporary outcomes for heart transplantation stratified by race and ethnicity as well as the new 2018 allocation system.

Methods and Results

Adult heart recipients from 2011 to 2020 were identified in the United Network for Organ Sharing database and stratified into 3 groups: Black, Hispanic, and White. We analyzed recipient and donor characteristics, and outcomes. Among 32 353 patients (25% Black, 9% Hispanic, 66% White), Black and Hispanic patients were younger, more likely to be women and have diabetes mellitus or renal disease (all,
P
<0.05). Over the study period, the proportion of Black and Hispanic patients listed for transplant increased: 21.7% to 28.2% (
P
=0.003) and 7.7% to 9.0% (
P
=0.002), respectively. Compared with White patients, Black patients were less likely to undergo transplantation (adjusted hazard ratio [aHR], 0.87; CI, 0.84–0.90;
P
<0.001), but had a higher risk of post‐transplant death (aHR, 1.14; CI, 1.04–1.24;
P
=0.004). There were no differences in transplantation likelihood or post‐transplant mortality between Hispanic and White patients. Following the allocation system change, transplantation rates increased for all groups (
P
<0.05). However, Black patients still had a lower likelihood of transplantation than White patients (aHR, 0.90; CI, 0.79–0.99;
P
=0.024).

Conclusions

Although the proportion of Black and Hispanic patients listed for cardiac transplantation have increased, significant disparities remain. Compared with White patients, Black patients were less likely to be transplanted, even with the new allocation system, and had a higher risk of post‐transplantation death.
Recruitment of Black Adults into Cardiovascular Disease Trials
Authors: Prasanna Anagha , Miller Hailey N. , Wu Yingfei , Peeler Anna , Ogungbe Oluwabunmi , Plante Timothy B. , Juraschek Stephen P.
Published: August 2021

Background

Although disproportionately affected by cardiovascular disease, Black adults remain underrepresented in clinical trials. The National Institutes of Health recommends that studies define goals for recruitment of underrepresented populations. However, the extent to which cardiovascular trials incorporate evidence‐based recruitment strategies in their protocols is understudied.

Methods and Results

We systematically reviewed National Institutes of Health‐funded cardiovascular clinical trials registered in ClinicalTrials.gov between 2000 and 2019. Based on publicly available or requested protocols, we focused on enrollment of Black adults as well as the following recruitment strategies: community‐based, electronic medical record‐based, and provider‐based recruitment. A total of 100 clinical trials focused on cardiovascular disease were included in our analysis, of which 62% had published protocols, and 46% of trials had enrolled populations that were <25% Black. In our analysis of available trial protocols, 21% of trials defined a recruitment target for underrepresented groups; however, only one study reported achieving its enrollment goal. While 13% of trial protocols referenced community‐based recruitment strategies, 5% explicitly mentioned involving community members in the trial design process. Defining recruitment targets was associated with higher enrollment of Black participants.

Conclusions

Black adults are underrepresented in National Institutes of Health‐funded cardiovascular trials, and the majority of these trials did not specify a Black enrollment target, did not meet targets, and largely did not report specific plans to enroll Black adults in their studies. Future interventions should target trial design and planning phases before study initiation to address these enrollment disparities.
Geographic and Socioeconomic Disparities in Major Lower Extremity Amputation Rates in Metropolitan Areas
Authors: Fanaroff Alexander C. , Yang Lin , Nathan Ashwin S. , Khatana Sameed Ahmed M. , Julien Howard , Wang Tracy Y. , Armstrong Ehrin J. , Treat‐Jacobson Diane , Glaser Julia D. , Wang Grace , Damrauer Scott M. , Giri Jay , Groeneveld Peter W.
Published: August 2021

Background

Rates of major lower extremity amputation in patients with peripheral artery disease are higher in rural communities with markers of low socioeconomic status, but most Americans live in metropolitan areas. Whether amputation rates vary within US metropolitan areas is unclear, as are characteristics of high amputation rate urban communities.

Methods and Results

We estimated rates of major lower extremity amputation per 100 000 Medicare beneficiaries between 2010 and 2018 at the ZIP code level among ZIP codes with ≥100 beneficiaries. We described demographic characteristics of high and low amputation ZIP codes, and the association between major amputation rate and 3 ZIP code–level markers of socioeconomic status—the proportion of patients with dual eligibility for Medicaid, median household income, and Distressed Communities Index score—for metropolitan, micropolitan, and rural ZIP code cohorts. Between 2010 and 2018, 188 995 Medicare fee‐for‐service patients living in 31 391 ZIP codes with ≥100 beneficiaries had a major lower extremity amputation. The median (interquartile range) ZIP code–level number of amputations per 100 000 beneficiaries was 262 (75–469). Though nonmetropolitan ZIP codes had higher rates of major amputation than metropolitan areas, 78.2% of patients undergoing major amputation lived in metropolitan areas. Compared with ZIP codes with lower amputation rates, top quartile amputation rate ZIP codes had a greater proportion of Black residents (4.4% versus 17.5%,
P
<0.001). In metropolitan areas, after adjusting for clinical comorbidities and demographics, every $10 000 lower median household income was associated with a 4.4% (95% CI, 3.9–4.8) higher amputation rate, and a 10‐point higher Distressed Communities Index score was associated with a 3.8% (95% CI, 3.4%–4.2%) higher amputation rate; there was no association between the proportion of patients eligible for Medicaid and amputation rate. These findings were comparable to the associations identified across all ZIP codes.

Conclusions

In metropolitan areas, where most individuals undergoing lower extremity amputation live, markers of lower socioeconomic status and Black race were associated with higher rates of major lower extremity amputation. Development of community‐based tools for peripheral artery disease diagnosis and management targeted to communities with high amputation rates in urban areas may help reduce inequities in peripheral artery disease outcomes.
Cardiovascular Health Disparities in Racial and Other Underrepresented Groups: Initial Results From the All of Us Research Program
Authors: Acosta Julián N. , Leasure Audrey C. , Both Cameron P. , Szejko Natalia , Brown Stacy , Torres‐Lopez Victor , Abdelhakim Safa , Schindler Joseph , Petersen Nils , Sansing Lauren , Gill Thomas M. , Sheth Kevin N. , Falcone Guido J.
Published: August 2021

Background

All of Us is a novel research program that aims to accelerate research in populations traditionally underrepresented in biomedical research. Our objective was to evaluate the burden of cardiovascular disease (CVD) in broadly defined underrepresented groups.

Methods and Results

We evaluated the latest data release of All of Us. We conducted a cross‐sectional analysis combining survey and electronic health record data to estimate the prevalence of CVD upon enrollment in underrepresented groups defined by race, ethnicity, age (>75 years), disability (not able to carry out everyday physical activities), sexual orientation and gender identity lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+), income (annual household income <$35 000 US dollars) and education (less than a high school degree). We used multivariate logistic regression to estimate the adjusted odds ratio (OR) and product terms to test for interaction. The latest All of Us data release includes 315 297 participants. Of these, 230 577 (73%) had information on CVD and 17 958 had CVD (overall prevalence, 7.8%; 95% CI, 7.7–7.9). Multivariate analyses adjusted by hypertension, hyperlipidemia, type 2 diabetes mellitus, body mass index, and smoking indicated that, compared with White participants, Black participants had a higher adjusted odds of CVD (OR, 1.21; 95% CI, 1.16–1.27). Higher adjusted odds of CVD were also observed in underrepresented groups defined by other factors, including age >75 years (OR, 1.90; 95% CI, 1.81–1.99), disability (OR, 1.60; 95% CI, 1.53–1.68), and income <$35 000 US dollars (OR, 1.22; 95% CI, 1.17–1.27). Sex significantly modified the odds of CVD in several of the evaluated groups.

Conclusions

Among participants enrolled in All of Us, underrepresented groups defined based on race, ethnicity and other factors have a disproportionately high burden of CVD. The All of Us research program constitutes a powerful platform to accelerate research focused on individuals in underrepresented groups.
Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke
Authors: Esenwa Charles , Cheng Natalie T. , Luna Jorge , Willey Joshua , Boehme Amelia K. , Kirchoff-Torres Kathryn , Labovitz Daniel , Liberman Ava L. , Mabie Peter , Moncrieffe Khadean , Soetanto Ainie , Lendaris Andrea , Seiden Johanna , Goldman Inessa , Altschul David , Holland Ryan , Benton Joshua , Dardick Joseph , Fernandez-Torres Jenelys , Flomenbaum David , Lu Jenny , Malaviya Avinash , Patel Nikunj , Toma Aureliana , Lord Aaron , Ishida Koto , Torres Jose , Snyder Thomas , Frontera Jennifer , Yaghi Shadi
Published: August 2021

Background and Purpose:

We sought to determine if biomarkers of inflammation and coagulation can help define coronavirus disease 2019 (COVID-19)–associated ischemic stroke as a novel acute ischemic stroke (AIS) subtype.

Methods:

We performed a machine learning cluster analysis of common biomarkers in patients admitted with severe acute respiratory syndrome coronavirus 2 to determine if any were associated with AIS. Findings were validated using aggregate data from 3 large healthcare systems.

Results:

Clustering grouped 2908 unique patient encounters into 4 unique biomarker phenotypes based on levels of c-reactive protein, D-dimer, lactate dehydrogenase, white blood cell count, and partial thromboplastin time. The most severe cluster phenotype had the highest prevalence of AIS (3.6%,
P
<0.001), in-hospital AIS (53%,
P
<0.002), severe AIS (31%,
P
=0.004), and cryptogenic AIS (73%,
P
<0.001). D-dimer was the only biomarker independently associated with prevalent AIS with quartile 4 having an 8-fold higher risk of AIS compared to quartile 1 (
P
=0.005), a finding that was further corroborated in a separate cohort of 157 patients hospitalized with COVID-19 and AIS.

Conclusions:

COVID-19–associated ischemic stroke may be related to COVID-19 illness severity and associated coagulopathy as defined by increasing D-dimer burden.
A European Turn in Early American History?
Authors: Harris Tim , Beneke Chris , Kaplan Benjamin J. , Brake Wayne Te , Haefeli Evan
Published: August 2021

From the nineteenth century onwards, Americans have naturalized their colonial origins into a consensual nationalist history, emphasizing America’s perceived role as a refuge for the persecuted, while smoothing out a myriad of complexities in the process. Evan Haefeli attempts to overturn the assumptions underpinning this narrative and is convinced that many important aspects of early America need to be understood within a broader European context. In Accidental Pluralism, he argues that the collapse of religious unity in England lies at the root of the emergence of pluralism in colonial America, in which he includes Canada and the Caribbean. Relationships among states, churches, and publics were contested from the earliest decades of colonization and created a pluralistic religious landscape that no one had anticipated. The four reviewers are fulsome in their praise, calling it an impressive, important, powerful, and sweeping book that few scholars could have written. The reviewers also raise questions, for instance by problematizing the incorporation of the colonial American dimension into early British history, criticizing the validity of the chosen end date, and questioning his definitions of diversity, pluralism, and religious toleration. In his response Evan Haefeli takes the opportunity to reflect on what drove him to write the book and to organize it in this way. He acknowledges that connecting early American history with its broader European context was more difficult than it should have been, as the dominant questions in the two historiographies are an ocean apart. While the argument of the book is aimed at early Americanists, Haefeli is grateful that the reviewers situate the story he tells within the broader early modern European history of toleration.
Mémoire et histoire. Aspects théoriques et méthodologiques de l’approche historienne. Le débat des années 60
Authors: Hoock Jochen
Published: August 2021

Après la fin de la Seconde guerre mondiale, un débat s’est instauré autour de la question du temps mémoriel qui lie passé et présent. Avec le statut historique acquis par la mémoire collective, une contradiction apparaît alors entre une mémoire multiple et une histoire univoque qui a suscité la défiance d’historiens. Ils optent pour « une histoire critique de la mémoire » et scrutent les « filtres des expériences vécues ». Après une décennie de refoulement du passé, une rupture s’opère au début des années 1960. À la question d’une « histoire critique de la mémoire » des années trente, du IIIe Reich et de ses crimes, les historiens répondent par des théories des fascismes et des analyses de la fin de la République de Weimar. À la fin des années 1970 – alors qu’apparaît le terme Holocauste – le débat sur le temps mémoriel prend en compte la thématique victimes-bourreaux. S’ouvre dès lors en Allemagne de l’Ouest des lieux de mémoire locaux ou régionaux, des itinéraires mémoriels inscrits dans le pavé des villes avec mention nominative des victimes et des « acteurs » directs de l’époque. De vives polémiques apparaissent. Le travail de mémoire reste alors pour l’historien un travail critique qui doit intégrer dans la remémoration volontaire du passé l’interrogation du futur.
Analytische und hermeneutische Dimensionen einer historischen Rechtshistorie
Authors: Hoock Jochen
Published: August 2021

Der Artikel erörtert die methodischen Probleme einer „historischen Rechtsgeschichte“. Nach einer kritischen Analyse verschiedener Ansätze veranschaulichen zwei Fälle – die Entwicklung der Handelsgerichtsbarkeit im modernen Deutschland und Frankreich – den analytischen Ansatz zur Freilegung der rechtlichen Struktur von Wirtschafts- und Sozialsystemen, für den der Autor plädiert. Durch die Analyse des langsamen Prozesses der Ausdifferenzierung der komplexen Funktionen, die in den Handelsgerichten beider Länder von Bedeutung waren, versucht er, die Theorie der juristischen Zeitlichkeiten mit einer historischen Kritik der juristischen Topik bei der Konstruktion einer Methode zu verbinden. Dies dient der Konstruktion einer Methode, die geeignet wäre, die Mechanismen der Anpassung zu berücksichtigen, die die historische Effizienz der juristischen Praxis kennzeichnen.
Mapping Travel
Authors: Dym Jordana
Published: August 2021

More often than not, readers of travel narratives expect to find one or several maps showing, as English privateer William Dampier wrote, “the Course of the Voyage,” that is, where the author-traveler went and, implicitly, a sense of what was seen and experienced. Dampier used a now-common cartographic strategy to tell the story from beginning to end as well as focus on significant places on the way by marking the journey with a “pricked” line. Despite the lines’ popularity and present ubiquity, the complex intellectual processes of considering travel as a continuum rather than as a series of stops and of plotting a journey onto a map have attracted relatively little academic attention. Drawing on a thousand years of European travel writing and map-making, this work suggests that in fifteenth-century Europe, maps joined text-based itineraries and on-the-spot directions to guide travelers and accompany reports of land and sea travel. Called in subsequent centuries “route maps,” “itinerary maps,” and “travel maps,” often interchangeably, what are defined here as journey maps added lines of travel. Since their emergence, most journey maps have taken one of two forms: itinerary maps, which connected stages with line segments, and route maps, which tracked unbroken lines between endpoints. In the seventeenth century, journey mapping conventions were codified and incorporated into travel writing and other genres that represented individual travel. With each succeeding generation, journey maps have become increasingly common and complex, responding to changes in forms of transportation, such as air and motor car “flight” and print technology, especially the advent of multi-color printing.