bluuebunny/crossref_metadata_2025 huggingface dataset:
Coding complete genomes of an iridovirus and two parvoviruses identified in lab-reared social spiders (
Stegodyphus dumicola
)
Authors: Millerwise Sydney , Lund Michael C. , Schimidlin Kara , Kraberger Simona , Pinter-Wollman Noa , Varsani Arvind
Published: October 2024

Coding complete genomes of an iridovirus (194,403 nts) and two parvoviruses (4,689, 3,764 nts) were identified in social spiders (
Stegodyphus dumicola
). The iridovirus and one of the parvovirus are most closely related to those from house crickets (
Acheta domesticus
), whereas the other is most closely related to one from a social spider.
Complete genome sequence of deformed wing virus isolated from honeybees (
Apis mellifera
L.) in Iraq
Authors: Sadiq Ali , Alisawi Osamah , Mansor Mohammed Shakir
Published: October 2024

Here, we report the complete genome sequence of deformed wing virus (DWV) isolated from honeybees (
Apis mellifera
L.) in Iraq, named the Tikrit isolate. The phylogeny revealed that the Tikrit isolate has a close relationship to the Iraqi isolate DWV-Iraq-2023 and related to isolates from France, the United Kingdom, and Israel.
Genome sequence of
Mycoplasma gallisepticum
strain A5969
Authors: Leigh Spencer A. , Evans Jeff D.
Published: October 2024

Mycoplasma gallisepticum
strain A5969 is one of the earliest identified and studied avian mycoplasma strains, valued for its ease of growth and production of uniformly sized colonies. Here, we report the genomic sequence of the A5969 strain.
Complete genome sequencing of four marine bacteria,
Gilvimarinus japonicus
NBRC 111987
T
,
Halioxenophilus aromaticivorans
JCM 19134
T
,
Maricurvus nonylphenolicus
JCM 17778
T
, and
Simiduia litorea
JCM 19759
T
belonging to the family
Cellvibrionaceae
Authors: Miura Takamasa , Miyakawa Tomoyo , Kusuya Yoko , Kamino Kei
Published: October 2024

We report on the complete genomes of
Gilvimarinus japonicus
NBRC 111987
T
,
Halioxenophilus aromaticivorans
JCM 19134
T
,
Maricurvus nonylphenolicus
JCM 17778
T
, and
Simiduia litorea
JCM 19759
T
, isolated from the sea. Strains JCM 19134
T
, JCM 17778
T
, and JCM 19759
T
contain genes predicted to be polyhydroxyalkanoate-degrading enzymes.
Complete genome sequence of marine prosthecate bacterium
Fretibacter rubidus
type strain JCM 15585
Authors: LaSarre Breah , Watson Mark L. , Corby Emma M. , Randich Amelia M.
Published: October 2024

Fretibacter rubidus
is a dimorphic, prosthecate member of the family
Maricaulaceae
, order Caulobacterales, in the class Alphaproteobacteria. Here, we report the genome of type strain JCM 15585
T
(JC2236
T
), sequenced with Oxford Nanopore Technology.
Development of a droplet digital PCR assay for the detection of BK polyomavirus
Authors: Ai Lu , Zhao Yating , Tan Chianru , Bai Lu , Huang Gang , Wang Ruizhi , Huang Hao , Yu Xuegao , Guo Yong , Chen Peisong
Published: October 2024

The objective of this study was to establish a more sensitive and specific diagnostic method for detecting plasma BK polyomavirus (BKPyV) DNA load in patients after renal transplantation using droplet digital polymerase chain reaction (ddPCR) and to validate the methodology. The linear range, lower limit of detection, accuracy, precision, and specificity of the detection system were evaluated by using the WHO BKPyV standard (7.2 log
10
IU/mL) as a reference, in accordance with the relevant documents of the Clinical and Laboratory Standards Institute. Plasma samples were collected from 74 renal transplantation patients with urinary BKPyV-DNA levels exceeding 7 log
10
copies/mL. Quantitative PCR (qPCR) and ddPCR were performed, and their diagnostic efficacy for BKPyV-DNA in the diagnosis of BK polyomavirus-associated nephropathy was evaluated using a receiver operating characteristic (ROC) curve. The coefficients of variation for the repeated detection of BKPyV standard DNA were 2.55 and 4.71 at concentrations of 6.2 and 3.2 log
10
IU/mL, respectively. The linear range was 2.2–6.2 log
10
IU/mL, and the lowest detection limit was 100 IU/mL. By utilizing histopathological examination of renal biopsy as the gold standard for BKPyV diagnosis, the area under the ROC curve of 74 post-transplantation plasma samples detected by the ddPCR system was found to be 0.875 (95% CI: 0.797–0.953,
P
< 0.01). The optimal threshold was 512.86 copies/mL, with a sensitivity of 90.0% and a specificity of 67.6%. In comparison, the area under the ROC curve for qPCR was 0.668 (95% CI: 0.583–0.752,
P
< 0.01), with an optimal threshold of 11,481.54 copies/mL, a sensitivity of 35.0%, and a specificity of 100.0%. Pairwise comparison (Delong test) of the ROC curves of the two systems showed a significant difference in the area under the curve, with a difference of 0.207 and a
P
-value <0.01. The BKPyV nucleic acid detection system, based on ddPCR, is appropriate for the regular monitoring of the BK polyomavirus, specifically in plasma samples containing low viral DNA loads while it provides the benefits of both absolute quantification and high sensitivity.

IMPORTANCE

It was previously believed that droplet digital polymerase chain reaction had limitations, including high cost, limited throughput, and cumbersome operation, which hindered its widespread application in clinical practice. However, the current fully automated digital PCR platform, combined with streamlined operations, can detect 96 samples at once, and the entire process can be completed within an hour, laying a solid foundation for its extensive use.
Nanoemulsion is an effective antimicrobial for methicillin-resistant
Staphylococcus aureus
in infected swine skin burn wounds
Authors: Cao Zhengyi , Chen Jesse , Cannon Jayme , Meyer Zachary , Li Yongqing , Ouyang Wenlu , Baker James , Wang Su He
Published: October 2024

Burns are one of the most common injuries in both civilian and combat settings and are difficult to treat. This is particularly true when the wounds are infected with antibiotic-resistant bacteria such as methicillin-resistant
Staphylococcus aureus
(MRSA). A new generation of safe, broadly effective, and easily applied anti-infection agents is needed to successfully prevent and treat infections. Nanoemulsions (NEs) are nanometer-sized particles with a positively charged surfactant at their oil-water interface. In the current study, we further investigated antimicrobial NEs as a treatment to address burn wounds infected by MRSA. Specifically, using a porcine skin model, we infected partial thickness thermal burn wounds with MRSA and then treated it with the nanoemulsion formulation (NB-201) or placebo controls. Bacterial viability after treatment was determined, and inflammation indexes in wounds were scored by histopathology. Topical treatment of infected wounds with NB-201 resulted in reduced colony-forming units (CFUs) compared to placebo treatment. In addition, NB-201 was effective in significantly alleviating inflammation in the treated wounds and promoting wound healing. These results indicate that NB-201 is a promising new agent to treat skin burn wounds infected with MRSA.

IMPORTANCE

The findings of this study are focused on therapeutic applications of nanotechnology. In the current study, we demonstrated that a nanoemulsion formulation could effectively kill methicillin-resistant
Staphylococcus aureus
(MRSA) infection in porcine skin burn wounds. Infection of MRSA in burn wound is a common threat to public health and is usually difficult to treat due to limited therapies available. NB-201 was effective in significantly alleviating inflammation in the treated wounds and promoting wound healing. Therefore, the finding of this study has a great potential to make this formulation a novel antimicrobial agent against MRSA.
Study on Audit Risk Model Based on Data Mining Algorithm
Authors: Fu Meng
Published: October 2024

With the widespread application of modern information technologies such as big data, enterprises have generated a large amount of data in their daily operations. The traditional audit methods have drawbacks such as high cost and high consumption, and can no longer meet the needs of audit work in the digital era. Therefore, it is urgent to adopt audit methods suitable for the digital era to improve audit quality and reduce enterprise Audit risk. For professional auditors in enterprises, it is very important to utilize emerging technologies such as data mining algorithms. The audited enterprise may tamper with its financial statements, and identifying high-quality audit data from massive amounts of data is a huge challenge. Compared to traditional audit methods, data mining algorithms can significantly improve the efficiency and accuracy of audit work. For example, the BP neural network, with its powerful nonlinear mapping ability, can capture complex relationships in data; Support vector machines classify data by finding the optimal hyperplane in high-dimensional space and have good generalization ability; random forest reduces overfitting and improves prediction accuracy by integrating multiple decision trees; Association rule algorithms can discover interesting relationships between data items, helping auditors identify potential fraudulent behavior or abnormal transactions. Therefore, the purpose of this study is to accurately evaluate and reduce the audit risk of enterprises, and to build an audit risk model using computer data mining algorithms. This provides necessary reference and guidance for auditors to conduct data analysis and mine valuable data during the audit process of enterprises, thereby improving audit efficiency.
Hand Surgical Operating Room Size Allocation: A Comparative Space Utilisation Study
Authors: WOODS David , ILLING Damian , CAO Jue , BOLSON Rajshri M. , LAUDER Alexander , IPAKTCHI Kyros
Published: October 2024

Background: This study evaluated operating room (OR) space required for various hand surgical procedures. We analysed the size requirements for hand surgical cases divided into four settings: (1) large OR setting requiring fluoroscopy and microsurgical equipment, (2) medium-sized OR setting for cases requiring fluoroscopy, (3) smaller OR setting and (4) minor procedural room without anaesthesia with the aim to describe room size requirements for hand surgery practices.

Methods: A variety of hand surgical cases were selected: large cases (microvascular digit replantation), medium-sized cases (closed reduction percutaneous pinning [CRPP] of phalangeal fractures) and smaller cases (carpal tunnel release [CTR]) with and without anaesthesia. Space requirements were compared to general surgery cases (laparoscopic appendectomy) and general orthopaedic surgery cases (cephalomedullary nail [CMN]). Necessary operative equipment was measured (ft2) to calculate requirements for each procedure.

Results: Large hand cases such as digit replantation necessitated the most OR space (125 ft2), followed by general orthopaedic cases (CMN; 118 ft2), medium-sized hand cases (CRPP phalanx; 107 ft2), general surgery laparoscopic appendectomy (68 ft2), small hand cases (CTR; 85 ft2) and minor procedures (49 ft2).

Conclusions: Hand procedures can be divided into major procedures requiring significant OR space (125 ft2), medium procedures in standard OR suites (107 ft2), procedures in small ORs with anaesthesia (81 ft2) or office-based setting without anaesthesia (49 ft2). These findings help define space utilisation for hand procedures and may have practical implications related to efficiency, cost and patient safety in the hospital and outpatient setting.

Level of Evidence: Level IV (Economic and Decision Analyses)
A Trust Establishment and Key Management Architecture for Hospital-at-Home
Authors: Åkesson Alfred , Gehrmann Christian , Hedin Görel , Johnsson Björn A. , Magnusson Boris , Nordahl Mattias , Ramezanian Sara , Stankovski Wagner Paul
Published: October 2024

The landscape of healthcare is experiencing a digitalization shift, transferring many medical activities to the patients’ homes, a phenomenon commonly referred to as Hospital-at-Home. While Internet of Things (IoT) devices facilitate the building of such systems, there is a need for powerful middleware that encapsulates device-to-device communication and enables the construction of user-friendly, secure, and robust Hospital-at-Home systems. A key challenge for such middleware is to build a trustworthy and lightweight key management system allowing different devices in the system to exchange messages securely. In this article, we present a simple, easily manageable and scalable such architecture which, in addition, supports long-term data protection using post-quantum cryptographic primitives. Our proposed solution utilizes a Merkle tree to enable the IoT devices to establish trust between each other automatically, even in the absence of an Internet connection. We have implemented the architecture and present performance figures as well as a security analysis of our approach.
Human-AI Synergy in Survey Development: Implications from Large Language Models in Business and Research
Authors: Ke Ping Fan , Ng Ka Chung
Published: October 2024

This study examines the novel integration of Large Language Models (LLMs) into the survey development process in business and research through the development and evaluation of the Behavioral Research Assistant (BRASS) Bot. We first analyzed the traditional scale development process to identify tasks suitable for LLM integration, including both human-in-the-loop and automated LLM data collection methods. Following this analysis, we developed the details of BRASS Bot, incorporating design principles of falsifiability and reproducibility. We then conducted a comprehensive evaluation of the BRASS Bot across a diverse set of LLMs, including GPT, Claude, Gemini, and Llama, to assess its usability, validity, and reliability. We further demonstrated the practical utility of the BRASS Bot by conducting a user study and a predictive validity simulation. Our research presents both theoretical and practical implications. The augmentation approach of the BRASS Bot enriches the theoretical foundations of behavioral constructs by identifying previously overlooked patterns. Additionally, the BRASS Bot offers significant time and resource efficiency gains while enhancing scale validity. Our work lays the foundation for future research on the broader application of LLMs as both assistants and collaborators in survey analysis and behavioral research design and execution, highlighting their potential for a transformative impact on the field.
Dynamic Behaviors and Analytical Solutions of the Damped (2+1)‐Dimensional Nonlinear Schrödinger Equation
Authors: Gu Yongyi , Ye Feng , Chen Baixin , Aminakbari Najva
Published: October 2024

In this paper, abundant analytical solutions of the damped (2 + 1)‐dimensional nonlinear Schrödinger equation are achieved by taking advantage of the extended systematic method. By considering various values of parameters, dynamic behaviors of bright, dark soliton, period wave, and kink solitary solutions are displayed with different amplitudes and directions in 3D graphs, lines, contour maps, and time evolution plots. Further analysis of the obtained results is studied to show the efficient effect of the parameters on the propagation and configuration of waves. In addition, computer simulations are considered to show the correlation between parameters and velocity. Our results indicate that the extended systematic method for solving differential equations is more convenient and yields richer solutions. The other mathematical physics equations that appear in nonlinear science can also be investigated by the concept of this study.
Supplementary Fig. 2 from Peroxisome Proliferator–Activated Receptor δ Suppresses the Cytotoxicity of CD8+ T Cells by Inhibiting RelA DNA-Binding Activity
Authors: Cen Bo , Wei Jie , Wang Dingzhi , DuBois Raymond N.
Published: October 2024

Supplementary Fig. 2 shows PPARδ negatively regulates the expression of perforin, granzyme B, and IFNγ.
The Influence of Birth Weight, Socio-Economic Status, and Adult Health on Brain Volumes during Ageing
Authors: McNeil Christopher J. , Habota Tina , Sandu Anca-Larisa , Waiter Gordon , Whalley Heather , Murray Alison D.
Published: October 2024

Introduction: Greater late-life brain volumes are associated with resilience against dementia. We examined relationships between birth weight, lifelong socio-economic status, and health with late-life brain volumes. We hypothesised that early life factors directly affect late-life brain volumes. Methods: Adults aged 59–67 y underwent MRI and brain volumes were measured. Birth weight and lifelong health, and socio-economic status were quantified and the principal components of each extracted. Relationships were examined using regression and structural equation analysis. Results: Birth weight (β = 0.095, p = 0.017) and childhood socio-economic status (β = 0.091, p = 0.033, n = 280) were directly associated with brain volume. Childhood socio-economic status was further associated with grey matter volume (β = 0.04, p = 0.047). Adult health was linked to increased brain volume (β = 0.15, p = 0.003). Conclusion: Birth weight and childhood socio-economic status are associated with whole and regional brain volume through direct mechanisms. Optimal fetal development, reduced childhood poverty, and good adult health could reduce brain atrophy and delay dementia onset in late-life.
Disease Progression for Histologic Diagnosis of Metabolic Dysfunction-Associated Steatotic Liver Disease in the Real-World: A Nationwide US Study
Authors: Zhang Xinrong , Kam Leslie Yeeman , Barnett Scott D. , Henry Linda , Cheung Ramsey , Nguyen Mindie H.
Published: October 2024

Introduction: We compared clinical characteristics and outcomes in real-world metabolic dysfunction-associated steatotic liver disease (MASLD) patients with or without liver biopsy using a nationwide cohort in United States (USA) to fill in gaps in selection of biopsy patients. Methods: We conducted a retrospective cohort study of adult MASLD patients using Marketscan® Databases (1/2007–12/2021). Patients were categorized into those with or without liver biopsy during follow-up. Results: We analyzed 540,326 MASLD patients: 23,732 with and 516,594 without biopsy. Only 4% of MASLD patients received liver biopsy and biopsy rate decreased in the last 5 years (9.4%–3.6%). After 1:5 propensity score matching on baseline characteristics including age, sex, and comorbidities, a total of 23,731 patients with biopsy and 118,396 matched patients without biopsy were analyzed. The incidence per 1,000 person-years for hepatocellular carcinoma (HCC) was 0.22 versus 2.18, cirrhosis 29.75 versus 90.44, and hepatic decompensation 15.84 versus 28.25 compared patients with and without biopsy. In multivariable analysis, patients with biopsy had more than 9 times higher risk of developing HCC, 3 times higher risk of cirrhosis, and 78% higher risk of hepatic decompensation. In subgroup analysis, the association remained consistent when stratified by age (<50 and ≥50), sex, and diabetes mellitus. Predictors of having biopsy included age, metabolic diseases, and living in North central or Northeast of USA. Conclusion: These data can inform clinical patient management that biopsy patients likely represent a selected group at higher risk for disease progression, especially in clinical trials for MASLD therapies.
Cytopathology of a Newly Described Salivary Gland Neoplasm: A Case Report of Microsecretory Adenocarcinoma Presenting in the Parotid Gland
Authors: Razack Rubina , Bishop Justin A. , Alwan Julandi , Coetzee Liezel , De Wet Daniel Rudolph , Mahomed Wasim , Merven Marc , Schubert Pawel Tomasz , Afrogheh Amir
Published: October 2024

Introduction: Microsecretory adenocarcinoma (MSA) is a novel entity defined by distinctive histology, a specific immunophenotype, and unique molecular fusion MEF2C::SS18. It occurs mainly in intra-oral minor salivary glands and the skin, with only one reported case affecting the parotid gland. To the best of our knowledge, no cytomorphological features of MSA have been published to date. We report the first case of fine-needle aspiration biopsy (FNAB) cytology of MSA diagnosed in the parotid gland. Case Presentation: A 48-year-old man presented with a 3.5 × 2.5-cm parotid mass. FNAB of the tumour revealed a cellular smear comprising a predominantly epithelial cell population showing luminal differentiation with secretory features and a distinctive background matrix with both myxoid and mucinous qualities. Scattered, but conspicuous multinucleated giant cells were present, a feature not commonly observed in salivary gland aspirates. Histology of the excised tumour revealed classic features of MSA with supportive immunohistochemistry and SS18 break apart fusion detected by fluorescence in situ hybridisation (FISH). Next-generation sequencing confirmed a MEF2C::SS18 gene fusion. Conclusion: MSA is a rare neoplasm and should be considered in the cytological differential diagnosis of low-grade salivary gland neoplasms. Its unique cytomorphological features should raise the possibility of MSA in salivary gland FNABs. The diagnosis can be established on cellular cell block preparations using immunohistochemistry and FISH or PCR.
Urgent-Start Peritoneal Dialysis in Metformin-Associated Lactic Acidosis: A Critical Alternative when Immediate Hemodialysis Is Unavailable
Authors: Parapiboon Watanyu , Banjong Jakkrid , Siangtrong Chirakhana , Boonsayomphu Theerapun , Silakun Wirayut
Published: October 2024

Introduction: Intermittent hemodialysis (IHD) is a preferable renal replacement therapy (RRT) option in metformin-associated lactic acidosis (MALA) due to rapid correct metabolic acidosis. However, IHD might not be started immediately. Immediate urgent-start peritoneal dialysis (iUSPD) is used as a life-saving dialysis option and then followed by IHD. The outcomes of iUSPD were compared with other extracorporeal dialysis in MALA. Methods: In two tertiary hospitals in Thailand, the outcomes of patients with MALA who had received three different RRT modalities (iUSPD followed by IHD, IHD, and continuous renal replacement therapy [CRRT]) from January 2015 to December 2019 were compared. The primary outcome was 30-day mortality. The secondary outcomes were door-to-dialysis time and 90-day RRT dependence. Results: A total of 180 MALA cases that required dialysis were included (20 iUSPD, 120 IHD, and 40 CRRT). Their mean age was 64 years. Most of the patients had severe metabolic acidosis (mean pH 6.91, HCO3 6 mmol/L, and anion gap 40 mmol/L) and were critically ill. The 30-day mortality was 30% in iUSPD, 9.2% in IHD, and 32.5% in CRRT (p = 0.001). The mortality risk in the iUSPD group was not significantly different from those of the IHD and CRRT groups (adjusted HR 2.5, 95% CI: 0.65–9.6, and adjusted HR 0.75, 95% CI: 0.2–2.78, respectively). All dialysis modalities had comparable 90-day dialysis dependence. iUSPD exhibited the shortest door-to-dialysis time. Conclusion: In MALA, iUSPD followed by IHD might be a viable RRT option to save patient lives if no other dialysis options are available.
Impact of Sex and Gender in Stroke in South and Southeast Asia: A Rapid Scoping Review
Authors: Mascarenhas Rinita , Gandhi Dorcas B.C. , Sesgundo Jaime Angeles , Babu Veena , Mani Vinita Elizabeth , Sebastian Ivy Anne
Published: October 2024

Background: South Asia and Southeast Asia account for more than 40% of the global stroke burden, with differences in stroke risk factors, mortality, and outcomes compared to high-income countries. Sociocultural norms compound the preexisting biological risk differences, resulting in a disproportionate burden of stroke in women in this region. This review summarizes the sex and gender differences across the stroke care continuum in South Asia and Southeast Asia over the past 20 years. Summary: Despite a higher incidence of stroke in men than women in South and Southeast Asia, women have greater stroke severity and poorer outcomes after stroke. Higher levels of premorbid disability and poor physical health at baseline may be contributory. There is a high prevalence of vascular risk factors such as hypertension, dyslipidemia, cardiac sources of embolism, as well as metabolic syndrome and insulin resistance, among the women in this region. Smoking is uncommon among women; however, other forms of smokeless tobacco, such as tobacco leaf and betel nut chewing, are more prevalent, especially in the rural areas in these countries. Women are more likely to have delayed presentations to the hospital due to untimely recognition of stroke symptoms; however, with regards to door-to-needle times or intravenous thrombolysis (IVT) rates, we found equivocal data. Wide gaps exist in stroke awareness and healthcare-seeking behaviors, with women more commonly opting for public hospitals and low-cost wards, more likely to discontinue treatment, and less likely to adhere to poststroke rehabilitation. Key Findings: This review exposes the gender lacunae in stroke service provision across South Asia and Southeast Asia while acknowledging the many knowledge gaps in our understanding. Although the biological risk differences are non-modifiable, educational, policy, and economic measures to mitigate sociocultural barriers are much needed in the region. Sound epidemiological data are needed from more countries to better understand these differences and bridge this gap. It is imperative to advocate and implement policies and programs for stroke care viable for women, cognizant of the gender and cost bias, as well as the interplay of social and cultural structures specific to the regions.
Suplemento especial - Anais do Congresso de Graduação USP 2023
Authors: Massabni Vânia Galindo
Published: October 2024

Os resumos que constam nesses Anais foram avaliados pela Comissão Científica do Congresso de Graduação USP 2023 e apresentados no campus da USP em São Carlos, nos dias 31/10/2023 e 01/11/2023.
Judicialização do Zolgensma no Ministério da Saúde: custos e perfil clínico dos pacientes
Authors: Silva Everton Nunes da , Kretzschmar Ana Katheryne Miranda , Teixeira Ellen , Galato Dayani
Published: October 2024

OBJETIVO: Investigar os custos e o perfil dos pacientes que demandaram judicialmente o onasemnogene abeparvoveque (Zolgensma®) para o tratamento da atrofia muscular espinhal (AME) no Ministério da Saúde. MÉTODOS: Estudo transversal, de natureza descritiva e desenho censitário, com base em registros de ações judiciais movidas contra o Ministério da Saúde no período de janeiro de 2019 a setembro de 2022. Os dados foram solicitados ao Ministério da Saúde, via Lei de Acesso à Informação. Foram extraídas informações sobre o perfil epidemiológico dos beneficiários das ações judiciais, bem como os gastos dispendidos pelo Ministério da Saúde nos casos de deferimento das solicitações. RESULTADOS: Foram identificados 136 processos judiciais, dos quais 113 (83%) foram favoráveis aos pacientes ao custo de R$ 944,8 milhões no período analisado. Características demográficas (sexo e idade), clínicas (subtipos da AME, uso de suporte ventilatório ou nutricional) e do processo judicial (tipo de serviço advocatício) não foram associadas com o deferimento das ações judiciais. O uso prévio de medicamento (nusinersena ou ridisplam) foi associado com o indeferimento dos processos judiciais. Das 113 ações judiciais concedidas em favor dos pacientes, apenas seis (5,3%) atenderiam aos critérios estabelecidos atualmente pela Comissão Nacional de Incorporação de Tecnologias – Conitec (crianças com até seis meses sem suporte ventilatório e nutricional). Houve dispêndio de R$ 146 milhões com o fornecimento do Zolgensma para crianças com idade superior a dois anos, que está fora da recomendação contida na bula do medicamento. CONCLUSÕES: O Ministério da Saúde incorre em um alto custo com a judicialização do Zolgensma para AME, representando 2,45% do gasto total com medicamentos no Sistema Único de Saúde, incluindo gastos das três esferas administrativas. Parte das demandas judiciais tem sido deferida em divergência com os critérios estabelecidos por agências de avaliação de tecnologias em saúde e recomendações do fabricante do medicamento.
Abstract 15: Cell-Free Mitochondrial DNA Drives Endothelial Cell Activation and Vascular Dysfunction via Toll-Like Receptor 9 and Inflammasome Pathway Activation
Authors: dos Passos Rinaldo , Bomfim Gisele , Vieira Cintia , Priviero Fernanda , Silva Carneiro Fernando , Webb R Clinton
Published: October 2024

Immune system activation has been shown to play an important role in the pathogenesis of hypertension and substantial evidence has been highlighting the importance of inflammasomes in vascular disease progression. Mitochondria damage leads to mitochondrial DNA (mtDNA) releasing into the cytoplasm, which, in turn, triggers the activation of leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes, thereby exacerbating inflammation. However, whether mtDNA release-dependent exacerbation of inflammasomes drives endothelial cell activation and vascular damage remains to be elucidated. We hypothesize that cytosolic mtDNA release triggers endothelial cell activation and inflammation via Toll-Like Receptor 9 (TLR9) and inflammasome pathway activation, leading to vascular dysfunction. To assess this hypothesis, a concentration-response curve to endothelin-1 (ET-1) was performed in mesenteric resistance arteries (MRAs) isolated from wild-type and TLR9 knockout C57 mice in the presence or absence of mtDNA (4ug/mL) for one hour. To test inflammasome pathway activation, vascular smooth muscle cells (VSMC) and endothelial cells (EC) were incubated with TLR9 agonist (ODN2395, 3uM) or mtDNA (4ug/mL) and co-incubated with TLR9/AIM2 inhibitor (ODN2088, 2uM) or NLRP3 inhibitor (MCC950, 10uM) for 24 hours. Protein expression was assessed via Western blot and immunophenotyping was performed by flow cytometry. Data are presented as mean ± S.E.M and significance was set at p<0.05. After incubation with mtDNA, MRAs from wild-type mice presented an increased contractile response to ET-1 which was prevented in TLR9 KO mice. In VSMC, TLR9 expression increased after incubation with ODN2395 (vehicle: 1.2 ± 0.2 vs ODN2395: 4 ± 1.5) or mtDNA (vehicle: 1.2 ± 0.2 vs mtDNA: 4.2 ± 1.2) while co-incubation with ODN2088 reversed this effect. Additionally, mtDNA promoted increased TNF-alpha (vehicle: 1 ± 0.1 vs mtDNA: 2.6 ± 0.5) and IL-6 (vehicle: 1 ± 0.1 vs mtDNA: 4.6 ± 0.3) expression in VSMC which was abolished in the presence of ODN2088. In EC, flow cytometry indicated that incubation with mtDNA promoted a 4-fold increase in the expression of CD31+ and a 2-fold increase in CD54+ cells while co-incubation with ODN2088 or MCC950 reversed this effect. Altogether these data suggest that cell-free mtDNA triggers the innate immune response via TLR9 and inflammasomes driving EC activation, vascular dysfunction, and inflammation.
Abstract 29: Blood Pressure Phenotypes in an Interventional Study of Participants with Heart Failure with Preserved Ejection Fraction
Authors: Hossain Alavi , Greenip Audrey , Afable Jessica Loren , Maynard Hannah , Chirinos Julio , Townsend Raymond , Cohen Jordana
Published: October 2024

Background:
Heart failure (HF) with preserved ejection fraction (HFpEF) affects engenders high morbidity and mortality. Hypertension is a major risk factor for HFpEF progression. We aimed to evaluate the prevalence of and factors associated with abnormal home blood pressure (BP) phenotypes in a trial cohort of individuals with hypertension and HFpEF.

Methods:
We evaluated baseline office and home BP measurements in 36 participants of BLOCK HFpEF, an ongoing trial of antihypertensive treatment in HFpEF (NCT04434664). Office BP was measured using a standardized approach with the average of 3 seated readings. Home BP was measured for the first 7 days of the trial, prior to initiating the intervention. Participants were asked to perform nocturnal home BP one night, taken 3 times while sleeping. We used a conservative threshold for controlled BPs, defined as office systolic BP (SBP) <140 mmHg, office diastolic BP (DBP) <90 mmHg, home daytime SBP <135 mmHg, and home daytime DBP <85 mmHg. White coat effect was defined as elevated office and controlled home BP. Masked uncontrolled hypertension was defined as controlled office and elevated home BP. Sustained hypertension was defined as controlled office and elevated home BP. Nocturnal hypertension was defined as nighttime SBP ≥120 mmHg or DBP ≥70 mmHg.

Results:
Of the 36 participants with home BP data, 7 (19%) had controlled hypertension, 6 (17%) had white coat effect, 6 (17%) had masked uncontrolled hypertension, and 17 (47%) had sustained hypertension. 27 participants completed nighttime home BP readings, among whom 23 (85%) had nocturnal hypertension. Of those with nocturnal hypertension, 2 (9%) had controlled hypertension based on their daytime home BPs, 3 (13%) had white coat effect, 5 (22%) had masked uncontrolled hypertension, and 13 (56%) had sustained hypertension. There was no significant difference in age, sex, race, history of atrial fibrillation, and history of diabetes mellitus across BP phenotypes. The mean number of cardiology visits in the two years before enrollment was 4.3 (SD 2.8), which did not differ across home BP phenotypes.

Conclusion:
Masked uncontrolled hypertension and nocturnal hypertension were common in patients enrolled in the BLOCK HFpEF trial. These home BP phenotypes cannot be determined using office BP alone. While this is a small sample, patients with HFpEF may particularly benefit from careful BP phenotyping using out-of-office monitoring, including nocturnal BP monitoring.
Abstract 34: Elevation of Plasma anti-Endothelin A Receptor Autoantibodies in Lupus Subjects Correlates with Plasma Vascular Adhesion Molecule-1 Independent of Blood Pressure
Authors: McCrorey Marice , Hawkins Kennedy , Oates Jim , Tsao Betty , Abdul Yasir , Ergul Adviye , Cunningham Melissa , Van Beusecum Justin
Published: October 2024

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by deposition of autoantibodies and their immune complexes, resulting in inflammation, and end-organ damage to the kidney and vasculature. SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women and patients often have cardiovascular complications including hypertension (HTN). The activation of the endothelin (ET) system has been implicated in numerous pathological disease states including HTN, SLE, and diabetes. Recently, dual ET receptor antagonism was approved for treatment of patients with uncontrolled hypertension. Studies have demonstrated the presence of biologically active endothelin A receptor autoantibodies (ETAR-AAs) in systemic sclerosis and cystic fibrosis patients. Few studies have investigated the role of the synergistic interplay of SLE and HTN on ETAR-AAs. We hypothesized that women with SLE and HTN would have elevated plasma ETAR-AAs compared to control or SLE only subjects. To investigate this, we recruited non-SLE non-HTN controls (n=10), non-SLE HTN (n=10), SLE non-HTN (n=8), and SLE-HTN (n=10) female human subjects and analyzed clinical characteristics, plasma ETAR-AAs, soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1). Plasma ETAR-AAs did not significantly correlate with either age (r=-0.1375; p=0.4453) or body mass index (r=-0.3149; p=0.0743). When subjects were categorized by SLE or HTN diagnosis, we found that subjects with SLE had a profound increase in ETAR-AAs compared to non-SLE controls (p<0.0001) while the levels were similar between HTN and non-HTN controls (p=0.7626). Next, we stratified subjects by blood pressure status and found a significant elevation in plasma ETAR-AAs in SLE non-HTN over non-SLE HTN subjects (p=0.0121), while SLE-HTN subjects had significant elevations in ETAR-AAs compared to both non-SLE non-HTN (p=0.0183) and non-SLE HTN (p=0.0014) subjects. We correlated plasma levels of ETAR-AA with sVCAM-1 and sICAM-1 and found that plasma ETAR-AAs were positively associated with plasma sVCAM-1 (r=0.4288; p=0.0114) and sICAM-1 (r=0.3812; p=0.0286). These data indicate that irrespective of blood pressure status, elevated plasma ETAR-AAs are associated with markers of vascular dysfunction in SLE subjects. Further investigation of cell-specific ETAR-AA and ETAR signaling should be performed in murine models and human subjects with SLE.
Abstract 38: Loop Diuretic Resistance in a Preclinical Model of Cardiorenal Syndrome 2: Role of Enhanced Distal Convoluted Tubule Sodium Transport
Authors: Baiden Isaac , Mendez Mariela , Ortiz Pablo , Rhaleb NourEddine , Liao Tang-Dong , Xu Jiang
Published: October 2024

Nearly 60% of heart failure (HF) patients develop a progressive decline in kidney function. Decompensated HF also causes edema, usually treated with loop diuretics, like furosemide, that inhibit the Na-K-2Cl cotransporter NKCC2 in the thick ascending limb (TAL). However, nearly 50% of HF patients do not respond adequately to loop diuretics and become resistant. The mechanisms causing loop diuretic resistance are unclear but may involve TAL-dependent and independent mechanisms. Few have used the mouse as a model of cardiorenal syndrome due to its resistance to renal damage. We hypothesize that mice develop loop diuretic resistance and lower GFR after chronic HF induced by myocardial infarction (MI). MI was induced in C57Bl6J mice through ligation of the left anterior descending coronary artery and compared to a sham surgery group. We assessed heart function by echocardiography and GFR (FITC inulin) in conscious mice. The response to diuretics was studied in metabolic cages. MI mice had a 50% reduction in ejection fraction (EF) one month after MI (MI: 29.94 ± 1.94, Sham: 67.02 ± 1.14%, n= 8, p<0.05). EF was still lower 3 and 6 months after MI. The MI group showed decreased GFR, 6 months after MI (MI: 0.50 ± 0.06, Sham: 0.75±0.05 µl/min, n= 5, p<0.05). Urinary albumin was similar in both groups (n=8). In metabolic cages, a saturating dose of the NKCC2 inhibitor bumetanide (20 mg/Kg), induced diuresis and natriuresis in sham mice (Delta UV: 1.96 ± 0.27 ml/4h, Delta UNa: 117.2 ± 11.02µmols/4h, n= 6) but had an attenuated response in MI mice (Delta UV: 0.88 ± 0.23 ml/4h, Delta UNa: 65.00 ± 4.53 µmols/4h, n= 4, p<0.05 vs sham). To study the distal convoluted tubule (DCT) we measured the response to hydrochlorothiazide (HCTZ). HCTZ (100 mg/Kg) induced a natriuretic response in sham mice (Delta UNa: 75.24±11.18µmols/4h, n= 10) and a higher response in the MI group (Delta UNa: 129.54±11.59µmols/4h, n= 12, p<0.05 vs sham). RNAseq in isolated mTALs from MI and sham mice identified 85 up- and 160 down-regulated genes (n=5, p<0.025). Up-regulated genes involved those in the sphingosine pathway, protein trafficking, PKA signaling (PDE4B, PRKD2) and cell growth/tubule differentiation (FREM2, WFDC1). mRNA expression of TAL NaCl transporters was not affected. We conclude that HF decreases GFR, induces loop diuretic resistance and affects mTAL signaling in mice. Loop diuretic resistance may involve enhanced DCT NaCl reabsorption.
Abstract 42: Fecal Microbiota Transplantation Decreases Autoantibody Production and Lowers Blood Pressure in an Experimental Model of Autoimmune Disease
Authors: Taylor Erin , Ceesay Aja , Mendoza Luciano , Sandifer Jayla , Hart Jordan , Case Clinton
Published: October 2024

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that disproportionately affects women. It is characterized by a breach of immunological self-tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. Autoantibody production leads to downstream chronic inflammation resulting in high rates of hypertension, renal injury, and cardiovascular disease. Gut dysbiosis is associated with many autoimmune diseases, including SLE. In the present study, we hypothesized that gut dysbiosis in SLE may play a role in the development of immune system dysfunction and hypertension in an experimental model of SLE, and that fecal microbiota transplantation (FMT) with microbes from control mice may improve these parameters. To test this hypothesis, we treated 26-week-old female control (NZW, n=10) and SLE (NZBWF1, n=9) mice with broad spectrum antibiotics in drinking water for one week to deplete the existing microbiota. Subsequently, mice were given 0.1 mL of fecal microbes from either control or SLE mice via oral gavage two times per week for four weeks in the following groups (n=9-10 mice/group): Control-vehicle, Control-SLE microbes, SLE-vehicle, SLE-Control microbes. Changes in the gut microbiome after FMT were assessed by metagenomic sequencing of fecal pellets from all four groups. Mean arterial pressure (MAP, mmHg) was higher in SLE mice compared to control mice (Control: 112±3 vs. SLE: 140±2 mmHg, p<0.0001). SLE mice that received FMT with control microbes had lower blood pressure (SLE-FMT: 126±4 mmHg, p=0.03). While there were no changes in circulating and splenic B cell percentages, SLE mice had significantly higher percentages of CD11b
+
CD11c
+
autoimmune-associated B cells compared to control mice (Control: 0.41±0.04% vs. SLE: 1.2±0.1%, p=0.0006), which were significantly decreased in SLE-FMT mice (SLE-FMT: 0.76±0.1%, p=0.02). Circulating autoantibodies were also measured at the conclusion of the study. Anti-dsDNA IgG was elevated in SLE mice compared to control (Control: 149±38 vs. SLE: 527±114 kU/mL, p=0.02), and were significantly lower in SLE mice treated with control microbes (SLE-Control microbes: 126±4 mmHg, p=0.03). These data suggest that gut microbiota present in NZBWF1 mice contribute to the accumulation of activated B cells and increased autoantibody production, which are known pathogenic factors in the development of hypertension in SLE.
Abstract 48: Cardiovascular Health Modifies Genetic Risk for the Hypertensive Disorders of Pregnancy
Authors: Mathew Vineetha , Khan Raiyan , McNeil Rebecca , Yan Qi , Pe er Itsik , Truong Buu , Natarajan Pradeep , Yee Lynn , Sharma Garima , Patel Aniruddh , Cho So Mi , Jowell Amanda , Pabon Maria , Silver Robert , Levine Lisa , Grobman William , Catov Janet , Haas David , Honigberg Michael
Published: October 2024

Introduction:
Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal/perinatal mortality. In recent work, a genetic risk score improved prediction of HDPs beyond standard clinical risk factors, but the extent to which cardiovascular health (CVH) modifies HDP genetic risk is unknown.

Hypothesis:
First-trimester CVH can offset genetic risk for HDPs.

Methods:
We examined genotyped participants of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be (nuMoM2b). Individual HDP genetic risk was calculated using a validated polygenic score. A composite first-trimester CVH score was adapted from the Life’s Essential 8 model; cholesterol was incorporated in a subset (47%) with available first-trimester values. Genetic risk and CVH were each grouped as low (bottom quintile), intermediate (Q2-4), and high (top quintile). Logistic regression tested the joint association of CVH and genetic risk with HDP, adjusted for age and sociodemographic covariates.

Results:
Among 5,446 participants (mean age 27.5 years), 1,339 (24.6%) developed HDP (344 [6.3%] preeclampsia, 995 [18.3%] gestational hypertension [GH]). Higher genetic risk and lower CVH were additively associated with risk of HDP (
Figure 1A-B
) with no significant interaction (P[interaction] >0.05). HDP incidence ranged from 11% (low genetic risk, favorable CVH) to 37% (high genetic risk, unfavorable CVH) (
Figure 1C
). Favorable vs. unfavorable CVH was associated with 35-62% lower risk of HDPs across genetic risk groups. Findings were broadly consistent when examining preeclampsia and GH separately and when incorporating cholesterol (i.e., using a complete Life’s Essential 8 score). Among CVH components, nonideal BMI, blood pressure, and diet conferred highest population attributable HDP risk (25%, 14%, and 12%, respectively).

Conclusion:
Higher genetic risk and lower first trimester CVH were additively associated with risk of developing HDP. Favorable CVH in early pregnancy may partially offset a higher genetic risk for HDP.
Abstract 52: HIV-derived Proteins Induce Neuroinflammation, Hypertension, and Sympatho-activation via T cell-dependent mechanisms in the Tg26 Mouse Model
Authors: Khakina Beryl , Kress Taylor , Kennard Simone , Belin De Chantemele Eric
Published: October 2024

Combination antiretroviral therapy (cART) has extended life expectancy in people living with HIV (PLWH), shifting the primary cause of death to cardiovascular disease (CVD). Hypertension affects over 65% of PLWH. However, the mechanisms underlying HIV-associated hypertension remain poorly understood. In PLWH on cART, T cells persist as viral reservoirs, secreting viral proteins that circulate and localize in the central nervous system (CNS). Here, we used theTg26 mouse model, clinically relevant to cART-controlled PLWH, to test the hypothesis that HIV-derived proteins elevate blood pressure (BP) and induce sympatho-activation through blood-brain barrier disruption, microglial activation, and neuroinflammation. Telemetry-based BP measurements revealed a hypertensive phenotype in male and female Tg26 mice (male: WT=112.3 ±1.3 vs. Tg26=121.9 ±4.0 mmHg; female: WT=110.6 ±3.01 vs. Tg26=120.3 ±6.9 mmHg). Tg26 mice displayed increased sympathetic contribution to BP, indicated by a larger BP decrease following ganglionic blockade compared to WT, with no changes in heart rate responses to muscarinic and β-adrenergic receptor blockade, suggesting increased neurogenic BP regulation. Tg26 mice also showed increased aortic vasoconstriction to phenylephrine (P<0.05). LC/MS analysis revealed no significant differences in circulating catecholamine and metabolites between WT and Tg26 mice (n=5). MRI-based brain perfusion measurements also showed no significant differences, indicating an alteration in brain perfusion is not responsible for increased sympathetic activation. Inhibiting T-cell activation using abatacept, a CTLA-4-Ig fusion protein, significantly reduced BP, sympatho-activation, and phenylephrine-induced vasoconstriction in Tg26 mice (n=5, p<0.05). We analyzed the brains of Tg26 mice to investigate how T cells promote hypertension and sympatho-activation. Quantitative PCR confirmed viral protein expression in brain tissues and microglia of Tg26 mice, associated with increased markers of neuroinflammation, microglia activation, and T-cell infiltration (fold change>1.5, n=6, p<0.05). Tg26 mice also showed increased expression of NADPH oxidases and matrix metalloproteinase. However, there were no changes in the expression of tight junction proteins. Our data suggest that the expression of HIV-derived proteins in Tg26 mice induces central inflammation and T cell infiltration, leading to sympatho-activation through T cell-dependent mechanisms.