bluuebunny/crossref_metadata_2025 huggingface dataset:
Abdominoplasty With Umbilical Hernia Repair: A Long-term Comparative Analysis of Clinical Outcomes
Authors: Messa Charles A , Davis Harrison D , Habarth-Morales Theodore E , Amro Chris , Broach Robyn B , Fischer John P
Published: November 2024

Background

The risks and benefits of performing small fat-containing ventral or umbilical hernia repair (HR) during cosmetic abdominoplasty remains a reconstructive and aesthetic challenge for plastic surgeons.

Objectives

In this study, we aimed to compare clinical outcomes in patients undergoing abdominoplasty with concurrent HR and abdominoplasty alone.

Methods

Retrospective review of patients undergoing abdominoplasty with and without concurrent HR from January 2015 to June 2022 was performed. Patients were stratified by concurrent HR. All hernia patients underwent primary fascial repair, without mesh. Demographics, surgical site occurrences (SSO), and cosmetic complications, including delayed healing and necrosis, were assessed. Multivariate analysis was performed to compare association of umbilical hernia repair with clinical outcomes.

Results

One hundred and six patients underwent abdominoplasty, and 68 (64%) had concurrent HR. No significant difference in demographics was identified between groups, including mean BMI (HR = 27.2 kg/m2 and no HR = 26.3 kg/m2, P = .73), and number of previous open hernia repairs (P = .09). After a mean follow-up of 1.5 years, hernia recurrence rate was 1.4% (n = 1), with a time to hernia recurrence of 12.2 months. After controlling for confounders, there was no difference in risk of SSO (OR 1.02 [0.31-3.36] P = .978), cosmetic complications (OR 0.80 [0.14-4.57] P = .805), procedure length (−21.5 minutes [−46.92-22.93] P = .501), readmission (2.8% vs 0%, P = .336), or reoperation (8.8% vs 10%, P = .766) between groups.

Conclusions

Abdominoplasty with concurrent HR can be performed safely and effectively, with no increase in adverse outcomes or cosmetic complications. The benefit of performing mesh-free HR with abdominoplasty can achieve an enhanced aesthetic outcome and reduce long-term abdominal wall morbidity.

Level of Evidence: 3 (Therapeutic)
Insights Into Minimally Invasive Aesthetic Procedure-Defining Demographic Factors and Impact of the Treatment on Self-Perception: A Propensity-Matched Cross-Sectional Study
Authors: Ozturk Mahmut , Oliveira Filipa Almeida , Teixeira Marta Ribeiro , Wellenbrock Sascha , Tav Baksan , Kueckelhaus Maximillian , Wiebringhaus Philipp , Hirsch Tobias , Aitzetmüller-Klietz Marie-Luise , Aitzetmüller-Klietz Matthias
Published: November 2024

Background

The lion's share of the research on facial aesthetic procedures focuses on visual results and patient satisfaction.

Objectives

To characterize treated and untreated potential patients and the identification of determinants that influence the decision making as well as the impact of such treatments on patients’ self-perception.

Methods

A cross-sectional, propensity-score-matched study on minimally invasive aesthetic procedures was performed through a survey comprising elements regarding demographics, conduct toward minimally invasive facial plastic interventions, as well as psychological well-being and social self-esteem domains of the validated Face-Q module.

Results

Complete data were collected from 598 participants. Among those, 88% (n = 529) were females and 12% (n = 69) were males. Forty-six percent (n = 277) of the participants were below the age of 30, and 39% (n = 233) were between 30 and 45 years of age. Of the 598 participants, 22% (n = 134) of the participants had undergone a minimally invasive aesthetic procedure of botulinum toxin and/or hyaluronic acid injection, and 78% (n = 464) of the participants had never received any aesthetic treatment. Female gender, 30 to 45 years of age, self-employment, and an income over 75,000€ were significant predictors of undergoing minimally invasive aesthetic procedures. Among treated participants, the overall FACE-Q score as well as the scores for the social esteem and the psychological well-being domains improved significantly with the aesthetic treatment.

Conclusions

This study highlights the major role of healthcare providers in better informing patients and the positive impact of facial aesthetic treatments on patients’ appearance as well as on psychological well-being and self-esteem.

Level of Evidence: 5 (Risk)
DeepMEns: an ensemble model for predicting sgRNA on-target activity based on multiple features
Authors: Ding Shumei , Zheng Jia , Jia Cangzhi
Published: November 2024

The CRISPR/Cas9 system developed from Streptococcus pyogenes (SpCas9) has high potential in gene editing. However, its successful application is hindered by the considerable variability in target efficiencies across different single guide RNAs (sgRNAs). Although several deep learning models have been created to predict sgRNA on-target activity, the intrinsic mechanisms of these models are difficult to explain, and there is still scope for improvement in prediction performance. To overcome these issues, we propose an ensemble interpretable model termed DeepMEns based on deep learning to predict sgRNA on-target activity. By using five different training and validation datasets, we constructed five sub-regressors, each comprising three parts. The first part uses one-hot encoding, wherein 0–1 representation of the secondary structure is used as the input to the convolutional neural network (CNN) with Transformer encoder. The second part uses the DNA shape feature matrix as the input to the CNN with Transformer encoder. The third part uses positional encoding feature matrices as the proposed input into a long short-term memory network with an attention mechanism. These three parts are concatenated through the flattened layer, and the final prediction result is the average of the five sub-regressors. Extensive benchmarking experiments indicated that DeepMEns achieved the highest Spearman correlation coefficient for 6 of 10 independent test datasets as compared to previous predictors, this finding confirmed that DeepMEns can accomplish state-of-the-art performance. Moreover, the ablation analysis also indicated that the ensemble strategy may improve the performance of the prediction model.
ToxGIN: an In silico prediction model for peptide toxicity via graph isomorphism networks integrating peptide sequence and structure information
Authors: Yu Qiule , Zhang Zhixing , Liu Guixia , Li Weihua , Tang Yun
Published: November 2024

Peptide drugs have demonstrated enormous potential in treating a variety of diseases, yet toxicity prediction remains a significant challenge in drug development. Existing models for prediction of peptide toxicity largely rely on sequence information and often neglect the three-dimensional (3D) structures of peptides. This study introduced a novel model for short peptide toxicity prediction, named ToxGIN. The model utilizes Graph Isomorphism Network (GIN), integrating the underlying amino acid sequence composition and the 3D structures of peptides. ToxGIN comprises three primary modules: (i) Sequence processing module, converting peptide 3D structures and sequences into information of nodes and edges; (ii) Feature extraction module, utilizing GIN to learn discriminative features from nodes and edges; (iii) Classification module, employing a fully connected classifier for toxicity prediction. ToxGIN performed well on the independent test set with F1 score = 0.83, AUROC = 0.91, and Matthews correlation coefficient = 0.68, better than existing models for prediction of peptide toxicity. These results validated the effectiveness of integrating 3D structural information with sequence data using GIN for peptide toxicity prediction. The proposed ToxGIN and data can be freely accessible at https://github.com/cihebiyql/ToxGIN.
Adversarial regularized autoencoder graph neural network for microbe-disease associations prediction
Authors: He Limuxuan , Zou Quan , Dai Qi , Cheng Shuang , Wang Yansu
Published: November 2024

Background

Microorganisms inhabit various regions of the human body and significantly contribute to numerous diseases. Predicting the associations between microbes and diseases is crucial for understanding pathogenic mechanisms and informing prevention and treatment strategies. Biological experiments to determine these associations are time-consuming and costly. Therefore, integrating deep learning with biological networks can efficiently identify potential microbe-disease associations on a large scale.

Methods

We propose an adversarial regularized autoencoder graph neural network algorithm, named Stacked Adversarial Regularization for Microbe-Disease Associations Prediction (SARMDA), for predicting associations between microbes and diseases. First, we integrate topological structural similarity and functional similarity metrics of microbes and diseases to construct a heterogeneous network. Then, utilizing an autoencoder based on GraphSAGE, we learn both the topological and attribute representations of nodes within the constructed network. Finally, we introduce an adversarial regularized autoencoder graph neural network embedding model to address the inherent limitations of traditional GraphSAGE autoencoders in capturing global information.

Results

Under the five-fold cross-validation on microbe-disease pairs, SARMDA was compared with eight advanced methods using the Human Microbe-Disease Association Database (HMDAD) and Disbiome databases. The best area under the ROC curve (AUC) achieved by SARMDA on HMDAD was 0.9891$\pm$0.0057, and the best area under the precision-recall curve (AUPR) was 0.9902$\pm$0.0128. On the Disbiome dataset, the AUC was 0.9328$\pm$0.0072, and the best AUPR was 0.9233$\pm$0.0089, outperforming the other eight MDAs prediction methods. Furthermore, the effectiveness of our model was demonstrated through a detailed analysis of asthma and inflammatory bowel disease cases.
Unveiling novel regulatory mechanisms of miR-5195-3p in pelvic organ prolapse pathogenesis
Authors: Zhang Hao , Wang Xinlu , Dong Meng , Wang Jie , Ren Weidong
Published: November 2024

Pelvic organ prolapse is a condition that significantly affects women’s quality of life. The pathological mechanism of pelvic organ prolapse is not yet fully understood, and its pathogenesis is often caused by multiple factors, including the metabolic imbalance of the extracellular matrix. This study aims to investigate the role of miR-5195-3p, a microRNA, in the pathology of pelvic organ prolapse and its regulatory mechanism. Using various molecular biology techniques such as real-time reverse transcription Polymerase Chain Reaction (PCR), fluorescence in situ hybridization, immunohistochemistry, and Western blot, miR-5195-3p expression was examined in vaginal wall tissues obtained from pelvic organ prolapse patients. Results revealed an up-regulation of miR-5195-3p expression in these tissues, showing a negative correlation with the expression of extracellular matrix–related proteins. Further analysis using bioinformatics tools identified Lipoxygenase (LOX) as a potential target in pelvic organ prolapse. Dual luciferase reporter gene experiments confirmed LOX as a direct target of miR-5195-3p. Interestingly, regulating the expression of LOX also influenced the transforming growth factor β1 signaling pathway and had an impact on extracellular matrix metabolism. This finding suggests that miR-5195-3p controls extracellular matrix metabolism by targeting LOX and modulating the TGF-β1 signaling pathway. In conclusion, this study unveils the involvement of miR-5195-3p in the pathological mechanism of pelvic organ prolapse by regulating extracellular matrix metabolism through the LOX/TGF-β1 axis. These findings reveal new mechanisms in the pathogenesis of pelvic organ prolapse, providing a theoretical foundation and therapeutic targets for further research on pelvic organ prolapse treatment.
Bayesian pathway analysis over brain network mediators for survival data
Authors: Tian Xinyuan , Li Fan , Shen Li , Esserman Denise , Zhao Yize
Published: November 2024

Technological advancements in noninvasive imaging facilitate the construction of whole brain interconnected networks, known as brain connectivity. Existing approaches to analyze brain connectivity frequently disaggregate the entire network into a vector of unique edges or summary measures, leading to a substantial loss of information. Motivated by the need to explore the effect mechanism among genetic exposure, brain connectivity, and time to disease onset with maximum information extraction, we propose a Bayesian approach to model the effect pathway between each of these components while quantifying the mediating role of brain networks. To accommodate the biological architectures of brain connectivity constructed along white matter fiber tracts, we develop a structural model which includes a symmetric matrix-variate accelerated failure time model for disease onset and a symmetric matrix response regression for the network-variate mediator. We further impose within-graph sparsity and between-graph shrinkage to identify informative network configurations and eliminate the interference of noisy components. Simulations are carried out to confirm the advantages of our proposed method over existing alternatives. By applying the proposed method to the landmark Alzheimer’s Disease Neuroimaging Initiative study, we obtain neurobiologically plausible insights that may inform future intervention strategies.
Minimizing preparation time for repeated prolonged deep-inspiration breath holds during breast cancer irradiation using pre-oxygenation with high-flow nasal oxygen and voluntary hyperventilation
Authors: Vakaet Vincent , Van Hulle Hans , De Noyette Renée , Schoepen Max , Deseyne Pieter , Huybrechts Vincent , Van Caelenberg Els , Van Greveling Annick , Monten Chris , De Baerdemaeker Luc , De Neve Wilfried , Coppens Marc , Veldeman Liv
Published: November 2024

Objectives

Deep inspiration breath-holds (DIBHs) reduce heart and lung toxicity during breast cancer radiotherapy. Consecutive DIBHs are stressful, time-consuming, and leads to position changes. To facilitate the introduction of pre-oxygenation using high-flow nasal oxygen (HFNO) and hyperventilation to prolong DIBHs (L-DIBHs), we examined the effect of hyperventilation time on the duration of L-DIBHs. Additionally, to minimize total treatment time, the feasibility of several successive L-DIBHs was examined.

Methods

Our previous protocol imposed 3 min of hyperventilation at 16 breaths per minute with pre-oxygenation using HFNO, in prone position. In the first phase, the effect of hyperventilation time on the length of the L-DIBH was investigated. The aim of the second phase was to investigate the feasibility of shorter preparation times before the second and third L-DIBH in the case of 3 consecutive L-DIBHs of at least 2 minutes.

Results

There is a positive but weak correlation between preparation time and L-DIBH duration. With either 3 minutes 30 seconds or 6 minutes 20 seconds (depending on fitness) of voluntary hyperventilation duration, 93% of subjects could hold 3 consecutive L-DIBHs for over 2 minutes. The median duration of the third and last L-DIBH was 3 minutes 17 seconds (SD 1 min 4 seconds).

Conclusion

A weak relationship exists between the hyperventilation time and L-DIBH duration. Repeating L-DIBHs with shorter preparations is achievable, resulting in a shorter total treatment time required.

Advances in knowledge

It is possible to perform repeated L-DIBHs for breast cancer irradiation using HFNO and hyperventilation.
Shared orbitofrontal dynamics to a drug-themed movie track craving and recovery in heroin addiction
Authors: Kronberg Greg , Ceceli Ahmet O , Huang Yuefeng , Gaudreault Pierre-Olivier , King Sarah G , McClain Natalie , Alia-Klein Nelly , Goldstein Rita Z
Published: November 2024

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other stimuli share a continuous narrative context, functional MRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes.

Thirty inpatient iHUD (24 male) and 25 healthy controls (16 male) watched a drug-themed movie at baseline and at follow-up after 15 weeks.

Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks during ongoing inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD.
Adsorption behavior of zirconium metal–organic frameworks in multicomponent metal-ion solutions
Authors: Rani Reetu , Ueda Takahiro , Saeki Kentaro , Toda Kei , Ohira Shin-Ichi
Published: November 2024

In this study, the adsorptive behavior of zirconium metal–organic frameworks (Zr-MOFs) was investigated for the adsorption of alkali and alkaline earth metal ions from multi-element aqueous solutions. Zr-MOFs exhibit high water stability, notable surface area, and a significant pore volume, all of which contribute to their enhanced adsorption capacity. Three Zr-MOFs, namely bare UiO-66, amine-functionalized NH2-UiO-66, and carboxyl-functionalized UiO-66-(COOH)2, were tested for the adsorption of alkali and alkaline earth metal ions. Among the 3 MOFs that were tested, only the carboxyl group-functionalized Zr-MOF showed significant adsorption capacity toward divalent metal ions. Further, a thorough investigation was conducted to understand how the pH, initial concentration of the solution, and Zr-MOF dosage impact the adsorption properties of UiO-66-(COOH)2. At the natural pH (6.5) of the solution, UiO-66-(COOH)2 exhibited a superior adsorption capacity toward Sr2+ (15.3 mg g−1) and Ca2+ (7.9 mg g−1), which was attributable to the stronger electrostatic attraction of these ions relative to monovalent ions. The kinetic study results indicated that the preferred mechanism of adsorption was chemisorption for divalent metal ions. Additionally, the adsorption behavior of UiO-66-(COOH)2 for 24 elements was evaluated and the MOF showed significant adsorption of Sr2+ and Ca2+ alongside other divalent and trivalent metal ions. The experimental findings of the present study suggest that carboxylic-functionalized Zr-MOF holds significant potential toward the preparation of suitable sorbents for the extraction of higher-valence metal ions.
Development of triggerable peroxidase-tagged primers for colorimetric DNA detection applicable to various DNA polymerases
Authors: Munakata Hironao , Sohma Yuri , Utsumi Kaito , Ohno Rinka , Ishida Kotaro , Morita Eiji , Sato Shin-ichi , Hagihara Masaki
Published: November 2024

To meet the demand for more cost-effective rapid and sensitive nucleic acid detection methods to benefit various applications, we introduce a novel technique that uses a modified triggerable guanine quadruplex-based peroxidase (POD)-tagged primer. This technique allows sensitive colorimetric detection by activating an inactive POD tag during polymerase chain reaction amplification, which, importantly, functions independently of the type of DNA polymerase used.
Long-Acting Cabotegravir Plus Rilpivirine in People With Human Immunodeficiency Virus With Adherence Challenges and Viremia: Current Data and Future Directions
Authors: Davis Jennifer M , Rana Aadia , Sax Paul E , Bares Sara H
Published: November 2024

Long-acting injectable cabotegravir plus rilpivirine (LA CAB/RPV) is currently US Food and Drug Administration approved and Human Immunodeficiency Virus (HIV) treatment guideline endorsed as a switch strategy for patients with HIV (PWH) who are virologically suppressed on oral antiretroviral therapy without a history of treatment failure. Recent changes to the International Antiviral Society–USA and US Department of Health and Human Services’ Panel on Antiretroviral Guidelines recommend the consideration of LA CAB/RPV in select PWH with viremia who are unable to achieve suppression with oral antiretroviral therapy due to suboptimal medication adherence. In this article, we review the existing data on this off-label use of LA CAB/RPV, discuss the motivations and specific caveats implicit in the guideline change, and propose next steps in exploring this novel treatment in a vulnerable patient population.
Drug use and acute kidney injury: a Drug-Wide Association Study (DWAS) in Denmark and Sweden
Authors: Bosi Alessandro , Lund Lars Christian , Mahalingasivam Viyaasan , Mazhar Faizan , Christiansen Christian Fynbo , Sjölander Arvid , Pottegård Anton , Carrero Juan Jesus
Published: November 2024

Background

Knowledge of which medications may lead to acute kidney injury (AKI) is limited, relying mostly on spontaneous reporting in pharmacovigilance systems. We here conducted an exploratory drug-wide association study (DWAS) to screen for associations between dispensed drugs and AKI risk.

Methods

Using two large Danish and Swedish data linkages, we identified AKI hospitalizations occurring between April 1997 and December 2021 in Denmark and between March 2007 and December 2021 in Sweden. We used a case-time control design comparing drug dispensing in the 3 months prior to the AKI with earlier periods for the same patient. Odds ratios (ORs) for the association between each drug and AKI were estimated using conditional logistic regression and adjusting for the presence of comorbidities. We sought replication of signals in both health systems and explored the plausibility of findings through pharmacovigilance system analysis in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, appearance in the RESCUE list of medications that report AKI as a side effect, PubMed evidence review and causality assessment through direct acyclic graphs.

Results

We included 20 622 adults in Denmark and 13 852 in Sweden hospitalized for AKI. In total, 16 unique medications were identified in both cohorts as associated to increased AKI occurrence. Of these, 10 medications had higher reporting ORs in the FAERS database, 9 were listed by RESCUE, and 7 appearing in PubMed. This analysis identified some medications with known AKI risks (i.e. likely true positives such as furosemide, penicillin, spironolactone and omeprazole), medications that may have initiated in response to conditions that lead to AKI (i.e. false positives like metoclopramide provided to treat nausea/vomiting) and other candidates (e.g. opioids) that warrant further evaluation in subsequent studies.

Conclusions

This hypothesis-generating study identifies medications with potential involvement in AKI that require confirmation and validation.
Long-term outcomes after stress echocardiography in real-world practice: a 5-year follow-up of the UK EVAREST study
Authors: Woodward William , Johnson Casey L , Krasner Samuel , O’Driscoll Jamie , McCourt Annabelle , Dockerill Cameron , Balkhausen Katrin , Chandrasekaran Badrinathan , Firoozan Soroosh , Kardos Attila , Sabharwal Nikant , Sarwar Rizwan , Senior Roxy , Sharma Rajan , Wong Kenneth , Augustine Daniel X , Leeson Paul
Published: November 2024

Aims

Stress echocardiography is widely used to assess patients with chest pain. The clinical value of a positive or negative test result to inform on likely longer-term outcomes when applied in real-world practice across a healthcare system has not been previously reported.

Methods and results

Five thousand five hundred and three patients recruited across 32 UK NHS hospitals between 2018 and 2022, participating in the EVAREST/BSE-NSTEP prospective cohort study, with data on medical outcomes up to 2023 available from NHS England were included in the analysis. Stress echocardiography results were related to outcomes, including death, procedures, hospital admissions, and relevant cardiovascular diagnoses, based on Kaplan–Meier analysis and Cox proportional hazard ratios (HRs). Median follow-up was 829 days (interquartile range 224–1434). A positive stress echocardiogram was associated with a greater risk of myocardial infarction [HR 2.71, 95% confidence interval (CI) 1.73–4.24, P < 0.001] and a composite endpoint of cardiac-related mortality and myocardial infarction (HR 2.03, 95% CI 1.41–2.93, P < 0.001). Hazard ratios increased with ischaemic burden. A negative stress echocardiogram identified an event-free ‘warranty period’ of at least 5 years in patients with no prior history of coronary artery disease and 4 years for those with disease.

Conclusion

In real-world practice, the degree of myocardial ischaemia recorded by clinicians at stress echocardiography correctly categorizes risk of future events over the next 5 years. Reporting a stress echocardiogram as negative correctly identifies patients with no greater than a background risk of cardiovascular events over a similar time period.
Multicentre retrospective analysis of physician-modified fenestrated/inner-branched endovascular repair for complex aortic aneurysms
Authors: Shibata Tsuyoshi , Iba Yutaka , Yasuhara Kiyomitsu , Kuwada Noriaki , Katada Yoshiaki , Hashiguchi Hitoki , Uzuka Takeshi , Hosaka Itaru , Nakajima Tomohiro , Kawaharada Nobuyoshi
Published: November 2024

OBJECTIVES

In this multicentre retrospective observational study, we present the early outcomes of physician-modified fenestrated/inner-branched endovascular repair for pararenal and thoracoabdominal aortic aneurysms in patients at high risk for open surgical repair.

METHODS

We comprehensively reviewed the clinical data and outcomes of consecutive patients treated with physician-modified fenestrated/inner-branched endovascular repair for pararenal or thoracoabdominal aortic aneurysms at 6 centres between December 2020 and December 2021. Primary end-points included technical success, in-hospital mortality rates, major adverse events.

RESULTS

Seven and 31 patients (median age, 80.5 years) had pararenal and thoracoabdominal aortic aneurysms, respectively, involving 93 renal-mesenteric arteries incorporated through 10 fenestrations or 83 inner branches. Seven patients (18.4%) were treated non-elective conditions. The technical success rate was 89.5%. The median operative time was 334.5 min. Ten patients (26.3%) experienced major adverse events, including in-hospital mortality in 6 patients (15.8%), acute kidney injury in 3 patients (7.9%), respiratory failure in 3 patients (7.9%), bowel ischaemia in 1 patient (2.6%), stroke in 1 patient (2.6%) and paraplegia in 1 patient (2.6%). Among elective cases, in-hospital deaths occurred in 3 patients (9.7%), while in non-elective cases, the mortality rate was higher, with 3 patients (42.9%) succumbing. The median follow-up duration was 14 months.

CONCLUSIONS

Physician-modified fenestrated/inner-branched endovascular repair is a viable treatment for pararenal or thoracoabdominal aortic aneurysms in patients at high risk for open surgical repair. It provides customization without location constraints or production delays, but further validation is needed to ensure long-term reliability.
Variants in LPA are associated with familial hypercholesterolaemia: whole genome sequencing analysis in the 100 000 Genomes Project
Authors: Bird Martin , Rimbert Antoine , Pittman Alan Michael , Humphries Steve Eric , Futema Marta
Published: November 2024

Aims

Familial hypercholesterolaemia (FH) is an inherited disease of high LDL cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE, and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS), we examined genetic determinants of FH.

Methods and results

Whole genome sequencing data generated by the 100 000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon–Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study between 443 FH variant-negative unrelated FH cases and 77 275 control participants of the 100KGP was run using high-coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. An FH-causing variant was found in 17.4% of FH cases. Genome-wide association study identified the LPA gene locus being significantly associated (P < 1 × 10−8). Familial hypercholesterolaemia variant-negative participants had higher LDL and Lp(a) PRSs in comparison with the controls (P < 1.0 × 10−16 and P < 4.09 × 10−6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (P < 4.03 × 10−4 and P < 3.01 × 10−3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs.

Conclusion

This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogeneous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.
The impact of reminders on representativeness and survey estimates among web-mode invited in the Danish National Health Survey
Authors: Jezek Andrea Huber , Ekholm Ola , Thygesen Lau Caspar , Christensen Anne Illemann
Published: November 2024

Declining response proportions in health surveys may lead to increased non-response bias. Multiple reminders are often used to increase response proportions, and, thus, we aimed to determine if the use of reminders decreased the magnitude of non-response bias among web-mode invited in the Danish National Health Survey 2023. In the Danish National Health Survey 2023, a national random sample of 23 467 individuals (aged ≥16 years) with residence in Denmark were invited by a secure electronic mail service. Invited individuals received up to five inquiries: (i) web invitation, (ii) web reminder, (iii) paper invitation including a questionnaire and a prepaid return envelope, (iv) paper reminder, and (v) paper reminder including a questionnaire and a prepaid return envelope. The cumulative response proportions after first-, second-, third-, fourth-, and fifth inquiries were 19.1%, 28.9%, 37.2%, 39.3%, and 42.0%, respectively. In general, third, fourth, and fifth mailing respondents were more often men, at younger ages, with non-Western backgrounds, and unmarried compared to first mailing respondents. Furthermore, third, fourth, and fifth mailing respondents were in general found to have less favorable health behavior than first mailing respondents, but also a lower prevalence of fair or poor self-rated health and long-standing health problems. In conlusion, reminders are an effective way to increase the response proportion. Furthermore, the use of reminders was found to decrease the magnitude of non-response bias; however, the decrease was small due to the low number of individuals responding after fourth and fifth inquiries.
Exploring susceptibility and therapeutic targets for kidney stones through proteome-wide Mendelian randomization
Authors: Jiang Qinhong , Su Xiaozhe , Liao Wenbiao , He Ziqi , Wang Yunhan , Jiang Rong , Dong Caitao , Yang Sixing
Published: November 2024

Given the high recurrence rate of kidney stones, surgical lithotripsy and stone removal are not the ultimate treatments for kidney stones. There’s an urgent need to explore the genetic mechanisms behind the susceptibility to kidney stones and to identify potential targets for prevention, to reduce the renal damage caused by recurrent stone formation. In this study, we screened 4548 circulating proteins using proteome-wide Mendelian Randomization (MR) to find proteins with a causal relationship to kidney stone risk. Additionally, proteome-wide association study (PWAS) and colocalization analysis were used to validate and prioritize candidate proteins. Moreover, downstream analyses including single-cell analysis, enrichment analysis, protein–protein interaction (PPI), and druggability analysis were conducted on the proteins causally related to kidney stones, to further explore the genetic mechanisms of susceptibility and the potential of proteins as drug targets. Ultimately, 22 target proteins associated with the risk of kidney stones were identified. Six plasma proteins (COLGALT1, CLMP, LECT1, ITIH1, CDHR3, CPLX2) were negatively correlated with kidney stone risk, while the genetic overexpression of 16 target proteins (GJA1, STOM, IRF9, F9, TMPRSS11D, ADH1B, SPINK13, CRYBB2, TNS2, DOCK9, OXSM, MST1, IL2, LMAN2, ITIH3, KLRF1) increased the risk of kidney stones. Based on the PWAS and colocalization analysis results, the 22 target proteins were classified into 3 tiers: IL2, CPLX2, and LMAN2 as tier 1 proteins with the most compelling evidence, MST1, ITIH1, and ITIH3 as tier 2 proteins, and the rest as tier 3 proteins. Enrichment analysis and PPI showed that target proteins mainly affect the occurrence of kidney stones through leukocyte activation and cell junction assembly. Druggability analysis suggested that IL2, MST1, and ITIH1 have potential as drug targets, and potential drugs were evaluated through molecular docking. In summary, this study employed multiple analytical methods to screen plasma proteins related to susceptibility to kidney stones, providing new insights into the genetic mechanisms of kidney stones and potential targets for treatment and prevention.
Two novel alleles of the MYB transcription factor BjA06.GL1 and BjB02.GL1 control leaf trichomes and enhance resistance to aphids in Brassica juncea
Authors: Heng Shuangping , Li Xiaolin , Li Man , Jiang Lulu , Li Meng , Zeng Wei , Mao Guangzhi , Xing Feng , Wan Zhengjie , Wen Jing , Shen Jinxiong , Fu Tingdong
Published: November 2024

Leaf trichome formation is a very important agronomic trait as it confers resistance to biotic and abiotic stresses, but the causal genes involved in this process in Brassica juncea remain largely unexplored. In this study, we first characterized the haplotypes of BjB02.GL1 among different inbred lines with leaf trichomes or glabrous leaves. A comparative analysis of the number and density of leaf trichomes between the two mustard inbred lines was then performed. BSA analysis of leaves with trichomes and glabrous pools from the F2 segregating population mapped the candidate genes on Chr.A06 and Chr.B02. Two candidate genes, BjA06.GL1 and BjB02.GL1, were subsequently cloned. After sequence alignment of the BjGL1 genes, both single-nucleotide polymorphisms (SNPs) and indel were identified in the BjA06.GL1 and BjB02.GL1 genes. And quantitative real-time polymerase chain reaction (qRT-PCR) analysis further confirmed that both the BjA06.GL1 and BjB02.GL1 genes were more highly expressed in leaves with trichomes than in glabrous leaves. As the leaf size increased, the leaf trichome density decreased. Gene editing of both BjA06.GL1 and BjB02.GL1 changed the leaf trichome to a glabrous leaf phenotype in mustard. In addition, plants with leaf trichomes presented greater resistance to aphids. Taken together, our results revealed that both BjA06.GL1 and BjB02.GL1 positively regulate leaf trichome formation and help increase aphid resistance in mustard. This study provides valuable resources and helps to elucidate the molecular mechanism of leaf trichome formation in B. juncea.
Optimization planning of distributed photovoltaic integration in distribution networks using combinatorial search algorithm
Authors: Wang Yong , Hu Yahan , Wang Zhe , Liu Mengchen , Li Tao
Published: November 2024

The current scenario sees the potential emergence of challenges such as power imbalances and energy dissipation upon the incorporation of distributed photovoltaic (PV) systems into distribution networks, impacting power quality and economic viability. To address these identified risks, this study introduces an innovative combinatorial search algorithm designed to autonomously derive optimal planning strategies for distribution networks. The process begins by establishing distinct planning models for distributed PVs and distribution network systems, followed by the application of the search algorithm to align these models and generate relevant Pareto datasets and multi-objective positioning criteria. By strategically combining and optimizing existing solutions to bolster the distribution network’s load-carrying capacity, the optimal strategy is progressively refined under the guidance of multiple objective constraints. Subsequent multiphase simulation experiments validate the efficacy of our approach in minimizing energy losses when compared to analogous methodologies. The distribution network integration planning strategies derived through our method showcase outstanding performance in reducing energy losses, conducting steady-state voltage safety assessments, optimizing installation capacity utilization rates, and enhancing economic returns, thus emphasizing the substantial potential of our approach in facilitating the seamless integration of distributed PVs into distribution networks.
Optimizing mountain railway alignments considering geo-hazard impacts based on a knowledge graph
Authors: Hu Ting , Song Taoran , Schonfeld Paul , Pu Hao , Hu Jianping
Published: November 2024

Alignment design is pivotal in determining the macroscopic hazard to a railway, especially in complex mountainous regions with dense geologic hazards. In this work, to apply the experience of handling geo-hazards that accumulated in manual alignment design, the related alignment design principles are summarized via an event tree. Based on this, a method is proposed to construct a knowledge graph (called GeRAD-KG) for mountain railway alignment design considering geo-hazard impacts of debris flows, landslides, and rockfalls, with which to structurally represent corresponding design principles. Then, a construction cost-geologic hazard bi-objective optimization model incorporating the knowledge-driven hazard assessment is constructed. To solve the model, a GeRAD-KG-guided distance transform algorithm integrating a multicriteria tournament decision is tailored. Finally, a real-world case indicates that the alternative generated by the proposed method can reduce the construction cost and geological hazard compared to the single-objective optimization alternative, which verifies the effectiveness of the proposed method for assisting actual railway design in a mountainous region with dense geo-hazards.
Comparison of six natural language processing approaches to assessing firearm access in Veterans Health Administration electronic health records
Authors: Trujeque Joshua , Dudley R Adams , Mesfin Nathan , Ingraham Nicholas E , Ortiz Isai , Bangerter Ann , Chakraborty Anjan , Schutte Dalton , Yeung Jeremy , Liu Ying , Woodward-Abel Alicia , Bromley Emma , Zhang Rui , Brenner Lisa A , Simonetti Joseph A
Published: November 2024

Objective

Access to firearms is associated with increased suicide risk. Our aim was to develop a natural language processing approach to characterizing firearm access in clinical records.

Materials and Methods

We used clinical notes from 36 685 Veterans Health Administration (VHA) patients between April 10, 2023 and April 10, 2024. We expanded preexisting firearm term sets using subject matter experts and generated 250-character snippets around each firearm term appearing in notes. Annotators labeled 3000 snippets into three classes. Using these annotated snippets, we compared four nonneural machine learning models (random forest, bagging, gradient boosting, logistic regression with ridge penalization) and two versions of Bidirectional Encoder Representations from Transformers, or BERT (specifically, BioBERT and Bio-ClinicalBERT) for classifying firearm access as “definite access”, “definitely no access”, or “other”.

Results

Firearm terms were identified in 36 685 patient records (41.3%), 33.7% of snippets were categorized as definite access, 9.0% as definitely no access, and 57.2% as “other”. Among models classifying firearm access, five of six had acceptable performance, with BioBERT and Bio-ClinicalBERT performing best, with F1s of 0.876 (95% confidence interval, 0.874-0.879) and 0.896 (95% confidence interval, 0.894-0.899), respectively.

Discussion and Conclusion

Firearm-related terminology is common in the clinical records of VHA patients. The ability to use text to identify and characterize patients’ firearm access could enhance suicide prevention efforts, and five of our six models could be used to identify patients for clinical interventions.
Immunomodulatory potential of dietary soybean-derived saponins
Authors: White Cameron S , Dilger Ryan N
Published: November 2024

Soybeans are widely recognized as a valuable crop, often included as a high-quality protein source in production animal diets. In addition to contributing to the macronutrient composition of the diet, soybeans also contain many minor bioactive components which can influence the health and growth of animals. This review examined the immunomodulatory potential of soy saponins and their specific effects on the inflammatory response, oxidative stress, and intestinal barrier function. Saponins are amphiphilic molecules, a property imparted by their polar carbohydrate chains that attach to a nonpolar aglycone backbone. This structure also complicates their isolation, thus most research investigating soy saponins has been performed in models that only require small amounts of isolated material. Many experiments conducted in vitro or in rodents reported that saponins can reduce damage, particularly in conditions where a challenge was first introduced to stimulate inflammation or oxidative stress. It appears that saponins can exert their anti-inflammatory effects through modulation of the NF-κB pathway, reducing its activation and the release of pro-inflammatory molecules later in the cascade. Furthermore, soy saponins can influence levels of important anti-oxidative enzymes and reduce the generation of reactive oxygen species, thus attenuating levels of oxidative stress in the model. As these results were obtained from experiments done in vitro or in rodents, they neglect to provide a good representation of how soy saponins may affect some of the greatest consumers of soy-based products, with those being production animals. The work that has been done seems to indicate that soy saponins may exert similar anti-inflammatory and anti-oxidative effects in production animals as those observed in other research models along with immunostimulatory activity that may help boost host defense systems. Overall, there is a dearth of research regarding the effects of soy saponins on species that commonly consume soy products, which begins by developing more effective methods of saponin extraction.
Interleukin-10 inhibits important components of trained immunity in human monocytes
Authors: Röring Rutger J , Scognamiglio Flavia , de Jong Lisanne C , Groh Laszlo A , Matzaraki Vasiliki , Koeken Valerie A C M , Joosten Leo A B , Ziogas Athanasios , Netea Mihai G
Published: November 2024

Trained immunity induces antigen-agnostic enhancement of host defense and protection against secondary infections, but inappropriate activation can contribute to the pathophysiology of inflammatory diseases. Tight regulation of trained immunity is therefore needed to avoid pathology, but little is known about the endogenous processes that modulate it. Here, we investigated the potential of interleukin (IL)-10, a prototypical anti-inflammatory cytokine, to inhibit trained immunity. IL-10 induced tolerance and inhibited trained immunity in primary human monocytes at both functional and transcriptional levels. Inhibition of STAT3, a signaling route that mediates IL-10 signals, induced trained immunity. IL-10 downregulated glycolytic and oxidative metabolism in monocytes but did not impact the metabolic effects of β-glucan–induced trained immunity. Furthermore, IL-10 prevented increased reactive oxygen species production in Bacillus Calmette–Guérin (BCG)–induced training but did not influence phagocytosis upregulation. In a cohort study of healthy volunteers vaccinated with BCG, genetic variants that influenced IL-10 or its receptor modulated BCG-induced trained immunity. Furthermore, circulating IL-10 concentrations were negatively correlated with induction of trained immunity after BCG vaccination in a sex-specific manner. In conclusion, IL-10 inhibited several, albeit not all, immunological functions amplified after induction of trained immunity. Follow-up studies should explore the precise molecular mechanism that mediates the effects of IL-10 on trained immunity. Addressing these knowledge gaps is an important step toward optimizing IL-10's potential as a therapeutic target in diseases characterized by inappropriate induction of trained immunity.
Species distribution modeling of North American beavers from the late Pliocene into the future
Authors: Lubbers Kelly E , Samuels Joshua X , Joyner T Andrew
Published: November 2024

Beavers have occurred in North America since at least 7 Ma, but relatively little is known about their distribution across the continent. We modeled distributions of beavers in the late Pliocene (3.3 Ma), Pleistocene (130 ka and 21 ka), and recent Holocene (1970 to 2000) to understand their dispersal across North America, predict future distributions and predict their possible response to future climate and habitat changes. Occurrence data for Castor canadensis were derived from the Global Biodiversity Information Facility. Those data were used with both modern (1970 to 2000) and modeled future (EC-Earth-Veg 2081 to 2100) bioclimatic variables from WorldClim as well as past (Pliocene Marine Isotope Stage M2, Pleistocene Last Interglacial, and Pleistocene Last Glacial Maximum) bioclimatic variables from PaleoClim to model beaver distributions through time. Fossil locality points for Castor extracted from the New and Old Worlds Database of Fossil Mammals (NOW), NEOTOMA Paleoecology Database, and Paleobiology Database were overlain on past projection models to use as validation points. Models were run using MaxEnt with post-processing in ArcGIS. Accuracy for the 5 models ranged between 59.6% and 60.2%. Results for the present model (1970 to 2000) showed habitat suitability in areas beavers inhabit today. During the Pliocene MIS M2 cooling event (3.3 Ma) and Pleistocene Last Glacial Maximum (21 ka), habitat suitability shifted further south into Mexico and peninsular Florida and away from more periglacial northern regions. During the Last Interglacial period (130 ka) and modeled future (2081 to 2100) EC-Earth-Veg 2081 to 2100, habitat suitability was higher in coastal and central regions in North America and lower in southern regions compared to their present distribution. Distributions were most affected by precipitation seasonality, isothermality, and mean annual temperature. High variability in seasonal precipitation and temperatures is likely to influence surface water availability, vegetation type, and riparian vegetation composition, which consequently may reduce available food resources and habitat for beavers. Observed shifts during warmer periods may indicate areas in the late Miocene that facilitated dispersal into North America. Future models using other predicted climatic scenarios and shared socioeconomic pathways may provide better resolution of potential future shifts in beaver distribution with best- and worst-case climate scenarios, thereby permitting at-risk areas to be prioritized for conservation in the face of climate change.