bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sage’s Argument
Authors: Glasgow Joshua
Published: August 2024

We are cosmically insignificant: compared to the rest of the universe, we are small, short-lived, and weak. Some oppose this line of thought on the grounds that there is no cosmic perspective. But it just requires unimportance on a certain scale of comparison; it does not require its own perspective. Others oppose our cosmic significance by denying that size, duration, and power can affect our value, but it is argued here that these things can indeed affect our value. Another line of opposition is to say that we are the only ones with certain important qualities, like loving or rationality. But we are limited in those qualities, too. Finally, any postulation that we have some god-given purpose must first establish that we really do have that god-given purpose and then also explain how that doesn’t reduce our significance by making us an instrument of that god and removing our autonomy.
Refining Liposuction Safety and Efficacy: Surgeon Learning-Curve Analysis With Helium-Based Plasma Integration
Authors: Ruff Paul G , Martinez Allison , Burpee Nicholas
Published: August 2024

Background

The introduction of medical advancements requires ongoing critical evaluation of clinical practice and patient outcomes to improve results and safety. Since the development of minimally invasive, energy-based devices, this process has been occurring throughout the field of aesthetic medicine.

Objectives

To collect retrospective procedure and safety data of liposuction procedures with or without adjunct utilization of a helium-based plasma device, compare 3 groups, and delineate the learning curve.

Methods

A retrospective chart review at a single site included healthy patients ≥18 years of age treated by the principal investigator (PI). A total of 50 patients had an ultrasonic-assisted liposuction procedure, 50 patients had a liposuction procedure with the utilization of the helium-based plasma device, and 50 of the PI's most recent patients had a liposuction procedure with the utilization of the helium-based plasma device. All patients had at least 6 months of documented postoperative follow-up care.

Results

Totally, 150 patients were enrolled in the study. Most patients had multiple body areas treated, primarily hips and abdomen. Treatment settings varied, with significant relationships found between pain and treatment groups (P = .013). No serious or unexpected adverse events (AEs) were reported, and all AE resolved before the final follow-up.

Conclusions

The data collected support that patient outcomes and safety improve with continued use of the helium-based plasma device by the PI. The data also support the use of a helium-based plasma device as safe when used in combination with liposuction procedures.

Level of Evidence: 4 (Therapeutic)
An Ensemble Spectral Prediction (ESP) model for metabolite annotation
Authors: Li Xinmeng , Zhou Chen Yan , Kalia Apurva , Zhu Hao , Liu Li-ping , Hassoun Soha
Published: August 2024

Motivation

A key challenge in metabolomics is annotating measured spectra from a biological sample with chemical identities. Currently, only a small fraction of measurements can be assigned identities. Two complementary computational approaches have emerged to address the annotation problem: mapping candidate molecules to spectra, and mapping query spectra to molecular candidates. In essence, the candidate molecule with the spectrum that best explains the query spectrum is recommended as the target molecule. Despite candidate ranking being fundamental in both approaches, limited prior works incorporated rank learning tasks in determining the target molecule.

Results

We propose a novel machine learning model, Ensemble Spectral Prediction (ESP), for metabolite annotation. ESP takes advantage of prior neural network-based annotation models that utilize multilayer perceptron (MLP) networks and Graph Neural Networks (GNNs). Based on the ranking results of the MLP- and GNN-based models, ESP learns a weighting for the outputs of MLP and GNN spectral predictors to generate a spectral prediction for a query molecule. Importantly, training data is stratified by molecular formula to provide candidate sets during model training. Further, baseline MLP and GNN models are enhanced by considering peak dependencies through label mixing and multi-tasking on spectral topic distributions. When trained on the NIST 2020 dataset and evaluated on the relevant candidate sets from PubChem, ESP improves average rank by 23.7% and 37.2% over the MLP and GNN baselines, respectively, demonstrating performance gain over state-of-the-art neural network approaches. However, MLP approaches remain strong contenders when considering top five ranks. Importantly, we show that annotation performance is dependent on the training dataset, the number of molecules in the candidate set and candidate similarity to the target molecule.

Availability and implementation

The ESP code, a trained model, and a Jupyter notebook that guide users on using the ESP tool is available at https://github.com/HassounLab/ESP.
Pandagma: a tool for identifying pan-gene sets and gene families at desired evolutionary depths and accommodating whole-genome duplications
Authors: Cannon Steven B , Lee Hyun-Oh , Weeks Nathan T , Berendzen Joel
Published: August 2024

Identification of allelic or corresponding genes (pan-genes) within a species or genus is important for discovery of biologically significant genetic conservation and variation. Similarly, identification of orthologs (gene families) across wider evolutionary distances is important for understanding the genetic basis for similar or differing traits. Especially in plants, several complications make identification of pan-genes and gene families challenging, including whole-genome duplications, evolutionary rate differences among lineages, and varying qualities of assemblies and annotations. Here, we document and distribute a set of workflows that we have used to address these problems.

Results

Pandagma is a set of configurable workflows for identifying and comparing pan-gene sets and gene families for annotation sets from eukaryotic genomes, using a combination of homology, synteny, and expected rates of synonymous change in coding sequence.

Availability and implementation

The Pandagma workflows, example configurations, implementation details, and scripts for retrieving public datasets, are available at https://github.com/legumeinfo/pandagma
Eliater: a Python package for estimating outcomes of perturbations in biomolecular networks
Authors: Mohammad-Taheri Sara , Navada Pruthvi Prakash , Hoyt Charles Tapley , Zucker Jeremy , Sachs Karen , Gyori Benjamin M , Vitek Olga
Published: August 2024

We introduce Eliater, a Python package for estimating the effect of perturbation of an upstream molecule on a downstream molecule in a biomolecular network. The estimation takes as input a biomolecular network, observational biomolecular data, and a perturbation of interest, and outputs an estimated quantitative effect of the perturbation. We showcase the functionalities of Eliater in a case study of Escherichia coli transcriptional regulatory network.

Availability and implementation

The code, the documentation, and several case studies are available open source at https://github.com/y0-causal-inference/eliater.
Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway
Authors: Shu Wan , Hua Teng , Xin Xiaoyan , Zhang Jun , Lin Jing , Shi Rui , Zhao Rong , Zhang Wei , Dong Ke-jun , Wang Hongbo , Zhou Xing
Published: August 2024

Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products, activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.
Quantum chemical analysis and biochemical evaluation of the inhibitory activity of puerarin on CYP1B1 enzyme
Authors: Li Xue , Lu Jinyue , Yang Lianrong , Tian Yuan , Jia Liwei , Meng Xin
Published: August 2024

The inhibitory activity of puerarin on the CYP1B1 enzyme was evaluated by the 7-ethoxyresorufin O-dealkylation method. At the same time, the density functional theory algorithm, molecular docking, and molecular dynamics simulations were used to verify the stability of the puerarin–CYP1B1 complex. It has been found that puerarin is a potent uncompetitive inhibitor of CYP1B1 (IC50: 1.06 ± 0.15 μM).
Isochalcogenourea-catalyzed asymmetric (4 + 2)-heterocycloadditions of allenoates
Authors: Waser Mario
Published: August 2024

Allenoates are versatile reagents that can be used for numerous (formal) cycloaddition reactions under (chiral) Lewis base catalysis. Most commonly, the catalysts of choice are phosphines, amines, and N-heterocyclic carbenes. We have recently established the use of readily available chiral isochalcogenoureas as catalysts for asymmetric (4 + 2)-heterocycloadditions of allenoates with various vinylogous acceptors. This represents a complementary approach for allenoate activation and gives access to various highly functionalized chiral dihydropyrans with good to excellent enantioselectivities and diastereoselectivities.
A fluorescent complex with peptide nucleic acids modified by boronic acid and its ligand detects target RNA in cells
Authors: Ishii Koki , Hattori Yoshihide , Shigeto Hajime , Yamamura Shohei , Kitamatsu Mizuki
Published: August 2024

We have developed peptide nucleic acids (PNAs) modified with boronic acid (Boa) and its ligand 2-(pyridin-2-yl)phenol (Pyp) as a probe for fluorescence detection of a target nucleic acid. Boa and Pyp successfully showed fluorescence by complexing via hybridization with PNA and the target. This fluorescent PNA probe also successfully responded to the target RNA in cells.
Kidney function–specific cut-off values of high-sensitivity cardiac troponin T for the diagnosis of acute myocardial infarction
Authors: Chen Ruixuan , Pang Mingzhen , Yu Hongxue , Luo Fan , Zhang Xiaodong , Su Licong , Li Yanqin , Zhou Shiyu , Xu Ruqi , Gao Qi , Gan Daojing , Xu Xin , Nie Sheng , Hou Fan Fan ,   for the CRDS study Investigators, Xu Hong , Liu Bicheng , Weng Jianping , Chen Chunbo , Liu Huafeng , Yang Qiongqiong , Li Hua , Li Guisen , Wan Qijun , Zha Yan , Hu Ying , Xu Gang , Shi Yongjun , Zhou Yilun , Tang Ying , Gong Mengchun , Wang Chen , Liu Dehui , Luo Pengli , Shen Jie , Bai Yihua
Published: August 2024

Background

The diagnosis of acute myocardial infarction (AMI) using high-sensitivity cardiac troponin T (hs-cTnT) remains challenging in patients with kidney dysfunction.

Methods

In this large, multicenter cohort study, a total of 20 912 adults who underwent coronary angiography were included. Kidney function–specific cut-off values of hs-cTnT were determined to improve the specificity without sacrificing sensitivity, as compared with that using traditional cut-off value (14 ng/L) in the normal kidney function group. The diagnostic accuracy of the novel cut-off values was validated in an independent validation cohort.

Results

In the derivation cohort (n = 12 900), 3247 patients had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Even in the absence of AMI, 50.2% of participants with eGFR <60 mL/min/1.73 m2 had a hs-cTnT concentration ≥14 ng/L. Using 14 ng/L as the threshold of hs-cTnT for diagnosing AMI led to a significantly reduced specificity and positive predictive value in patients with kidney dysfunction, as compared with that in patients with normal kidney function. The kidney function–specific cut-off values were determined as 14, 18 and 48 ng/L for patients with eGFR >60, 60–30 and <30 mL/min/1.73 m2, respectively. Using the novel cut-off values, the specificities for diagnosing AMI in participants with different levels of kidney dysfunction were remarkably improved (from 9.1%–52.7% to 52.8–63.0%), without compromising sensitivity (96.6%–97.9%). Similar improvement of diagnostic accuracy was observed in the validation cohort (n = 8012).

Conclusions

The kidney function–specific cut-off values of hs-cTnT may help clinicians to accurately diagnose AMI in patients with kidney dysfunction and avoid the potential overtreatment in practice.
The association between klotho and kidney and cardiovascular outcomes: a comprehensive systematic review and meta-analysis
Authors: Kanbay Mehmet , Brinza Crischentian , Ozbek Lasin , Guldan Mustafa , Sisman Uluman , Copur Sidar , Covic Andreea , Scripcariu Dragos-Viorel , Burlacu Alexandru , Covic Adrian
Published: August 2024

Background

Chronic kidney disease (CKD) and end-stage renal disease (ESKD) are significant global health challenges associated with progressive kidney dysfunction and numerous complications, including cardiovascular disease and mortality. This study aims to explore the potential association between plasma klotho levels and various prognostic outcomes in CKD and ESKD, including all-cause mortality, cardiovascular events, metabolic syndrome development and adverse renal events necessitating renal replacement therapies.

Methods

A literature search was conducted through 3 June 2024 using the electronic databases Cochrane Library, Ovid MEDLINE, CINAHL, Web of Science, SCOPUS and PubMed. This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results

Fourteen studies were included. For all-cause mortality, comparing CKD patients with low versus high klotho levels showed a significant association {odds ratio [OR] 1.81 [95% confidence interval (CI) 1.34–2.44], P = .0001}, with substantial heterogeneity (I2 = 69%). Excluding one study reduced heterogeneity (I2 = 43%) while maintaining significance [OR 1.97 (95% CI 1.45–2.66), P < .0001]. Cardiovascular mortality was higher in patients with low klotho levels [OR 2.11 (95% CI 1.61–2.76), P < .00001], with low heterogeneity (I2 = 25%). Excluding one study eliminated heterogeneity (I2 = 0%) while maintaining significance [OR 2.39 (95% CI 1.83–3.12), P < .00001]. Composite cardiovascular events did not differ significantly between low and high klotho groups [OR 1.51 (95% CI 0.82–2.77), P = .18], but with high heterogeneity (I2 = 72%). Patients with low klotho levels had a higher risk of adverse renal events [OR 2.36 (95% CI 1.37–4.08), P = .002], with moderate heterogeneity (I2 = 61%). Sensitivity analysis reduced heterogeneity (I2 = 0%) while maintaining significance [OR 3.08 (95% CI 1.96–4.85), P < .00001]. Specifically, for ESKD or kidney replacement therapy risk, low klotho levels were associated with an increased risk [OR 2.30 (95% CI 1.26–4.21), P = .007]. Similarly, CKD progression risk was higher in patients with lower klotho levels [OR 2.48 (95% CI 1.45–4.23), P = .0009].

Conclusion

Lower serum klotho levels serve as a significant predictor of adverse outcomes, including increased risks of all-cause mortality, cardiovascular mortality and progression to end-stage kidney disease among CKD patients.
Dynamic assessment of left ventricular coupling and myocardial reserve in patients with cardiogenic shock
Authors: Kanelidis Anthony J , Randazzo Michael J , Kalantari Sara , Smith Bryan , Nguyen Ann , Chung Ben B , Swat Stanley , Sarswat Nitasha , Salerno Christopher , Jeevanandam Valluvan , Kim Gene , Belkin Mark N , Grinstein Jonathan
Published: August 2024

Aims

Pulmonary artery catheter haemodynamics are associated with improved survival in cardiogenic shock (CS). We investigated the utility of aortic pulsatility index (API) and cardiac power output (CPO) as surrogates for left ventricular (LV) coupling and myocardial reserve, respectively, in patients with CS undergoing dynamic assessment after a milrinone bolus.

Methods and results

Patients with SCAI Stage C CS underwent a milrinone drug study (50 mcg/kg bolus infused over 10 min) to assess inotropic response. Haemodynamic measurements were obtained at baseline and following the bolus. Aortic pulsatility index and CPO were used to risk-stratify patients with the incidence of LV assist device (LVAD), orthotopic heart transplantation (OHT), or death at 1 year as the primary composite endpoint. Two hundred and twenty-four patients in SCAI Stage C CS underwent haemodynamics prior to milrinone bolus, and 117 patients had low baseline API < 1.45. Of the 117 patients, 88 had a final API < 2.2 after milrinone load, consistent with LV decoupling, in which 73% met the composite endpoint. The remaining 29 patients had a final API ≥ 2.2 consistent with LV recoupling, and only 55% met the composite endpoint (P = 0.046). Of the 117 patients, 40 patients had low myocardial reserve (final CPO < 0.77 W), in which 78% met the composite endpoint. Of the 77 patients who demonstrated myocardial reserve (final CPO ≥ 0.77 W), only 64% met the composite endpoint (P = 0.039).

Conclusion

The use of API and CPO in a dynamic assessment after provocative testing led to improved risk stratification in patients with SCAI Stage C CS for clinical outcomes including LVAD, OHT, or death at 1 year.
Decellularized aortic homografts versus mechanical composite grafts for aortic root replacement
Authors: Andreeva Alexandra , Werner Paul , Coti Iuliana , Kocher Alfred , Laufer Guenther , Ehrlich Marek , Zimpfer Daniel , Andreas Martin
Published: August 2024

OBJECTIVES

Mechanical composite valve grafts (MCVGs) are the first-line therapy for aortic root replacement in young adults. Decellularized aortic homografts (DAH) present a promising novel alternative due to their lower thrombogenicity. We aimed to compare both treatment options regarding survival and valve-related adverse events.

METHODS

This study was designed as a single-centre retrospective cohort study including patients who underwent root replacement with MCVG or DAH between 2000 and 2022. Urgent or emergent procedures were excluded.

RESULTS

The study cohort included 289 patients (MCVG n = 216, DAH n = 73) with a mean age of 48.5 ± 12 years (MCVG 49 ± 12 years vs DAH 47 ± 11 years; P = 0.23) and a median EuroScore II of 1.7% (1.2, 2.6). The 30-day mortality was 1% (n = 3). Cumulative survival at 3 years was 99% for DAH and 94% for MCVG, respectively (P = 0.15). Mean follow-up was 98.9 ± 72.7 months. Bleeding events (n = 14, 6.5%) and thromboembolism (n = 14, 6.5%) were only observed in the MCVG group (P = 0.19 and 0.09, respectively). Four cases (5%) of moderate structural valve deterioration occurred, all in the DAH group (P ≤ 0.001). The cumulative incidence of a composite end point of valve-related adverse events was significantly higher in the MCVG group (P = 0.0295).

CONCLUSIONS

Aortic root replacement with MCVGs and decellularized aortic homografts showed low mortality in an elective setting. Patients in the homograft cohort demonstrated significantly higher freedom from valve-related adverse events. DAH present a promising treatment option for young patients requiring root replacement; however, data on long-term durability are needed.
Surgical prognosis of lung invasive mucinous and non-mucinous adenocarcinoma: propensity score matched analysis
Authors: Lee Jun Oh , Lee Geun Dong , Choi Sehoon , Kim Hyeong Ryul , Kim Yong-Hee , Kim Dong Kwan , Park Seung-Il , Yun Jae Kwang
Published: August 2024

OBJECTIVES

Invasive mucinous adenocarcinoma exhibits distinct prognostic outcomes compared to non-mucinous adenocarcinoma (ADC). This study investigated and compared the clinical outcomes and prognostic factors of invasive mucinous and non-mucinous ADC patients.

METHODS

This retrospective study included patients who underwent curative surgery for ADC between 2011 and 2021. Patient characteristics were balanced using propensity score matching. Cumulative incidence was analysed to evaluate cancer recurrence incidence, and the Kaplan–Meier method was used to calculate overall survival (OS) for each group.

RESULTS

A total of 6101 patients were included. After matching, the non-mucinous group and mucinous groups comprised 798 and 408 patients, respectively. The patients in the mucinous group had a lower recurrence incidence than those in the non-mucinous group (P = 0.014). The recurrence incidence in the mucinous group was between those of grades 1 (P = 0.011) and 2 (P = 0.012) and the OS rates were comparable to those of grades 2 (P = 0.6) and 3 (P = 0.2). Multivariable analysis revealed that the maximal standardized uptake value [hazard ratio (HR): 1.13, P = 0.11] and progressed pathological stages (pStage II, HR: 3.9, P = 0.028; pStage III, HR: 8.33, P = 0.038) served as adverse prognostic factors for the mucinous group.

CONCLUSIONS

Patients with mucinous ADC demonstrated lower recurrence incidence and similar OS rates compared to those with non-mucinous ADC. The recurrence incidence of mucinous ADC was between those of International Association for the Study of Lung Cancer grades 1 and 2, with the OS rates comparable to those of grades 2 and 3.

CLINICAL REGISTRATION NUMBER

None.
No effect of surgery on kidney and cardiovascular risk factors in mild primary hyperparathyroidism: secondary analyses from a 10-year randomized controlled trial
Authors: Heck Ansgar , Pretorius Mikkel , Lundstam Karolina , Godang Kristin , Hellström Mikael , Ueland Thor , Bollerslev Jens
Published: August 2024

Objective

Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation.

Design

Prospective randomized controlled trial. ClinicalTrials.gov: NCT00522028.

Setting

Eight Scandinavian referral centers.

Participants

From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses.

Intervention

Seventy patients were randomized to PTX and 80 to observation without intervention (OBS).

Measures

e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide.

Results

No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years.

Limitations

Secondary analyses of a randomized controlled trial.

Conclusion

PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective.
When the Sun, the Moon and the Stars Align: Litigating LGBTQIA+ Rights and the Death Penalty in East Africa and the Caribbean
Authors: Caserta Salvatore , Madsen Mikael Rask
Published: August 2024

This article analyses LGBTQIA+ rights and death penalty litigation in the Caribbean and East Africa before and after the establishment of new regional international courts. LGBTQIA+ rights and the death penalty are both difficult and contested issues where global movements and litigation strategies easily clash with local sentiments. For litigation to have an impact in such issue areas, the article finds that three elements must align. First, there is a need for new institutional opportunities such as new judicial venues or laws. Second, there is a need for coordinated legal strategies that can utilize the available legal venues. Third, there is a need for a societal momentum for the cause, or at least the absence of strong political contestation against the cause. In our study, the establishment of new regional courts provided institutional opportunities that could be seized by transnational litigation networks. And as international courts operate at a distance from local politics, they have created a more neutral international legal opportunity structure. In the two regions and across the two issue areas studied, these three elements were most clearly aligned regarding death penalty litigation in the Caribbean and the least aligned regarding LGBTQIA+ litigation in East Africa.
Smoking timing, genetic susceptibility, and the risk of incident atrial fibrillation: a large prospective cohort study
Authors: Zhou Jian , Hu Ying , Tang Rui , Kou Minghao , Wang Xuan , Ma Hao , Li Xiang , Heianza Yoriko , Qi Lu
Published: August 2024

Aims

Although smoking is a well-known risk factor for atrial fibrillation (AF), the association of smoking timing with AF risk remains unclear. This study aimed to prospectively investigate the association of smoking timing with the risk of incident AF and test the modification effect of genetic susceptibility.

Methods and results

A total of 305 627 participants with detailed information for time from waking to the first cigarette were enrolled from UK Biobank database. The Cox proportional hazard model was employed to assess the relationship between smoking timing and AF risk. The weighted genetic risk score for AF was calculated. Over a median 12.2-year follow-up, 13 410 AF cases were documented. Compared with non-smokers, time from waking to the first cigarette showed gradient inverse associations with the risk of incident AF (P-trend <0.001). The adjusted hazard ratio related to smoking timing was 1.13 [95% confidence interval (CI): 0.96–1.34] for >120 min, 1.20 (95% CI: 1.01–1.42) for 61–120 min, 1.34 (95% CI: 1.19–1.51) for 30–60 min, 1.43 (95% CI: 1.26–1.63) for 5–15 min, and 1.49 (95% CI: 1.24–1.63) for <5 min, respectively. Additionally, we found that the increased risk of AF related to shorter time from waking to the first cigarette was strengthened by the genetic susceptibility to AF.

Conclusion

Our findings suggest gradient inverse association between time from waking to the first cigarette and risk of incident AF, and the association is strengthened by the genetic susceptibility to AF.
Ecological speciation in sympatric palms: 5. Evidence for pleiotropic speciation genes using gene knockout and high-throughput phenotyping
Authors: Coathup Matthew J , Mouhu Katriina , Himanen Kristiina , Turnbull Colin G N , Savolainen Vincent
Published: August 2024

Theoretical models predict that sympatric, ecological speciation may be facilitated more readily when so-called ‘magic traits’ are present, linking traits under divergent selection with assortative mating. Such traits might be encoded by pleiotropic genes, that is, genes that affect multiple, apparently unrelated, phenotypes. However, few convincing examples of sympatric speciation exist, and empirical evidence for the role of magic traits in driving such speciation is rare. One of the strongest cases of sympatric speciation is the Howea palms of Lord Howe Island, Australia, comprising the sister species Howea belmoreana and Howea forsteriana, which have diverged due to soil substrate preferences and flowering time displacement. Here we investigate the role that pleiotropy may have played in the speciation process by carrying out high-throughput phenotyping experiments using 1830 Arabidopsis thaliana plants with knockouts of candidate Howea ‘speciation genes’. We identify several genes that show signatures of adaptive divergence between the Howea species and demonstrate pleiotropic roles in soil stress tolerance and flowering time, consistent with the Howea speciation scenario—notably, Howea orthologues of the A. thaliana loci At2-MMP, DCL1, RCD1, SAL1, and SIZ1. Empirical evidence is provided, therefore, for a range of pleiotropic genes with the potential to have driven sympatric speciation by generating magic traits which link divergent selection to non-random mating.
Impaired Neurocirculatory Control in Chronic Kidney Disease: New Evidence for Blunted Sympathetic Baroreflex and Reduced Sympathetic Transduction
Authors: Sabino-Carvalho Jeann L , Mekonnen Elsa , Zanuzzi Matias , Li Sabrina , Cui Xiangqin , Park Jeanie
Published: August 2024

Chronic kidney disease (CKD) is characterized by over-activation of the sympathetic nervous system (SNS) that increases cardiovascular risk. Whether sympathetic baroreflex sensitivity (sBRS) is impaired or intact in CKD remains under-studied and controversial. Furthermore, the downstream effect of SNS activation on blood pressure transduction has not been previously examined in CKD. We tested the hypothesis that sBRS is attenuated, while sympathetic transduction is augmented in CKD. In 18 sedentary patients with CKD stages III-IV (eGFR: 40±14 mL/min) and 13 age-matched controls (eGFR: 95±10 mL/min), beat-to-beat blood pressure (BP; finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest for 10-min. Weighted linear regression analysis between MSNA burst incidence and diastolic BP was used to determine the spontaneous sBRS. Sympathetic-BP transduction was quantified using signal averaging, whereby the BP response to each MSNA burst was tracked over 15 cardiac cycles and averaged to derive the peak change in BP. Compared with controls, CKD patients had an attenuated sBRS [CKD: −1.34 ± 0.59 versus CON: −2.91 ± 1.09 bursts (100 heartbeats)−1 mmHg−1; P = 0.001]. |sBRS| was significantly associated with eGFR (r = 0.69, P < 0.001). CKD patients had attenuated sympathetic-BP transduction compared to controls (0.75 ± 0.7 vs. 1.60 ± 0.8 mmHg; P = 0.010). Resting MSNA was negatively associated with sympathetic transduction (r = −0.57, P = 0.002). CKD patients exhibit impaired sBRS that may contribute to SNS overactivation and cardiovascular risk in this patient population. In addition, CKD patients had an attenuated sympathetic transduction that may counteract the vascular effects of SNS overactivation.
Expression levels of core spliceosomal proteins modulate the MBNL-mediated spliceopathy in DM1
Authors: Louis Jiss M , Frias Jesus A , Schroader Jacob H , Jones Lindsey A , Davey Emily E , Lennon Claudia D , Chacko Jacob , Cleary John D , Berglund J Andrew , Reddy Kaalak
Published: August 2024

Myotonic dystrophy type 1 (DM1) is a heterogeneous multisystemic disease caused by a CTG repeat expansion in DMPK. Transcription of the expanded allele produces toxic CUG repeat RNA that sequesters the MBNL family of alternative splicing (AS) regulators into ribonuclear foci, leading to pathogenic mis-splicing. To identify genetic modifiers of toxic CUG RNA levels and the spliceopathy, we performed a genome-scale siRNA screen using an established HeLa DM1 repeat-selective screening platform. We unexpectedly identified core spliceosomal proteins as a new class of modifiers that rescue the spliceopathy in DM1. Modest knockdown of one of our top hits, SNRPD2, in DM1 fibroblasts and myoblasts, significantly reduces DMPK expression and partially rescues MBNL-regulated AS dysfunction. While the focus on the DM1 spliceopathy has centered around the MBNL proteins, our work reveals an unappreciated role for MBNL:spliceosomal protein stoichiometry in modulating the spliceopathy, revealing new biological and therapeutic avenues for DM1.
Food-Based Interventions as Therapy for Inflammatory Bowel Disease: Important Steps in Diet Trial Design and Reporting of Outcomes
Authors: Day Alice S , Ballard Tessa M , Yao Chu K , Gibson Peter R , Bryant Robert V
Published: August 2024

Diet therapy for inflammatory bowel disease (IBD) is an international research priority but guidance for IBD-specific diet trial design is lacking. This review critically evaluates key elements of prospective IBD food-based intervention trials and identifies gaps. Electronic databases were searched for interventional IBD diet studies. Prospective primary studies/trials were included if used food-based dietary strategies. Forty studies/trials evaluating 29 food-based strategies as therapy for IBD were identified. Considerable heterogeneity in diets, trial design, and methodology exists. Thirty-one trials (78%) intended the diet to modulate inflammation but 14/31 (46%) did not have a primary endpoint measuring an objective change in inflammatory activity and 20/31 (65%) controlled for medication stability prior to application of diet at baseline. Higher-quality IBD diet trials used symptom-based assessment tools coupled with an objective evaluation of inflammatory activity. Dietary advice trials are the most common. One-third of trials developed and administered diet education without a dietitian. Evaluation and reporting on adherence to diet therapy occurred in <60% of trials. Failure to include or report on key elements of trial design reduced the interpretability and validity of the results. This is a considerable limitation to advancing scientific knowledge in this area. Diet therapy trials should adhere to similar rigorous quality standards used to develop other IBD therapies. Therefore, a set of practical recommendations was generated to provide the authors’ perspective to help inform the future design of high-quality IBD diet trials.
Long-term outcomes of minimally invasive concomitant mitral and tricuspid valve surgery with surgical ablation
Authors: Yoon Sungsil , Kim Kitae , Yoo Jae Suk , Kim Joon Bum , Chung Cheol Hyun , Jung Sung-Ho
Published: August 2024

OBJECTIVES

We compared the outcomes of a right mini-thoracotomy (RMT) versus those of a sternotomy for concomitant mitral and tricuspid valve surgery and surgical ablation.

METHODS

We analysed patients who underwent concomitant mitral and tricuspid valve surgery and surgical ablation at a single institution (mean follow-up: 7 years) after propensity score matching. The primary and secondary outcomes were all-cause death, composite major adverse events (including stroke, reoperation, readmission, permanent pacemaker insertion) and recurrence of atrial fibrillation (A-fib). A subgroup analysis was performed.

RESULTS

A total of 797 procedures (mean age: 61.6 years; RMT: 45.2%; female: 66.5%; mitral valve repair: 33.6%) were done; 267 pairs were matched. The 5- and 10-year overall survival in the matched cohort was 92.7% and 86.9% for the RMT group and 92.1% and 83.1% for the sternotomy group (P = 0.879). Significant differences were not observed in major adverse events (P = 0.273; hazard ratio: 0.76) and A-fib recurrence (P = 0.080; hazard ratio: 0.72). The RMT group had lower rates of postoperative low cardiac output syndrome (P = 0.019) and acute renal failure (P = 0.003). Atrial fibrillation high-risk factors (including long-standing A-fib, enlarged left atrium, old age) exhibited significant interactions (P for interaction = 0.002) with the approach regarding A-fib recurrence.

CONCLUSIONS

In this study, an RMT exhibited no significant differences in long-term outcomes compared to a sternotomy, but it could remain a clinically reasonable option. Patients with a high risk of A-fib may have favourable ablation outcomes with a sternotomy.
Digital literacy education for UK undergraduate pharmacy students: a mixed-methods study
Authors: Alowais Mashael , Nazar Hamde , Tolley Clare
Published: August 2024

Objectives

Digital literacy is increasingly crucial in pharmacy practice, and relevant education and training are required to prepare the future workforce. This study aims to explore the current and planned inclusion of digital literacy education in the undergraduate curricula of UK pharmacy schools.

Methods

A mixed-methods approach was conducted with two phases. The first involved a content analysis of published curricula from all 30 UK pharmacy schools. The second phase included a survey based on the Health Education England Digital Capabilities Framework, distributed to academic staff across all pharmacy schools.

Key findings

Data from 14 pharmacy schools’ curricula were included in the analysis, with 10 reporting digital literacy education. Key themes identified from the analysed documents included understanding of health informatics, applied informatics, information technology skills, and the emerging digital health technology. Nineteen respondents from 16 schools participated in the survey; digital literacy inclusion was reported by 18 participants. There was variable alignment of digital literacy competencies with the Health Education England framework. Digital literacy was mainly integrated into existing teaching sessions, predominantly through self-learning (n = 12). Electronic Health Records and remote counselling were the main focus areas within the curricula. Challenges in implementing digital literacy include a lack of expertise (n = 13), and time constraints (n = 10).

Conclusions

The trend towards embedding digital literacy in UK pharmacy curricula is clear, but disparities suggest the need for a more unified strategy. Recommendations include establishing a specific digital literacy framework aligned with professional needs, improving accessibility and transparency in curricula documents, and investing in faculty development.
Characterizing apparent treatment resistant hypertension in the United States: insights from the All of Us Research Program
Authors: Alshahawey Mona , Jafari Eissa , Smith Steven M , McDonough Caitrin W
Published: August 2024

Background

Hypertension (HTN) remains a significant public health concern and the primary modifiable risk factor for cardiovascular disease, which is the leading cause of death in the United States. We applied our validated HTN computable phenotypes within the All of Us Research Program to uncover prevalence and characteristics of HTN and apparent treatment-resistant hypertension (aTRH) in United States.

Methods

Within the All of Us Researcher Workbench, we built a retrospective cohort (January 1, 2008–July 1, 2023), identifying all adults with available age data, at least one blood pressure (BP) measurement, prescribed at least one antihypertensive medication, and with at least one SNOMED “Essential hypertension” diagnosis code.

Results

We identified 99 461 participants with HTN who met the eligibility criteria. Following the application of our computable phenotypes, an overall population of 81 462 were further categorized to aTRH (14.4%), stable-controlled HTN (SCH) (39.5%), and Other HTN (46.1%). Compared to participants with SCH, participants with aTRH were older, more likely to be of Black or African American race, had higher levels of social deprivation, and a heightened prevalence of comorbidities such as hyperlipidemia and diabetes. Heart failure, chronic kidney disease, and diabetes were the comorbidities most strongly associated with aTRH. β-blockers were the most prescribed antihypertensive medication. At index date, the overall BP control rate was 62%.

Discussion and Conclusion

All of Us provides a unique opportunity to characterize HTN in the United States. Consistent findings from this study with our prior research highlight the interoperability of our computable phenotypes.
BioASQ Synergy: a dialogue between question-answering systems and biomedical experts for promoting COVID-19 research
Authors: Krithara Anastasia , Nentidis Anastasios , Vandorou Eirini , Katsimpras Georgios , Almirantis Yannis , Arnal Magda , Bunevicius Adomas , Farre-Maduell Eulalia , Kassiss Maya , Konstantakos Vasileios , Matis-Mitchell Sherri , Polychronopoulos Dimitris , Rodriguez-Pascual Jesus , Samaras Eleftherios G , Samiotaki Martina , Sanoudou Despina , Vozi Aspasia , Paliouras Georgios
Published: August 2024

Objective

This article presents the novel BioASQ Synergy research process which aims to facilitate the interaction between biomedical experts and automated question-answering systems.

Materials and Methods

The proposed research allows systems to provide answers to emerging questions, which in turn are assessed by experts. The assessment of the experts is fed back to the systems, together with new questions. With this iteration, we aim to facilitate the incremental understanding of a developing problem and contribute to solution discovery.

Results

The results suggest that the proposed approach can assist researchers to navigate available resources. The experts seem to be very satisfied with the quality of the ideal answers provided by the systems, suggesting that such systems are already useful in answering open research questions.

Discussion

BioASQ Synergy aspires to provide a tool that gives the experts easy and personalized access to the latest findings in a fast-growing corpus of material.

Conclusion

In this article, we envisioned BioASQ Synergy as a continuous dialogue between experts and systems to issue open questions. We ran an initial proof-of-concept of the approach, in order to evaluate its usefulness, both from the side of the experts, as well as from the side of the participating systems.
Volume-based Feeds: A Quality Improvement Project for Better Nutrition
Authors: Jagasia Puja , Ladele Olatundun , Slutsky Hanna , Troche Maria , Cogle Sarah , Strock Anna , Shoch Erica , Gondek Steve , Wagner Anne , Slater Elizabeth D
Published: August 2024

This quality improvement project at a single institution aimed to increase the proportion of prescribed tube feeds delivered to adult patients in the burn population with greater than 20% affected TBSA. A retrospective chart review was performed on all adult patients with burns from January 2018 to July 2022 with greater than 20% TBSA burns to compare quantitative measures such as length of stay, change in weight, and mean tube feeds delivered over hospitalization. Prospective data collection began in August 2022, when the first intervention was implemented, and continued until July 2023 in the same patient population to serve as a postintervention cohort. Using a multidisciplinary approach, the team implemented 8 interventions, which increased the mean proportion of tube feeds delivered to patients from 43% to 78%, marking a significant increase in nutrition delivered to patients, which is critical for wound healing following burn injuries.
A Randomized Controlled Trial of Home-based Virtual Rehabilitation to Improve Adherence to Prescribed Home Therapy After Burn Injury: A Northwest Regional Burn Model System Trial
Authors: Sibbett Stephen H , Carrougher Gretchen J , Orton Caitlin M , Sabel Jody I , Terken Tonya , Humbert Andrew , Bunnell Aaron , Gibran Nicole S , Pham Tam N , Stewart Barclay T
Published: August 2024

Daily rehabilitation after burn injury is vital for the prevention of function-limiting contractures. However, adherence to prescribed therapy following acute burn hospitalization has historically been low and not well-studied. Studies involving virtual reality technology have demonstrated an association with improved functional outcomes in burn therapy. We conducted a 5-year randomized controlled trial comparing 12 weeks of a home-based virtual rehabilitation (HBVR) system with standard burn therapy. Our primary outcome was adherence to prescribed home therapy, measured by e-diary self-report. Secondary outcomes included steps walked daily and patient-reported outcomes regarding stiffness, upper extremity function, and mobility. We enrolled 50 subjects, of which 48 provided data for analysis (23 HBVR, 25 control). Overall adherence to prescribed home therapy was low, 37.2% in the HBVR group and 60.0% in the control group. Reasons for nonadherence in the HBVR group included lack of time, engagement, and replacement of therapy with other physical activity. However, some subjects enjoyed HBVR and believed it aided their recovery. There was no difference in daily steps walked between the 2 groups. Daily walking gradually improved from 3500 steps per day in the first week after baseline and plateaued at 6000 steps per day at week 5. There were no differences in stiffness, upper extremity function, and mobility between the 2 groups at baseline and 3-, 6-, and 12-month follow-up. Subjects demonstrated improved upper extremity function and mobility in the first year after discharge, which coincided with increasing stiffness.
Unraveling spontaneous humoral immune responses against human cancer: a road to novel immunotherapies
Authors: Conejo-Garcia Jose R , Lopez-Bailon Luis U , Anadon Carmen M
Published: August 2024

In immuno-oncology, the focus has traditionally been on αβ T cells, and immune checkpoint inhibitors that primarily target PD-1 or CTLA4 in these lymphocytes have revolutionized the management of multiple human malignancies. However, recent research highlights the crucial role of B cells and the antibodies they produce in antagonizing malignant progression, offering new avenues for immunotherapy. Our group has demonstrated that dimeric Immunoglobulin A can penetrate tumor cells, neutralize oncogenic drivers in endosomes, and expel them from the cytosol. This mechanistic insight suggests that engineered antibodies targeting this pathway may effectively reach previously inaccessible targets. Investigating antibody production within intratumoral germinal centers and understanding the impact of different immunoglobulins on malignant progression could furnish new tools for the therapeutic arsenal, including the development of tumor-penetrating antibodies. This review aims to elucidate the nature of humoral adaptive immune responses in human cancer and explore how they could herald a new era of immunotherapeutic modalities. By expanding the scope of antitumor immunotherapies, these approaches have the potential to benefit a broader range of cancer patients, particularly through the utilization of tumor cell–penetrating antibodies.