bluuebunny/crossref_metadata_2025 huggingface dataset:
Story of a Community-Based Writing Resource - And a Call to Engage
Authors: Blakeslee Ann M , Gatchel Kristine M. , Boeving David , Miller Brent
Published: December 2023

This article tells the story of YpsiWrites, a community writing resource that provides support, resources, and programs for all writers. It shows how ideas from adrienne maree brown's
Emergent Strategy
(2017) provide a generative framework for community-engaged initiatives. It uses this framework to examine the work of YpsiWrites, and, in doing so, illustrates the value of the framework for planning, carrying out, and assessing community-engaged work (CEW). The authors share responses to questions they posed to stakeholders, along with themes from those responses, which paint a more nuanced picture of the nature and potential of this work. They conclude with a call to engage and an invitation for others to use these questions as a heuristic in pursuing their own, unique community-engaged work.
Review of "Violent Exceptions: Children's Human Rights and Humanitarian Rhetorics by Wendy S. Hesford," Hesford, W. S. (2021). Violent Exceptions: Children's Human Rights and Humanitarian Rhetorics. The Ohio State University Press.
Authors: Lantz Susan Jennings
Published: December 2023

Will someone please think of the children?

W.C. Fields has been notoriously associated with the warning "never to work with children and animals." And he was right! Both varieties of co-performers are guaranteed to steal the show from any adult in the general vicinity. It is generally accepted that commercials with a cute puppy and a Sarah Mclachlan soundtrack, or a baby amid famine and natural disaster is much more likely tug at heartstrings and garner cash donations than a city planner with a spreadsheet and a clip board. Consequently, the "adorable baby" cliché can be found everywhere from sitcoms to advertisements for products as diverse as healthcare, luxury brand cars, and banking securities services.
PACE: A Program Analysis Framework for Continuous Performance Prediction
Authors: Biringa Chidera , Kul Gökhan
Published: December 2023

Software development teams establish elaborate continuous integration pipelines containing automated test cases to accelerate the development process of software. Automated tests help to verify the correctness of code modifications decreasing the response time to changing requirements. However, when the software teams do not track the performance impact of pending modifications, they may need to spend considerable time refactoring existing code. This article presents
PACE
, a program analysis framework that provides continuous feedback on the performance impact of pending code updates. We design performance microbenchmarks by mapping the execution time of functional test cases given a code update. We map microbenchmarks to code stylometry features and feed them to predictors for performance predictions. Our experiments achieved significant performance in predicting code performance, outperforming current state-of-the-art by 75% on neural-represented code stylometry features.
Second-Harmonic Nonlinear Electrochemical Impedance Spectroscopy: Part I. Analytical Theory and Equivalent Circuit Representations for Planar and Porous Electrodes
Authors: Ji Yuefan , Schwartz Daniel T.
Published: December 2023

Analytical theory for second harmonic nonlinear electrochemical impedance spectroscopy (2nd-NLEIS) of planar and porous electrodes is developed for interfaces governed by Butler-Volmer kinetics, a Helmholtz (mainly) or Gouy-Chapman (introduced) double layer, and transport by ion migration and diffusion. A continuum of analytical EIS and 2nd-NLEIS models is presented, from nonlinear Randles circuits with or without diffusion impedances to nonlinear macrohomogeneous porous electrode theory that is shown to be analogous to a nonlinear transmission-line model. EIS and 2nd-NLEIS for planar electrodes share classic charge transfer RC and diffusion time-scales, whereas porous electrode EIS and 2nd-NLEIS share three characteristic time constants. In both cases, the magnitude of 2nd-NLEIS is proportional to nonlinear charge transfer asymmetry and thermodynamic curvature parameters. The phase behavior of 2nd-NLEIS is more complex and model-sensitive than in EIS, with half-cell NLEIS spectra potentially traversing all four quadrants of a Nyquist plot. We explore the power of simultaneously analyzing the linear EIS and 2nd-NLEIS spectra for two-electrode configurations, where the full-cell linear EIS signal arises from the sum of the half-cell spectra, while the 2nd-NLEIS signal arises from their difference.
A Pulsar Vector Observation-Based Link Acquisition Method for X-Ray Communications
Authors: Song Shibin , Lu Xiao , Wang Haixia
Published: December 2023

X-ray communication (XCOM) is an emerging laser communication technique for deep space applications. Traditional link acquisition of laser communications depends significantly on Earth support and shows little autonomy. For XCOM, a pulsar vector observation-based link acquisition method is proposed, which utilizes noncooperative pulsars in deep space as beacons to acquire absolute attitude information and accomplish link acquisition. Firstly, a pulsar vector observation model was established based on the coordinate definition of the X-ray detector and X-ray collimator model. Secondly, a modified “success-failure” pulsar vector search algorithm with two degrees of freedom was proposed to acquire the pulsar vector. With the pulsar vector and the relative attitude obtained from inertial sensors, the link acquisition pointing vector could be determined. Finally, the performance of the proposed method was evaluated using numerical experiments, and factors that influence the performance are discussed and analyzed.
Objetivos del BC en la Propuesta Constitucional y la importancia de tener una baja tasa de inflación
Authors: Romero Rafael
Published: December 2023

Recientemente, una persona que trabaja en una empresa en labores de aseo y sin educación formal en economía, al saber que soy profesor universitario en temas de economía y finanzas, me preguntó: ¿Por qué no hay ninguna agencia u organismo del gobierno que evite que la UF (Unidad de Fomento) suba?. Continuar leyendo...
Impuestos entre errores, riesgos y desafíos
Authors: Borges Humberto
Published: December 2023

Los impuestos en la propuesta de constitución actual es un tema muy comentado y controversial, todo esto es debido a la incapacidad (de algunos sectores políticos) de abstenerse de crear o eximir de impuestos a un grupo específico. Las constituciones deben entregar las características y principios de los tributos para que el legislador en el congreso pueda tener una base y legislar sobre el tema. Continuar leyendo...
Educación: Elementos Comparativos de la Propuesta de Texto Constitucional y la Constitución Política de la República de Chile Vigente
Authors: Barrientos Nicolás
Published: December 2023

Incluir el tema de la educación en una constitución política de una república es importante por varias razones. Entre las más importantes está el establecimiento de la educación como garantía de derecho fundamental, asegurar el compromiso del Estado, estabilidad y continuidad de las políticas educativas; ofrece un marco legal amplio que permite definir los principios fundamentales, los objetivos y los valores que deben guiar la educación en el país, estableciendo así los fundamentos para la formulación de leyes y políticas específicas. Además, otorga protección contra la discriminación, desarrollo de la sociedad, participación ciudadana, protección de la autonomía universitaria y garantía de continuidad de las instituciones educativas. Continuar leyendo...
Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells
Authors: Xia Li , Liu Jie-Yang , Yang Meng-Ying , Zhang Xue-Hong , Jiang Yue , Yin Qian-Qian , Luo Chen-Hui , Liu Hong-Chen , Kang Zhi-Jie , Zhang Cheng-Tao , Gao Bei-Bei , Zhou Ai-Wu , Cai Hai-Yan , Waller Edmund K. , Yan Jin-Song , Lu Ying
Published: December 2023

Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non–small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34− cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia.

Significance:

Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment
Authors: Niu Xiaoteng , Martinez Luis
Published: December 2023

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting ICB effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in patients with lung cancer. Pole-induced high TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors, which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations, which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. On the basis of the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for patients with lung cancer with high TMB.
Exploring the Role of Hyperinsulinemia in Obesity-Associated Tumor Development
Authors: Vélez-Bonet Ericka , Gumpper-Fedus Kristyn , Cruz-Monserrate Zobeida
Published: December 2023

Although there has been a long-standing connection between hyperinsulinemia and cancer development, there is a lack of understanding of the role of the insulin receptor on cells that can become cancerous. In a recent issue of Cell Metabolism, Zhang and colleagues, using a diet-induced obesity mouse model, identified a direct function of insulin receptors on pancreatic acinar cells expressing a KRASG12D mutation in promoting obesity-associated pancreatic cancer. Furthermore, insulin receptor signaling from hyperinsulinemia promoted the secretion of digestive enzymes that contributed to acinar to ductal metaplasia. These findings highlight an important connection between obesity, diabetes, and pancreatic tumor development and suggest potential strategies for obesity-associated cancer prevention targeting the insulin receptor signaling pathways.
TABLE 1 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Descriptive characteristics of prostate cancer cases and controls
Supplementary Table 7 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Carrier frequency of P/LP/D variants in BRCA2, ATM, NBN, and PALB2 by PRS category in African ancestry men.
Supplementary Table 6 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Aggregate effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African ancestry men.
Supplementary Table 5 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Association of PRS and PCa risk in African ancestry men.
Supplementary Table 21 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Absolute risk of metastatic PCa by PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 combined in African ancestry men.
Supplementary Table 20 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Absolute risk of PCa by PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 combined in African ancestry men.
Supplementary Table 2 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Weighted independent effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African ancestry men.
Supplementary Table 18 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Absolute risk of PCa by PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 independently in African ancestry men.
Supplementary Table 17 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Aggregate effect of PRS and P/LP/D variants in BRCA1, RAD50, MLH1, and MSH6 on PCa risk in African ancestry men.
Supplementary Table 16 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Aggregate effect of P/LP/D carrier status across BRCA1, RAD50, MLH1, and MSH6 genes on PCa risk in African ancestry men.
Supplementary Table 12 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Aggregate effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African American men.
Data from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Authors: Hughley Raymond W. , Matejcic Marco , Song Ziwei , Sheng Xin , Wan Peggy , Xia Lucy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Lubmawa Alexander , Kiddu Vicky , Asiimwe Frank , Amanya Colline , Mutema George , Job Kuteesa , Ssebakumba Mbaaga K. , Ingles Sue A. , Hamilton Ann S. , Couch Fergus J. , Watya Stephen , Conti David V. , Darst Burcu F. , Haiman Christopher A.
Published: December 2023

Abstract
Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.
Significance:
These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.
Fragilidade e espacialização de pessoas idosas do município de Uberlândia com IVCF-20
Authors: Barra Rubia Pereira , Moraes Edgar Nunes de , Lemos Maria Margaret de Vasconcellos , Bonati Poliana Castro de Resende , Castro José Flávio Morais , Jardim André Augusto
Published: December 2023

OBJETIVO: Descrever o perfil clínico funcional dos idosos vinculados à atenção primária à saúde, por meio do Índice de Vulnerabilidade Clínico Funcional (IVCF-20) e realizar a espacialização dos de maior declínio funcional por unidades de atenção primária à saúde no município de Uberlândia-MG, no ano de 2022. MÉTODOS: Estudo transversal com dados secundários da Secretaria Municipal de Saúde de Uberlândia-MG. As variáveis foram comparadas através de testes de t de Student, Mann Whitney, qui-quadrado de Pearson e regressão logística multinomial para obter o efeito independente de cada variável. O nível de significância adotado foi de 5% (p < 0,05). Utilizou-se o banco de dados georreferenciado no ArcGIS®. RESULTADOS: Foram avaliados 47.182 idosos com idade média de 70,3 anos (60 a 113 anos), sendo 27.138 mulheres (57,52%) e observou-se franco predomínio de idosos de baixo risco ou robustos (69,40%). Todavia, 11,09% são idosos de alto risco e 19,52% estão em risco de fragilização. Idosos do sexo masculino tiveram chance independentemente inferior de risco moderado e alto comparados às mulheres idosas (OR = 0,53; p < 0,001). Foi observado alta prevalência de polifarmácia, 21,40% da população idosa, particularmente nos idosos frágeis, com prevalência de 63,08%. Houve maior distribuição dos idosos frágeis em torno da região central do município e nas unidades de saúde com maior área de abrangência. O IVCF-20 permitiu realizar o rastreio da fragilidade na atenção primária à saúde. CONCLUSÃO: O instrumento é capaz de estratificar o risco dos idosos nas redes de atenção à saúde pela atenção primária à saúde, possibilitando a aplicação de intervenções preventivas, promocionais, paliativas ou reabilitadoras individualizadas, conforme o estrato clínico funcional do idoso e os domínios funcionais comprometidos. A estratificação de risco e a distribuição espacial dos idosos mais frágeis pode ser uma boa estratégia de qualificação dos profissionais de saúde com o objetivo de maximizar a autonomia e independência dos idosos.
The Role of
MAPRE2
and Microtubules in Maintaining Normal Ventricular Conduction
Authors: Chiang David Y. , Verkerk Arie O. , Victorio Rachelle , Shneyer Boris I. , van der Vaart Babet , Jouni Mariam , Narendran Nakul , Kc Ashmita , Sampognaro James R. , Vetrano-Olsen Franki , Oh John S. , Buys Eva , de Jonge Berend , Shah Disheet A. , Kiviniemi Tuomas , Burridge Paul W. , Bezzina Connie R. , Akhmanova Anna , MacRae Calum A.
Published: December 2023

BACKGROUND:

Brugada syndrome is associated with loss-of-function
SCN5A
variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within
MAPRE2
, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome.

METHODS:

A
mapre2
knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with
cdh2
tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with
MAPRE2
knockdown and knockout, respectively.

RESULTS:

Voltage mapping of
mapre2
knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with
mapre2
loss of function, associated with a decrease of detyrosinated tubulin.
MAPRE2
knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of
ttl
encoding tubulin tyrosine ligase in
mapre2
knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential.

CONCLUSIONS:

Genetic ablation of
mapre2
led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with
ttl
knockdown led to rescue of voltage-gated sodium channel–related functional parameters in
mapre2
knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.
Single-Nucleus Analysis Reveals Tumor Heterogeneity of Aldosterone-Producing Adenoma
Authors: Murakami Masanori , Hara Kazunari , Ikeda Kenji , Horino Masato , Okazaki Rei , Niitsu Yoshihiro , Takeuchi Akira , Aoki Jun , Shiba Kumiko , Tsujimoto Kazutaka , Komiya Chikara , Nakamura Yuki , Kurata Morito , Akashi Takumi , Fujii Yasuhisa , Yamada Tetsuya
Published: December 2023

BACKGROUND:

Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells. Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA.

METHODS:

We conducted single-nucleus RNA sequencing of APAs with
KCNJ5
mutation and nonfunctional adenomas obtained from 3 and 2 patients, respectively.

RESULTS:

The single-nucleus RNA sequencing revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of nonfunctional adenoma and APA. In addition, we extracted 2 cell fates in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in 1 of these fates, whereas those related to the regulation of glycolysis were upregulated in the other fate. Furthermore, the total RNA reads in the nucleus were higher in hormonally activated clusters, indicating a marked activation of transcription per cell.

CONCLUSIONS:

The single-nucleus RNA sequencing revealed intratumoral heterogeneity of APA with
KCNJ5
mutation. The observation of 2 cell fates in
KCNJ5
-mutated APAs provides the postulation that a heterogeneous process of cellular differentiation was implicated in the pathophysiological mechanisms underlying APA tumors.
We don’t need no (Confucian) education! A Northern Song Reading of the Liezi
Authors: Sage Richard J.
Published: December 2023

One of the common traits ancient speculative Daoist texts share is their aversion to a society based on Confucian morals. The Liezi’s anecdote about Huazi has often been cited as prime example for this attitude and its inherent yearning for a return to the Dao. Remarkably, one of the most radical interpretations of this passage was authored by a high-ranking member of the Northern Song imperial court. Combining references to other classics with Buddhist concepts and terminology to expound a mysticism rooted in the Daoist tradition, Fan Zhixu’s 范致虛 (?–1129) commentary is not only a masterpiece of exegetical literature, but also provides valuable insights into the unique intellectual atmosphere at and around Emperor Huizong’s court. This case study serves as introduction to Fan’s forgotten work and simultaneously to a widely neglected set of sources regarding the religio-political developments during Huizong’s controversial reign.
The Zen of Mahāvairocana, Or: Does Bodhidharma’s Nose Preach the Dharma?
Authors: Licha Stephan Kigensan
Published: December 2023

This paper addresses the relationship between Zen and tantric or esoteric Buddhism in premodern Japan from the point of view of the Buddhas and Buddha bodies considered to be preaching these two traditions. After surveying theories on the dharmakāya teaching already present in Chinese Buddhism, it considers the development of this doctrinal notion in the Japanese tantric traditions. The paper demonstrates that this tantric discourse on the Buddha as preacher provided thinkers such as Enni 圓爾 (1202–1280) and Chikotsu Daie 癡兀大慧 (1229–1312) with a framework to integrate Zen into a tantric world. Eventually, and under the influence of embryological motifs circulating widely in medieval Buddhism, Zen practitioners came to establish their own theories on the human as Buddha body. The paper concludes that medieval Zen and medieval tantric Buddhism should be considered sister movements.
The thylacine (Thylacynus cynocephalus): a rebirth starting from the name
Authors: GANE YORICK R.S. GOMEZ
Published: December 2023

The generic name of the thylacine has two variants (or spellings), Thylacinus (meaning “marsupial”) and Thylacynus (“marsupial dog”), both created in the same zoological work by C. J. Temminck (1824). For the reasons explained here, the name that Temminck meant to use was Thylacynus. The variant Thylacinus became dominant after a mistaken use in an important nomenclature reference book by S. A. Neave (1935‒1941). However, according to the International Code of Zoological Nomenclature (Articles 24.2.3‒4), Temminck is to be considered the First Reviser, and the selected spelling (Thylacynus) is thereby to be fixed as the correct original spelling.
Challenges to Hegemonic Constructions of Militarized Masculinities in the Neoliberal Era: The Case of South Korea
Authors: Chung Seungeun
Published: December 2023

In South Korea, military conscription lies at the core of the construction of notions of manhood and gender order as a whole. In a divided country, the hegemonic meaning of military service as a crucial marker of adult manhood remained unquestioned. However, since the implementation of full-blown neoliberalism, there has been a shift in societal gender norms and this in turn has changed the way in which militarized masculinities are constructed and enacted at the individual level. Drawn from qualitative interviews with South Korean former conscripts, this article examines the tension between militarized and neoliberal masculine ideals and how hegemonic constructions of militarized masculinities are challenged in it.
Cell cross talk within the lymphoma tumor microenvironment: follicular lymphoma as a paradigm
Authors: Laurent Camille , Dietrich Sascha , Tarte Karin
Published: December 2023

Follicular lymphoma (FL) is an indolent yet incurable germinal center B-cell lymphoma retaining a characteristic follicular architecture. FL tumor B cells are highly dependent on direct and indirect interactions with a specific and complex tumor microenvironment (TME). Recently, great progress has been made in describing the heterogeneity and dynamics of the FL TME and in depicting how tumor clonal and functional heterogeneity rely on the integration of TME-related signals. Specifically, the FL TME is enriched for exhausted cytotoxic T cells, immunosuppressive regulatory T cells of various origins, and follicular helper T cells overexpressing B-cell and TME reprogramming factors. FL stromal cells have also emerged as crucial determinants of tumor growth and remodeling, with a key role in the deregulation of chemokines and extracellular matrix composition. Finally, tumor-associated macrophages play a dual function, contributing to FL cell phagocytosis and FL cell survival through long-lasting B-cell receptor activation. The resulting tumor-permissive niches show additional layers of site-to-site and kinetic heterogeneity, which raise questions about the niche of FL-committed precursor cells supporting early lymphomagenesis, clonal evolution, relapse, and transformation. In turn, FL B-cell genetic and nongenetic determinants drive the reprogramming of FL immune and stromal TME. Therefore, offering a functional picture of the dynamic cross talk between FL cells and TME holds the promise of identifying the mechanisms of therapy resistance, stratifying patients, and developing new therapeutic approaches capable of eradicating FL disease in its different ecosystems.
Polypharmacy and pattern of medication use among patients with gastroesophageal reflux disease: results from Pars Cohort study
Authors: Ghamar-Shooshtari Arash , Rahimian Zahra , Poustchi Hossein , Mohammadi Zahra , Mesgarpour Bita , Akbari Mohammadreza , Kamalipour Alireza , Abdipour-Mehrian Seyed Reza , Hashemi Elham-Sadat , Zare Pooria , Lankarani Kamran Bagheri , Malekzadeh Reza , Malekzadeh Fatemeh , Vardanjani Hossein Molavi
Published: December 2023

Background

Gastroesophageal Reflux Disease (GERD) is a common chronic condition. Its chronic nature may affect the pattern of medication use. This study aimed to investigate the prevalence, associated factors, and patterns of polypharmacy and medication use among GERD patients in southwestern Iran.

Methods

We used data from the Pars Cohort Study. We classified drugs using the Anatomical Therapeutic Chemical classification system. The Lexicomp® database was used to assess potential drug-drug interactions. Multivariable Poisson regression was applied. Adjusted prevalence ratio (PR) and its 95% confidence interval (CI) were estimated.

Results

A total of 9262 participants were included. Among 2,325 patients with GERD, age-standardized prevalence of polypharmacy was 9.5% (95% CI: 7.5%, 11.6%) in males, and 19.3% (95% CI: 17.2%, 21.4%) in females. The PR of experiencing Polypharmacy by GERD patients compared to non-GERD patients was 1.82 (95% CI: 1.61, 2.05%). Multimorbidity (PR: 3.33; CI: 2.66, 4.15), gender (PR: 1.68; CI: 1.30, 2.18), and metabolic syndrome (PR: 1.77; CI: 1.45, 2.15) were associated with polypharmacy among GERD patients. Drugs for acid-related disorders were the most common used drugs among men, women and elders. We found that 13.9%, 4.2%, and 1.1% of GERD patients had type C, D and X drug interactions, respectively.

Conclusion

GERD is correlated with a higher prevalence of polypharmacy. Among GERD patients, females, those with multi-morbidities, and those with metabolic syndrome may be affected more by polypharmacy. Considering the fairly high rate of interactions identified, a review of the medication list is essential when approaching GERD patients, and physicians must check for medications that may worsen GERD.
Impact of a wearable-based physical activity and sleep intervention in multimorbidity patients: protocol for a randomized controlled trial
Authors: Neves Bernardo , Haghighi Eduardo D. , Pereira Hugo V. , Costa Filipe , Carlos João S. , Ferreira Daniel , Moreno Plinio , Ferreira Pedro M. , Machado Jaime , Goncalves Breno , Moreira José Maria , Leite Francisca , da Silva Nuno André
Published: December 2023

Background

The benefits of physical activity (PA) and adequate sleep are well documented, and their importance strengthens with the increasing prevalence of chronic diseases and multimorbidity (MM). Interventions to promote physical activity and sleep that use commercial activity trackers may be useful non-pharmacological approaches to managing individual health; however, limited evidence exists on their use to improve physical activity in older adult patients with MM.

Methods

This study aims to measure the effects of behavioral change techniques (BCTs) delivered by a wearable device on physical activity and quality of sleep (QS) in older adult patients with MM. We designed an open-label randomized controlled trial with participants recruited through primary care and a specialist outpatient clinic. Participants must be more than 65 years old, have MM, and have access to smartphones. All eligible participants will receive PA promotion content and will be randomly assigned to wear a smartwatch. The primary outcome will be the participants’ PA measurement at baseline and at six months using the International Physical Activity Questionnaire - Short Form (IPAQ-SF). Secondary outcomes will include changes in the participants’ frailty status, biometric measurements, quality of life, and biopsychosocial assessments. A sample size of 40 participants per arm was calculated to detect group differences, with 50 participants planned to recruit and randomize into each arm.

Discussion

This study aims to contribute to a better understanding of PA patterns and the impact of wearable-based PA interventions in patients with MM. In addition, we aim to contribute to more knowledge about the relationship between PA patterns, Patient Reported Outcomes Measures (PROMs), and healthcare resource utilization in patients with MM. To achieve this, the study will leverage a locally developed PROMs registry and assess data from participants’ medical records, in order to understand the added impact of wearable data and medical information data on predicting PROMs and unplanned hospital admissions.

Trial registration

NCT05777291
Breast cancer quality of care in Syria: screening, diagnosis, and staging
Authors: Nahhat Fouad , Doyya Modar , Zabad Kareem , Laban Tarek Abo , Najjar Hasan , Saifo Maher , Badin Firas
Published: December 2023

Background

The Syrian decade-long war has severely affected the healthcare system, including almost vanishing cancer screening practices, war-destroyed medical facilities, and lack of continuous medical education. This study aims to present data on the affected breast cancer screening practices, methods of diagnosis, and stages distribution in Syria.

Methods

Medical charts of breast cancer patients treated at Albairouni University Hospital between January 2019 and May 2022 were retrospectively reviewed. Eligible patients were women diagnosed with primary breast cancer. Exclusion criteria included females receiving neoadjuvant chemotherapy and incomplete charts. Data regarding the patient’s age, city of residence, marital status, number of children, smoking habits, method of diagnosis, tumor size (T), lymph nodes (N), and distal metastasis (M) were collected. We used Microsoft Excel and Statistical Package for the Social Sciences (SPSS) to analyze data. Descriptive methodology (frequency [n], percentage) was used.

Results

The number of charts reviewed was 4,500. The number of remaining charts after applying the exclusion criteria was 2,367. The mean age was 51.8 (SD = 11.3). More than half of the patients (58.3%) came from outside Damascus -where the hospital is located- and its suburbs. Less than 5% of the population detected cancer by screening mammography. Only 32.4% of patients were diagnosed by a biopsy, while surgical procedures (lumpectomy and mastectomy) were used to diagnose 64.8% of the population. At the time of diagnosis, only 8% of patients presented with local-stage disease (stages 0 & I), 73% had a regional disease (stages II & III), and 19% had metastatic breast cancer (stage IV).

Conclusion

Our retrospective chart review analysis is the first comprehensive review in Syria for female breast cancer patients. We found a significant low percentage of patients diagnosed based on a screening mammogram, much higher surgical biopsies rather than a simple imaging-guided biopsy, and much lower than the national average of early-stage disease. Our alarming findings can serve as the base for future strategies to raise the population’s health awareness, create more serious national screening campaigns, and adopt a multidisciplinary approach to the disease in Syria.
Online and school bullying roles: are bully-victims more vulnerable in nonsuicidal self-injury and in psychological symptoms than bullies and victims?
Authors: Drubina Boglárka , Kökönyei Gyöngyi , Várnai Dóra , Reinhardt Melinda
Published: December 2023

Background

Bullying leads to adverse mental health outcomes and it has also been linked to nonsuicidal self-injury (NSSI) in community adolescents. It is not clear whether different roles of bullying (bully, victim, bully-victim) are associated with NSSI, furthermore the same associations in cyberbullying are even less investigated.

Methods

The aim of the current study was to test whether students involved in school or online bullying differed from their not involved peers and from each other in psychological symptoms (externalizing and internalizing problems) and in NSSI severity (number of episodes, number of methods). Furthermore, mediation models were tested to explore the possible role of externalizing and internalizing problems in the association of school and online bullying roles with NSSI. In our study, 1011 high school students (66.07% girls; n = 668), aged between 14 and 20 years (Mage = 16.81; SD = 1.41) participated.

Results

Lifetime prevalence of at least one episode of NSSI was 41.05% (n = 415). Students involved in bullying used more methods of NSSI than not involved adolescents. In general, victim status was associated mostly with internalizing symptoms, while bully role was more strongly associated with externalizing problems. Bully-victims status was associated with both types of psychological problems, but this group did not show a significantly elevated NSSI severity compared to other bullying roles. Externalizing and internalizing problems mediated the relationship between bullying roles and NSSI with different paths at different roles, especially in case of current NSSI that happened in the previous month.

Conclusions

Results highlight that students involved in bullying are more vulnerable to NSSI and to psychological symptoms compared to their peers who are not involved in bullying. It is suggested that bullying roles, especially bully-victim status, need to be identified in school and online settings and thus special attention should be addressed to them to reduce psychological symptoms and NSSI, for example by enhancing adaptive coping skills.
National Institutes of Health R-series Grants portfolio of racism and healthcare, 2017–2022
Authors: Aponte Judith , Roldós Maria Isabel
Published: December 2023

Background

Any form of racism in healthcare is an unacceptable barrier to receiving equitable and quality care, further contributing to health disparities among populations. For these reasons, it is critical to have a better understanding on the amount of research and scientific advances of funded projects aimed at racism in healthcare. An examination of the distribution of R-series funded research by the National Institutes of Health (NIH) on racism in healthcare during a 5-year fiscal year (FY) period (2017–2022) was conducted by the study team.

Methods

This cross-sectional study used publicly available data from the NIH RePORTER (Research Portfolio Online Reporting Tools: Expenditures and Results) for research project grants awarded on racism and healthcare during the FYs of 2017 to 2022. The number of R-series NIH funded projects on racism in healthcare were examined, including the abstract and public health relevance statement, number of publications, spending category, fiscal start and end dates, total amount of funding each year, funding agency/center(s), and type of funding opportunity announcements. Descriptive statistics were performed on the data by the research team.

Results

There were a total of 93 R-series grants funded during the FYs of 2017 to 2022. Most of the grants were R01s (77.4%); focused primarily on racism at the system-wide level (68.8%), and on patients (64.5%); the largest racial and ethnic minority group reported were African/American/Black (20.4%); and close to 40% did not report race or ethnicity. None of the grants focused in internalized racism, which is at the individual –level. From the FYs of 2017 to 2022, 0.07% of all NIH research funding was awarded to racism in healthcare.

Conclusion

The findings of this study showed the need for continued funding and of the need of more research on racism in healthcare, that potentially can reduce health disparities and inequities.
Effectiveness of simulation-based cesarean section education on improving non-physician clinician midwife’s competency in performing cesarean section in Ethiopia: a quasi-experimental study
Authors: Alemu Fekadu Mazengia , Yimer Nigus Bililgn , Kasegn Belete Belgu , Kassie Belayneh Ayanaw , Ibrahim Ibrahim Yimer , Abdo Abdella Amano , Worke Mulugeta Dile
Published: December 2023

Background

Simulation-based education enhances fundamental and clinical knowledge, procedural abilities, teamwork, and communication skills, as well as quality of care and patient safety. Due to excessive clinical loads and a lack of physicians, even classic teaching methods like bedside instruction are constrained in low-income settings. Thus, this study aimed to ascertain if simulation-based cesarean section education successfully raises non-physician clinician midwives’ competency in Ethiopia.

Methods

A quasi-experimental study design triangulated with a qualitative design was implemented. Sixty Masters Clinical Midwifery students (29 intervention and 31 control) were taken in 5 universities. Three questionnaires (knowledge, confidence levels, and skills) were used. Qualitative data was also collected from 14 participants. The data were analyzed using SPSS version 25. Descriptive and inferential analyses were conducted. P < 0.05 was used for statistical significance. A difference-in-difference with a 95% confidence level was employed to control the potential confounders for knowledge and self-confidence. Multiple linear regression was fitted to identify the independent effect of simulation-based education interventions while controlling for other variables. Thematic analysis was performed using MAXQDA 2020.

Result

The age of the respondents varies from 24 to 34 years, with the control group’s mean age being 28.8 (± 2.3) years and the intervention group’s mean age being 27.2 (± 2.01) years. The intervention and control groups’ pre-intervention and post-intervention knowledge scores showed a statistically significant difference. There was a substantial increase in self-confidence mean scores in both the intervention and control groups and between the pre-intervention and post-intervention periods in both the intervention and control groups. Furthermore, there was a substantial improvement in cesarean section skills in the intervention group as compared to the control group (59.6 (3.3) vs. 51.5 (4.8). The qualitative findings supported these.

Conclusions

The study showed that simulation-based education improved students’ procedural knowledge, self-confidence, and skills. As a result, professional care teams can create simulation-based teaching packages to help students prepare for their residency.