bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient New Technique for Solving Nonlinear Problems Involving the Conformable Fractional Derivatives
Authors: Ahmed Shams A.
Published: February 2024

In this paper, an efficient new technique is used for solving nonlinear fractional problems that satisfy specific criteria. This technique is referred to as the double conformable fractional Laplace‐Elzaki decomposition method (DCFLEDM). This approach combines the double Laplace‐Elzaki transform method with the Adomian decomposition method. The fundamental concepts and findings of the recently suggested transformation are presented. For the purpose of assessing the accuracy of our approach, we provide three examples and introduce the series solutions of these equations using DCLEDM. The results show that the proposed strategy is a very effective, reliable, and efficient approach for addressing nonlinear fractional problems using the conformable derivative.
The Malaria Burden: A South African Perspective
Authors: Balmith Marissa , Basson Charlise , Brand Sarel J.
Published: February 2024

Malaria is a deadly disease caused by protozoan pathogens of the Plasmodium parasite. Transmission to humans occurs through the bite of an infected female Anopheles mosquito. According to the World Health Organization (WHO), an estimated 247 million cases of malaria were recorded worldwide in 2021, with approximately 619 000 malaria deaths. The initial signs of malaria can be mild and challenging to diagnose due to the signs and symptoms being similar to those of other illnesses. The malaria burden remains largely concentrated in the WHO sub-Saharan African region and has been recognised as a significant contributor to morbidity and mortality. This review aims to contribute to the existing knowledge on malaria in South Africa, a region within sub-Saharan Africa, focusing on the epidemiology and life cycle of the malaria parasite as well as diagnostic approaches for detecting malaria. In addition, nonpharmacological and pharmacological interventions for treating and preventing malaria infections will also be discussed herein. While there has been a significant reduction in the global burden of this disease, malaria remains a public health issue in South Africa. As such, the implementation of effective preventative measures and strategies, early diagnosis, and appropriate treatment regimens are crucial to reducing the malaria burden in South Africa.
PD-L1, STAT3, IL6, and EGFR Immunoexpressions in High-Grade Osteosarcoma
Authors: Rahmadiani Nayla , Norahmawati Eviana , Endharti Agustina Tri , Hambalie Ailen Oktaviana , Isma Satria Pandu Persada
Published: February 2024

Introduction. Immunotherapy has been widely used in the treatment of various malignancies with satisfactory results. One of the agents for immunotherapy is an inhibitor of programmed cell death-1 and its ligands (PD-1 and PD-L1). However, attempts at utilizing PD-1/PD-L1 immunotherapy in osteosarcoma have not yielded favorable results. This may be due to differences in PD-L1 regulation and the immune landscape in osteosarcoma, as the mechanism is still poorly understood. Therefore, elucidating PD-L1 regulation in osteosarcoma is paramount in order to improve treatment results using immunotherapy. Methods. This is a cross-sectional study conducted in the Department of Anatomical Pathology of Saiful Anwar Hospital using 33 paraffin blocks of confirmed cases of osteosarcoma. Immunohistochemical staining using PD-L1, STAT3, IL6, and EGFR was performed. Statistical analyses were subsequently performed on the immunoexpression data of these antibodies. Results. PD-L1, STAT3, IL6, and EGFR expressions were found in 6 (18.2%), 6 (18.2%), 28 (84.8%), and 30 (90.9%) cases, respectively. There were significant correlations between PD-L1 and STAT3 (r = 0.620, p=<0.001), PD-L1 and EGFR (r = 0.449, p=0.009), as well as STAT3 and EGFR (r = 0.351, p=0.045). Conclusion. The existence of a correlation between PD-L1, STAT3, and EGFR indicates the potential role of STAT3 and EGFR in PD-L1 regulation in osteosarcoma, which may become the basis for targeted therapy.
Structural Basis for Multivalent MUC16 Recognition and Robust Anti-Pancreatic Cancer Activity of Humanized Antibody AR9.6
Authors: Aguilar Eric N. , Sagar Satish , Murray Brandy R. , Rajesh Christabelle , Lei Eric K. , Michaud Sarah A. , Goodlett David R. , Caffrey Thomas C. , Grandgenett Paul M. , Swanson Benjamin , Brooks Teresa M. , Black Adrian R. , van Faassen Henk , Hussack Greg , Henry Kevin A. , Hollingsworth Michael A. , Brooks Cory L. , Radhakrishnan Prakash
Published: February 2024

Mucin-16 (MUC16) is a target for antibody-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC) among other malignancies. The MUC16-specific monoclonal antibody AR9.6 has shown promise for PDAC immunotherapy and imaging. Here, we report the structural and biological characterization of the humanized AR9.6 antibody (huAR9.6). The structure of huAR9.6 was determined in complex with a MUC16 SEA (Sea urchin sperm, Enterokinase, Agrin) domain. Binding of huAR9.6 to recombinant, shed, and cell-surface MUC16 was characterized, and anti-PDAC activity was evaluated in vitro and in vivo. HuAR9.6 bound a discontinuous, SEA domain epitope with an overall affinity of 88 nmol/L. Binding affinity depended on the specific SEA domain(s) present, and glycosylation modestly enhanced affinity driven by favorable entropy and enthalpy and via distinct transition state thermodynamic pathways. Treatment with huAR9.6 reduced the in vitro growth, migration, invasion, and clonogenicity of MUC16-positive PDAC cells and patient-derived organoids (PDO). HuAR9.6 blocked MUC16-mediated ErbB and AKT activation in PDAC cells, PDOs, and patient-derived xenografts and induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. More importantly, huAR9.6 treatment caused substantial PDAC regression in subcutaneous and orthotopic tumor models. The mechanism of action of huAR9.6 may depend on dense avid binding to homologous SEA domains on MUC16. The results of this study validate the translational therapeutic potential of huAR9.6 against MUC16-positive PDACs.
A Cockayne-Syndrome-Like Phenotype with a Homozygous Truncating UVSSA Variant: Might This Be a New Cause?
Authors: Bahap Yusuf , Kayhan Gulsum
Published: February 2024

Introduction: UV-sensitive syndrome and Cockayne syndrome (CS) are rare autosomal recessive and transcription-coupled nucleotide excision repair disorders with different clinical manifestations, although some types are allelic. Case Presentation: We report on a patient who passed away at 15 years old with a progeroid-like appearance, cachexia, hearing loss, and dental anomalies, which led us to the diagnosis of Cockayne-like progeroid syndromes. Our clinical exome sequencing including all the known genes of progeroid syndromes revealed a homozygous stop-gain variant in the UVSSA gene. Conclusion: Although truncating variants in the UVSSA are known to cause UVsS3, their association with CS has not yet been defined. This case might be the first report of a CS-like phenotype caused by a defective UVSSA.
Remaining Issues Related to Serum Cytokines in Patients with Unresectable Hepatocellular Carcinoma Treated by Atezolizumab plus Bevacizumab Combination Treatment
Authors: Nagai Hidenari , Mukozu Takanori , Matsui Teppei , Mohri Kunihide , Nagumo Hideki , Yoshimine Naoyuki , Kobayashi Kojiro , Ogino Yu , Daido Yasuko , Wakui Noritaka , Momiyama Koichi , Matsuda Takahisa , Igarashi Yoshinori , Higai Koji
Published: February 2024

Introduction: Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. Methods: We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks’ treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. Results: In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. Conclusion: These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC.
Differential Pacing Maneuver From the Vein of Marshall
Authors: Kawaguchi Naohiko , Tanaka Yasuaki , Okubo Kenji , Tachibana Shinichi , Nakashima Emiko , Takagi Katsumasa , Hikita Hiroyuki , Sasano Tetsuo , Takahashi Atsushi
Published: February 2024

BACKGROUND:

Bidirectional mitral isthmus (MI) block is conventionally verified by differential pacing from the coronary sinus (CS) and its sequence change. This study aimed to evaluate the ability of differential pacing from the vein of Marshall (VOM) to detect epicardial MI connections.

METHODS:

Radiofrequency and VOM ethanol MI ablation were performed with a VOM electrode catheter inserted to the septal side of the ablation line. MI block was verified using conventional CS pacing. To perform differential VOM pacing analysis, initial pacing was delivered from a distal VOM bipole closer to the block line, and then from a proximal VOM bipole. The intervals from pacing stimulus during different VOM pacing sites to the electrogram recorded through the CS catheter on the opposite side of the line were compared. When the interval during distal VOM pacing was longer than that during proximal VOM pacing, it indicated a VOM connection block; however, if the former interval was shorter, the connection through the VOM was considered persistent.

RESULTS:

Overall, 50 patients were evaluated. According to CS pacing, MI ablation was incomplete in 9 patients, in whom the analysis indicated persistent VOM connection. Among 41 patients with complete MI block, confirmed by CS finding, in 30 (73%) patients, the interval during distal VOM pacing was longer than that during proximal VOM pacing by 11±5 ms. However, in 11 patients (27%) the former interval was revealed to be shorter than the latter by 16±8 ms, indicating residual VOM connection. Conduction time across the line was significantly shorter in 11 patients than in the other 30 (166±21 versus 197±36 ms;
P
<0.01). Ten successful reevaluated analyses after VOM ethanol and further radiofrequency ablation of the connection indicated VOM block achievement.

CONCLUSIONS:

Differential VOM pacing maneuver reflects the VOM conduction status. This maneuver can uncover residual epicardial connections that are missing with CS pacing.
Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism
Authors: Zhang Sheng , Zhang Yunkai , Duan Xuewen , Wang Bo , Zhan Zhenzhen
Published: February 2024

BACKGROUND:

Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair.

METHODS:

Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI.

RESULTS:

NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production. The oligomeric NPM1 recruited histone demethylase KDM5b to the promoter of
Tsc1
(
TSC complex subunit 1
), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI.

CONCLUSIONS:

Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI.
Mortality and Cardiovascular End Points In Relation to the Aortic Pulse Wave Components: An Individual-Participant Meta-Analysis
Authors: Norton Gavin R. , An De-Wei , Aparicio Lucas S. , Yu Yu-Ling , Wei Fang-Fei , Niiranen Teemu J. , Liu Chen , Stolarz-Skrzypek Katarzyna , Wojciechowska Wiktoria , Jula Antti M. , Rajzer Marek , Martens Dries S. , Verhamme Peter , Li Yan , Kawecka-Jaszcz Kalina , Nawrot Tim S. , Staessen Jan A. , Woodiwiss Angela J. ,   The International Database of Central Arterial Properties for Risk Stratification Investigators
Published: February 2024

BACKGROUND:

Wave separation analysis enables individualized evaluation of the aortic pulse wave components. Previous studies focused on the pressure height with overall positive but differing results. In the present analysis, we assessed the associations of the pressure of forward and backward (P
for
and P
ref
) pulse waves with prospective cardiovascular end points, with extended analysis for time to pressure peak (T
for
and T
ref
).

METHODS:

Participants in 3 IDCARS (International Database of Central Arterial Properties for Risk Stratification) cohorts (Argentina, Belgium, and Finland) aged ≥20 years with valid pulse wave analysis and follow-up data were included. Pulse wave analysis was done using the SphygmoCor device, and pulse wave separation was done using the triangular method. The primary end points consisted of cardiovascular mortality and nonfatal cardiovascular and cerebrovascular events. Multivariable-adjusted Cox regression was used to calculate hazard ratios.

RESULTS:

A total of 2206 participants (mean age, 57.0 years; 55.0% women) were analyzed. Mean±SDs for P
for
, P
ref
, T
for
, and T
for
/T
ref
were 31.0±9.1 mm Hg, 20.8±8.4 mm Hg, 130.8±35.5, and 0.51±0.11, respectively. Over a median follow-up of 4.4 years, 146 (6.6%) participants experienced a primary end point. Every 1 SD increment in P
for
, T
for
, and T
for
/T
ref
was associated with 27% (95% CI, 1.07–1.49), 25% (95% CI, 1.07–1.45), and 32% (95% CI, 1.12–1.56) higher risk, respectively. Adding T
for
and T
for
/T
ref
to existing risk models improved model prediction (∆Uno’s C, 0.020;
P
<0.01).

CONCLUSIONS:

Pulse wave components were predictive of composite cardiovascular end points, with T
for
/T
ref
showing significant improvement in risk prediction. Pending further confirmation, the ratio of time to forward and backward pressure peak may be useful to evaluate increased afterload and signify increased cardiovascular risk.
Consensus‐Based Development of a Pediatric Echocardiography Complexity Score: Design, Rationale, and Results of a Quality Improvement Collaborative
Authors: Balasubramanian Sowmya , Yu Sunkyung , Behera Sarina K. , Bhat Aarti H. , Camarda Joseph A. , Choueiter Nadine F. , Jone Pei‐Ni , Lopez Leo , Natarajan Shobha S. , Parra David A. , Parthiban Anitha , Sachdeva Ritu , Srivastava Shubhika , Tierney Elif Seda Selamet
Published: February 2024

Background

The complexity of congenital heart disease has been primarily stratified on the basis of surgical technical difficulty, specific diagnoses, and associated outcomes. We report on the refinement and validation of a pediatric echocardiography complexity (PEC) score.

Methods and Results

The American College of Cardiology Quality Network assembled a panel from 12 centers to refine a previously published PEC score developed in a single institution. The panel refined complexity categories and included study modifiers to account for complexity related to performance of the echocardiogram. Each center submitted data using the PEC scoring tool on 15 consecutive inpatient and outpatient echocardiograms. Univariate and multivariate analyses were performed to assess for independent predictors of longer study duration. Among the 174 echocardiograms analyzed, 68.9% had underlying congenital heart disease; 44.8% were outpatient; 34.5% were performed in an intensive care setting; 61.5% were follow‐up; 46.6% were initial or preoperative; and 9.8% were sedated. All studies had an assigned PEC score. In univariate analysis, longer study duration was associated with several patient and study variables (age <2 years, PEC 4 or 5, initial study, preoperative study, junior or trainee scanner, and need for additional imaging). In multivariable analysis, a higher PEC score of 4 or 5 was independently associated with longer study duration after controlling for study variables and center variation.

Conclusions

The PEC scoring tool is feasible and applicable in a variety of clinical settings and can be used for correlation with diagnostic errors, allocation of resources, and assessment of physician and sonographer effort in performing, interpreting, and training in pediatric echocardiography.
Genetic‐Guided Pharmacotherapy for Coronary Artery Disease: A Systematic and Critical Review of Economic Evaluations
Authors: Lim Ka Keat , Koleva‐Kolarova Rositsa , Kamaruzaman Hanin Farhana , Kamil Ahmad Amir , Chowienczyk Phil , Wolfe Charles D. A. , Fox‐Rushby Julia
Published: February 2024

Background

Genetic‐guided pharmacotherapy (PGx) is not recommended in clinical guidelines for coronary artery disease (CAD). We aimed to examine the extent and quality of evidence from economic evaluations of PGx in CAD and to identify variables influential in changing conclusions on cost‐effectiveness.

Methods and Results

From systematic searches across 6 databases, 2 independent reviewers screened, included, and rated the methodological quality of economic evaluations of PGx testing to guide pharmacotherapy for patients with CAD. Of 35 economic evaluations included, most were model‐based cost‐utility analyses alone, or alongside cost‐effectiveness analyses of PGx testing to stratify patients into antiplatelets (25/35), statins (2/35), pain killers (1/35), or angiotensin‐converting enzyme inhibitors (1/35) to predict CAD risk (8/35) or to determine the coumadin doses (1/35). To stratify patients into antiplatelets (96/151 comparisons with complete findings of PGx versus non‐PGx), PGx was more effective and more costly than non‐PGx clopidogrel (28/43) but less costly than non‐PGx prasugrel (10/15) and less costly and less effective than non‐PGx ticagrelor (22/25). To predict CAD risk (51/151 comparisons), PGx using genetic risk scores was more effective and less costly than clinical risk score (13/17) but more costly than no risk score (16/19) or no treatment (9/9). The remaining comparisons were too few to observe any trend. Mortality risk was the most common variable (47/294) changing conclusions.

Conclusions

Economic evaluations to date found PGx to stratify patients with CAD into antiplatelets or to predict CAD risk to be cost‐effective, but findings varied based on the non‐PGx comparators, underscoring the importance of considering local practice in deciding whether to adopt PGx.
Association of Cardiac Biomarkers in Combination With Cognitive Impairment After Acute Ischemic Stroke
Authors: Yang Pinni , Wang Shuyao , Zhong Chongke , Yin Jieyun , Yang Jingyuan , Wang Aili , Xu Tan , Zhang Yonghong
Published: February 2024

Background

Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance.

Methods and Results

This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity‐2 receptor), GDF‐15 (growth differentiation factor‐15), and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini‐Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF‐15, and NT‐proBNP;
P
trend
<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini‐Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48–4.07) and 1.86 (1.10–3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (
P
trend
<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini‐Mental State Examination‐defined cognitive impairment (net reclassification improvement=34.99%,
P
<0.001; integrated discrimination index=2.67%,
P
<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores.

Conclusions

An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01840072.
Liver X Receptor Agonist 4β‐Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease
Authors: Rahunen Roosa , Tulppo Mikko , Rinne Valtteri , Lepojärvi Samuli , Perkiömäki Juha S. , Huikuri Heikki V. , Ukkola Olavi , Junttila Juhani , Hukkanen Janne
Published: February 2024

Background

Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure–regulating mechanism involving 4β‐hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD.

Methods and Results

The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4βHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4βHC concentrations. However, in men, high plasma 4βHC was associated with all‐cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow‐up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6–8.7;
P
=0.002) and 4.18 (95% CI, 1.5–11.4;
P
=0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile.

Conclusions

High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex‐specific risk marker of cardiac death and especially SCD in chronic CAD.

Registration Information

clinicaltrials.gov
. Identifier NCT01426685.
Cost Effectiveness of Dapagliflozin for Heart Failure Across the Spectrum of Ejection Fraction: An Economic Evaluation Based on Pooled, Individual Participant Data From the DELIVER and DAPA‐HF Trials
Authors: Bhatt Ankeet S. , Vaduganathan Muthiah , Claggett Brian L. , Kulac Ian J. , Anand Inder S. , Desai Akshay S. , Fang James C. , Hernandez Adrian F. , Jhund Pardeep S. , Kosiborod Mikhail N. , Sabatine Marc S. , Shah Sanjiv J. , Vardeny Orly , McMurray John J. V. , Solomon Scott D. , Gaziano Thomas A.
Published: February 2024

Background

The sodium glucose cotransporter‐2 inhibitors are guideline‐recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter‐2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking.

Methods and Results

We conducted a US‐based cost‐effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA‐HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3‐state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality‐adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death.

Conclusions

The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifiers: NCT01035255 & NCT01920711.
Decoding the Cell Atlas and Inflammatory Features of Human Intracranial Aneurysm Wall by Single‐Cell RNA Sequencing
Authors: Ji Hang , Li Yue , Sun Haogeng , Chen Ruiqi , Zhou Ran , Yang Yongbo , Wang Rong , You Chao , Xiao Anqi , Yi Liu
Published: February 2024

Background

Intracranial aneurysm (IA) is common and occasionally results in life‐threatening hemorrhagic strokes. However, the cell architecture and inflammation in the IA dome remain less understood.

Methods and Results

Single‐cell RNA sequencing was performed on ruptured and unruptured human IA domes for delineating the cell atlas, gene expression perturbations, and inflammation features. Two external bulk mRNA sequencing–based data sets and serological results of 126 patients were collected for validation. As a result, a total of 21 332 qualified cells were captured. Vascular cells, including endothelial cells, smooth muscle cells, fibroblasts, and pericytes, were assigned in extremely sparse numbers (4.84%), and were confirmed by immunofluorescence staining. Pericytes, characterized by
ABCC9
and
HIGD1B
, were identified in the IA dome for the first time. Abundant immune cells were identified, with the proportion of monocytes/macrophages and neutrophils being remarkably higher in ruptured IA. The lymphocyte compartment was also thoroughly categorized. By leveraging external data sets and machine learning algorithms, macrophages were robustly associated with IA rupture, irrespective of their polarization status. The single nucleotide polymorphism rs2280543, which is identified in East Asian populations, was associated with macrophage metabolic reprogramming through regulating
TALDO1
expression.

Conclusions

This study provides insights into the cellular architecture and inflammatory features in the IA dome and may enlighten novel therapeutics for unruptured IA.
Severity and Remission of Metabolic Dysfunction–Associated Fatty/Steatotic Liver Disease With Chronic Kidney Disease Occurrence
Authors: Gao Jingli , Li Yuhao , Zhang Yijun , Zhan Xin , Tian Xue , Li Junjuan , Wang Ru , He Yan , Wang Anxin , Wu Shouling
Published: February 2024

Background

The association of the severity of hepatic steatosis in metabolic dysfunction–associated fatty liver disease (MAFLD)/metabolic dysfunction–associated steatotic liver disease (MASLD) and the remission of MAFLD/MASLD with CKD occurrence is unclear.

Methods and Results

The study enrolled 79 540 participants from the Kailuan cohort. Hepatic steatosis was diagnosed by ultrasound. MAFLD/MASLD was defined as hepatic steatosis combined with metabolic dysfunction and MASLD further excluded alcohol or other causes of liver disease. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate<60 mL/min per 1.73 m
2
or positive proteinuria (≥1+). Hazard ratio (HR) was calculated by Cox regression models. After a median follow‐up of 12.9 years, CKD occurred in 20 465 participants. After adjusting for potential confounders, MAFLD was associated with a higher risk of CKD compared with non‐MAFLD (HR, 1.12 [95% CI, 1.09–1.16]), and this risk increased with increasing severity of hepatic steatosis (
P
‐trend<0.001). Consistent findings were observed when MASLD was used as the exposure. Compared with persistent non‐MAFLD, no statistical difference was found in the risk of CKD in MAFLD remission (HR, 1.04 [95% CI, 0.95–1.15]); however, MASLD remission still had a higher risk of CKD compared with persistent non‐MASLD (HR, 1.15 [95% CI, 1.03–1.27]). When grouped according to the prior severity of hepatic steatosis, there was no statistically significant difference in risk of CKD in mild‐MAFLD/MASLD remission compared with persistent non‐MAFLD/MASLD, but moderated/severe‐MAFLD/MASLD remission still had a higher risk.

Conclusions

The risk of CKD in patients with MAFLD/MASLD increased with the severity of hepatic steatosis. Even after remission of the disease, patients with MAFLD/MASLD with prior moderate to severe hepatic steatosis still had a higher risk of CKD.
Discrimination, Smoking, and Cardiovascular Disease Risk: A Moderated Mediation Analysis With MESA
Authors: Cook Stephanie H. , Wood Erica P. , Stein James H. , McClelland Robyn L.
Published: February 2024

Background

Carotid intima‐media thickness (cIMT) and carotid plaque are reliable indicators of cardiovascular disease risk, and research highlights that racial and ethnic minority individuals generally exhibit higher cIMT and carotid plaque than White individuals. At present, the mechanisms driving these disparities among different racial and ethnic and biological sex groups are poorly understood.

Methods and Results

Data came from the baseline examination of MESA (Multi‐Ethnic Study of Atherosclerosis). A total of 6814 participants aged 45 to 84 years free of clinical cardiovascular disease completed assessments on health behavior and perceived discrimination. Four sex‐stratified moderated mediation models examined associations between discrimination, cigarette smoking, and mean cIMT and plaque. We hypothesized that cigarette use would mediate the association between discrimination and carotid artery disease features, and that these would differ by race and ethnicity. Indirect effects of discrimination on plaque were observed among Hispanic women such that discrimination was associated with cigarette use and, in turn, higher plaque (β=0.04 [95% CI, 0.01–0.08]). Indirect effects of discrimination on mean cIMT were found among Hispanic (β=0.003 [95% CI, 0.0001–0.007]) and White men (β=0.04 [95% CI, 0.01–0.08]) such that discrimination was associated with cigarette use and, in turn, higher cIMT. Finally, a positive indirect effect of discrimination on plaque was observed among Hispanic men (β=0.03 [95% CI, 0.004–0.07]). No other racial and ethnic differences were observed.

Conclusions

To understand and address social determinants of cardiovascular disease, researchers must incorporate an intersectional framework that will allow us to understand the complex nature of discrimination and cardiovascular disease risk for individuals of varying intersecting identities and social positions.
Echocardiographic Profiling Predicts Clinical Outcomes After Mitral Transcatheter Edge‐to‐Edge Repair
Authors: Hatab Taha , Samimi Sahar , Bou Chaaya Rody G. , Qamar Fatima , Kharsa Chloe , Wessly Priscilla , Faza Nadeen , Little Stephen H. , Atkins Marvin D. , Reardon Michael J. , Kleiman Neal S. , Zoghbi William A. , Nagueh Sherif F. , Zaid Syed , Goel Sachin S.
Published: February 2024

Background

Prior studies investigating the impact of residual mitral regurgitation (MR), tricuspid regurgitation (TR), and elevated predischarge transmitral mean pressure gradient (TMPG) on outcomes after mitral transcatheter edge‐to‐edge repair (TEER) have assessed each parameter in isolation. We sought to examine the prognostic value of combining predischarge MR, TR, and TMPG to study long‐term outcomes after TEER.

Methods and Results

We reviewed the records of 291 patients who underwent successful mitral TEER at our institution between March 2014 and June 2022. Using well‐established outcomes‐related cutoffs for predischarge MR (≥moderate), TR (≥moderate), and TMPG (≥5 mm Hg), 3 echo profiles were developed based on the number of risk factors present (optimal: 0 risk factors, mixed: 1 risk factor, poor: ≥2 risk factors). Discrimination of the profiles for predicting the primary composite end point of all‐cause mortality and heart failure hospitalization at 2 years was examined using Cox regression. Overall, mean age was 76.7±10.6 years, 43.3% were women, and 53% had primary MR. Two‐year event‐free survival was 61%. Predischarge TR≥moderate, MR≥moderate, and TMPG≥5 mm Hg were risk factors associated with the primary end point. Compared with the optimal profile, there was an incremental risk in 2‐year event‐rate with each worsening profile (optimal as reference; mixed profile: hazard ratio (HR), 2.87 [95% CI, 1.71–5.17],
P
<0.001; poor profile: HR, 3.76 [95% CI, 1.84–6.53],
P
<0.001). Echocardiographic profile was statistically associated with the 2‐year mortality end point (optimal as reference; mixed profile: HR, 3.55 [95% CI, 1.81–5.96],
P
<0.001; poor profile: HR, 3.39 [95% CI, 2.56–7.33],
P
=0.02).

Conclusions

The echocardiographic profile integrating predischarge TR, MR, and TMPG presents a novel prognostic stratification tool for patients undergoing mitral TEER.
Implementing Formal Mitral Heart Team Improves Multidisciplinary Evaluation Rate and Survival of Patients With Severe Primary Mitral Regurgitation
Authors: Waldron Christina , Mori Makoto , Krane Markus , Reinhardt Samuel W. , Ahmad Yousif , Kaple Ryan , Forrest John K. , Geirsson Arnar
Published: February 2024

Background

Multidisciplinary heart team (HT) evaluation is recommended for patients with severe primary mitral regurgitation to optimize treatment decisions. However, its impact on patient outcomes remains unknown. We evaluated the impact of implementing mitral HT on patient survival.

Methods and Results

We conducted a retrospective cohort study of patients with new diagnoses of severe primary mitral regurgitation in a large healthcare network echocardiogram database between 2016 and 2020. We compared the incidence of multidisciplinary evaluation by structural cardiology and cardiac surgery services and 2‐year survival before and after mitral HT implementation. The 1:1 propensity‐score matching between pre‐ and post‐mitral HT used Society of Thoracic Surgeons Predicted Risk of Mortality for mitral repair, age, sex, race, heart failure symptoms, inpatient setting, history of MI, and dementia as covariates. Logistic regression identified variables associated with the likelihood of undergoing multidisciplinary evaluation. Among 70 510 echocardiograms performed, 391 patients had severe primary mitral regurgitation (median age, 77 years; 46% women). Multidisciplinary evaluation increased from 29% to 89% (
P
<0.001), and intervention increased from 24% to 75% following mitral HT implementation (
P
<0.001). Among 180 propensity‐score matched patients, mortality was lower post‐mitral HT at 2 years (19% versus 32%,
P
=0.04). The multivariable model showed that mitral HT implementation and heart failure symptoms were associated with higher odds of undergoing multidisciplinary evaluation (OR [odds ratio], 18.7 and 2.72, respectively), whereas female sex and older age were associated with lower odds (OR, 0.39 and 0.93, respectively).

Conclusions

Implementation of mitral HT was associated with drastic improvement in multidisciplinary evaluation for patients with severe primary mitral regurgitation. This coincided with higher proportions of patients undergoing mechanical correction of MR and improved overall patient survival.
Impaired brain-heart axis in focal epilepsy: Alterations in information flow and implications for seizure dynamics
Authors: Frassineti Lorenzo , Catrambone Vincenzo , Lanatà Antonio , Valenza Gaetano
Published: February 2024

This study delves into functional brain-heart interplay (BHI) dynamics during interictal periods before and after seizure events in focal epilepsy. Our analysis focuses on elucidating the causal interaction between cortical and autonomic nervous system (ANS) oscillations, employing electroencephalography and heart rate variability series. The dataset for this investigation comprises 47 seizure events from 14 independent subjects, obtained from the publicly available Siena Dataset. Our findings reveal an impaired brain-heart axis especially in the heart-to-brain functional direction. This is particularly evident in bottom-up oscillations originating from sympathovagal activity during the transition between preictal and postictal periods. These results indicate a pivotal role of the ANS in epilepsy dynamics. Notably, the brain-to-heart information flow targeting cardiac oscillations in the low-frequency band does not display significant changes. However, there are noteworthy changes in cortical oscillations, primarily originating in central regions, influencing heartbeat oscillations in the high-frequency band. Our study conceptualizes seizures as a state of hyperexcitability and a network disease affecting both cortical and peripheral neural dynamics. Our results pave the way for a deeper understanding of BHI in epilepsy, which holds promise for the development of advanced diagnostic and therapeutic approaches also based on bodily neural activity for individuals living with epilepsy.
A Review of Saudi E-Commerce Regulation Under the Scope of the GDPR
Authors: Bouderhem Rabaï
Published: February 2024

The purpose of this article is to analyse and make an initial assessment of the Saudi legislative framework regarding E-commerce and data protection throughout a set of rules imposed on Internet service providers (ISPs) to ensure confidentiality, integrity of data and the safety of online transactions. Some efforts have been made in the Middle East and beyond and making an initial assessment may help us strengthen the existing legal instruments. The basic postulate is that we deal with cybercrimes and potential transnational offences. States should cooperate on a bilateral and multilateral basis in order to increase data protection and both security and predictability of E-commerce. The analysis of European law which opted very early for increased protection of personal data and strict regulation of cyberspace could allow us to put into perspective the evolution of Saudi law and possibly try to bridge or improve its approach to the matter.
From Athens to Alexandria: What Damascius Learned from Ammonius
Authors: Golitsis Pantelis
Published: February 2024

Damascius of Damascus, last ‘Platonic successor’ in Athens, is rarely compared to one of his masters, namely Ammonius, the philosopher of Alexandria. When scholars do compare the two Neoplatonist philosophers, they usually focus on the negative picture of Ammonius, which is drawn by Damascius in his Philosophical History. In this paper, I argue that Damascius admired Ammonius’ intellectual endeavours and espoused a basic feature of the philosophical exegesis of his master, namely his concordism regarding the philosophies of Plato and Aristotle, as is evident in Damascius’ surviving work on Plato and his (fragmentarily preserved) treatise On Time. Damascius’ downgrading of Ammonius came about rather as a disappointment, which is however by no means fully justified.
Wood of Qualea from the Piedra Chamana in-situ fossil forest (late Middle Eocene, Peru) and the comparative wood anatomy of Vochysiaceae and Myrtaceae
Authors: Woodcock Deborah W.
Published: February 2024

A wood from a late Middle Eocene in-situ fossil forest in northern Peru shows affinity with Qualea (Vochysiaceae), a genus of South American lowland tropical trees, based on features including vestured pits, aliform-confluent to banded paratracheal parenchyma, and homocellular rays. Additional features suggest adaptation to dry conditions. The fossil is named as a new species within Qualeoxylon (Q. lafila). Vochysiaceae and sister-group Myrtaceae share features unique to Myrtales (vestured pits, intraxylary phloem) or common in the order (vessels generally solitary and in >1 diameter class, heterocellular rays) but in other ways are clearly differentiated. Vochysiaceae has narrow to very wide vessels with elaborated axial parenchyma and lacks most characters considered less specialized such as scalariform perforations. Myrtaceae generally has vessels with vasicentric tracheids, usually exclusively solitary, very narrow to wide, and often diagonally arranged, and includes taxa with less to more specialized features. Woods with elaborated paratracheal parenchyma and vessels wide to very wide occur in wet tropical forest environments in both families Erisma, Vochysia and Qualea/Ruizterania (Vochysiaceae) in the Neotropics and Syzygium (Myrtaceae) in the Asian tropics. The Eucalyptus spp. dominating open forests in Australia have typical myrtaceous features (including vasicentric tracheids) plus homocellular rays, whereas the eucalypt clade Angophora + Corymbia, occurring mainly in the northern, monsoonal regions of Australia, has both vasicentric tracheids and aliform to banded axial parenchyma. The fossil is an early record for Vochysiaceae and adds to indications that Vochysiaceae and sister-group Myrtaceae showed significant diversification by the late Paleogene.
A Machine Learning Approach to Improve the Usability of Severe Thunderstorm Wind Reports
Authors: Tirone Elizabeth , Pal Subrata , Gallus William A. , Dutta Somak , Maitra Ranjan , Newman Jennifer , Weber Eric , Jirak Israel
Published: February 2024

Many concerns are known to exist with thunderstorm wind reports in the National Center for Environmental Information Storm Events Database, including the overestimation of wind speed, changes in report frequency due to population density, and differences in reporting due to damage tracers. These concerns are especially pronounced with reports that are not associated with a wind speed measurement, but are estimated, which make up almost 90% of the database. We have used machine learning to predict the probability that a severe wind report was caused by severe intensity wind, or wind ≥ 50 kt (∼25 m s−1). A total of six machine learning models were trained on 11 years of measured thunderstorm wind reports, along with meteorological parameters, population density, and elevation. Objective skill metrics such as the area under the ROC curve (AUC), Brier score, and reliability curves suggest that the best performing model is the stacked generalized linear model, which has an AUC around 0.9 and a Brier score around 0.1. The outputs from these models have many potential uses such as forecast verification and quality control for implementation in forecast tools. Our tool was evaluated favorably at the Hazardous Weather Testbed Spring Forecasting Experiments in 2020, 2021, and 2022.
Once a job crafter, always a job crafter? Investigating job crafting in organizations as a reciprocal self-concordant process across time
Authors: Clinton Michael E , Bindl Uta K , Frasca Keely J , Martinescu Elena
Published: February 2024

Research depicts job crafting as a desirable, ongoing employee behavior rather than a one-off event. However, insights are lacking into how employees’ active engagement in job crafting may be sustained across time. In this study, we advance a dynamic framework of how changes that follow employees’ periods of job crafting may, in turn, motivate versus impede continued crafting of one’s job role over time. Drawing from self-concordance theorizing, we propose and test a framework on how job crafting and employees’ attainment of self-concordant and organizational work goals are reciprocally related over time. Longitudinal data from a large, three-wave study collected over four years among church ministers support a positive reciprocal relationship between job crafting and self-concordant goal attainment, as well as an indirect positive relationship between job crafting and organizational goal attainment via self-concordant goal attainment. However, in line with our theorizing, organizational goal attainment did not predict subsequent job crafting. Instead, high organizational goal attainment weakened the extent to which job crafting at one time point positively related to job crafting at the next time point. We discuss the theoretical and practical implications of our findings for employees’ continued engagement in job crafting in organizations.