bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender Differences in Plastic Surgery Trainee Confidence: A Pilot Analysis During Cleft Lip Simulation
Authors: Stanek Krystof , Phillips Nicole , Staffa Steven J. , Saldanha Francesca Y. L. , Rogers-Vizena Carolyn R.
Published: December 2023

Background:

Underrepresentation of women in plastic surgery remains a concern. This study investigates gender-related differences in self-confidence and surgical ability among plastic surgery trainees in an effort to work toward gender parity.

Methods:

Residents and fellows were recorded performing up to three cleft lip repairs on a high-fidelity simulator. Demographic information was collected, and two questionnaires were completed to assess self-confidence after each simulation. Videos were rated blindly using the objective structured assessment of technical skills and unilateral cleft lip repair competency assessment tool. Differences between participants were estimated using generalized estimating equations modeling, and correlation between overall self-confidence and performance was examined using Pearson correlation (r).

Results:

Twenty-six participants (six self-identified women and 20 self-identified men) completed 73 simulated procedures. There was no gender-related difference in training level, volume of prior experience, speed with which participants completed each simulated procedure, or objective performance. However, a significant difference was found in overall procedural self-confidence, with women rating their confidence lower (mean = 16.9, SD = 4.3) than men (mean = 19.4, SD = 3.8); P = 0.021. Further analysis revealed that confidence scores correlated more strongly with objective performance for women (r = 0.83) than for men (r = 0.45).

Conclusions:

Women plastic surgery trainees overall reported lower self-confidence than their male counterparts, despite demonstrating at least as much skill. Confidence and skill were more closely related for women, suggesting that mentorship focused on concrete skill building may help close the confidence gap.
Challenges With the Implementation of Machine Perfusion in Clinical Liver Transplantation
Authors: De Goeij Femke H.C. , De Meijer Vincent , Mergental Hynek , Guarrera James V. , Asthana Sonal , Ghinolfi Davide , Boteon Yuri L. , Selzner Nazia , Kalisvaart Marit , Pulitano Carlo , Sonnenday Christopher , Martins Paulo N. , Berlakovich Gabriela , Schlegel Andrea
Published: December 2023

Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide.
Clinical Deployment of Machine Learning Tools in Transplant Medicine: What Does the Future Hold?
Authors: Rabindranath Madhumitha , Naghibzadeh Maryam , Zhao Xun , Holdsworth Sandra , Brudno Michael , Sidhu Aman , Bhat Mamatha
Published: December 2023

Medical applications of machine learning (ML) have shown promise in analyzing patient data to support clinical decision-making and provide patient-specific outcomes. In transplantation, several applications of ML exist which include pretransplant: patient prioritization, donor-recipient matching, organ allocation, and posttransplant outcomes. Numerous studies have shown the development and utility of ML models, which have the potential to augment transplant medicine. Despite increasing efforts to develop robust ML models for clinical use, very few of these tools are deployed in the healthcare setting. Here, we summarize the current applications of ML in transplant and discuss a potential clinical deployment framework using examples in organ transplantation. We identified that creating an interdisciplinary team, curating a reliable dataset, addressing the barriers to implementation, and understanding current clinical evaluation models could help in deploying ML models into the transplant clinic setting.
High Number of Plasma Exchanges Increases the Risk of Bacterial Infection in ABO-incompatible Living Donor Liver Transplantation
Authors: Choi Mun Chae , Min Eun-Ki , Yim Seung Hyuk , Kim Deok-Gie , Lee Jae Geun , Joo Dong Jin , Kim Myoung Soo
Published: December 2023

Background.

Bacterial infections are major complications that cause significant mortality and morbidity in living donor liver transplantation (LDLT). The risk of bacterial infection has not been studied in ABO-incompatible (ABOi) recipients with a desensitization protocol in relation to the number of plasma exchanges (PEs). Therefore, we aimed to analyze the risk of bacterial infection in ABOi LDLT recipients with a high number of PEs compared with recipients with a low number of PEs.

Methods.

A retrospective study was performed with 681 adult LDLT recipients, of whom 171 ABOi LDLT recipients were categorized into the high (n = 52) or low (n = 119) PE groups based on a cutoff value of 6 PE sessions. We compared bacterial infections and postoperative bacteremia within 6 mo after liver transplantation with the ABO-compatible (ABOc) LDLT group (n = 510) as a control group.

Results.

The high PE group showed a bacterial infection rate of 49.9% and a postoperative bacteremia rate of 28.8%, which were significantly higher than those of the low PE group (31.1%, 17.8%) and the ABOc group (26.7%, 18.0%). In multivariate analysis, the high PE group was found to have a 2.4-fold higher risk of bacterial infection (P = 0.008). This group presented a lower 5-y survival rate of 58.6% compared with the other 2 groups (81.5% and 78.5%; P = 0.030 and 0.001).

Conclusions.

A high number of preoperative PEs increases bacterial infection rate and postoperative bacteremia in ABOi LDLT.
Benchmarking Pediatric Trauma Care in Mixed Trauma Centers: Adult Risk-Adjusted Mortality Is Not a Reliable Indicator of Pediatric Outcomes
Authors: Melhado Caroline , Evans Lauren L , Miskovic Amy , Subacius Haris , Nathens Avery B , Stein Deborah M , Burd Randall S , Jensen Aaron R
Published: December 2023

BACKGROUND:

Trauma center benchmarking has become standard practice for assessing quality. The American College of Surgeons adult trauma center verification standards do not specifically require participation in a pediatric-specific benchmarking program. Centers that treat adults and children may therefore rely solely on adult benchmarking metrics as a surrogate for pediatric quality. This study assessed discordance between adult and pediatric mortality within mixed trauma centers to determine the need to independently report pediatric-specific quality metrics.

STUDY DESIGN:

A cohort of trauma centers (n = 493, including 347 adult-only, 44 pediatric-only, and 102 mixed) that participated in the American College of Surgeons TQIP in 2017 to 2018 was analyzed. Center-specific observed-to-expected mortality estimates were calculated using TQIP adult inclusion criteria for 449 centers treating adults (16 to 65 years) and using TQIP pediatric inclusion criteria for 146 centers treating children (0 to 15 years). We then correlated risk-adjusted mortality estimates for pediatric and adult patients within mixed centers and evaluated concordance of their outlier status between adults and children.

RESULTS:

The cohort included 394,075 adults and 97,698 children. Unadjusted mortality was 6.1% in adults and 1.2% in children. Mortality estimates had only moderate correlation (r = 0.41) between adult and pediatric cohorts within individual mixed centers. Mortality outlier status for adult and pediatric cohorts was discordant in 31% (32 of 102) of mixed centers (weighted Kappa statistic 0.06 [−0.11 to 0.22]), with 78% (23 of 32) of discordant centers having higher odds of mortality for children than for adults (6 centers with average adult mortality and high pediatric mortality and 17 centers with low adult mortality and average pediatric mortality, p < 0.01).

CONCLUSIONS:

Adult mortality is not a reliable surrogate for pediatric mortality in mixed trauma centers. Incorporation of pediatric-specific benchmarks should be required for centers that admit children.
A novel tamanavirus (Flaviviridae) of the European common frog (Rana temporaria) from the UK
Authors: Parry Rhys H. , Slonchak Andrii , Campbell Lewis J. , Newton Natalee D. , Debat Humberto J. , Gifford Robert J. , Khromykh Alexander A.
Published: December 2023

Flavivirids are small, enveloped, positive-sense RNA viruses from the family Flaviviridae with genomes of ~9–13 kb. Metatranscriptomic analyses of metazoan organisms have revealed a diversity of flavivirus-like or flavivirid viral sequences in fish and marine invertebrate groups. However, no flavivirus-like virus has been identified in amphibians. To remedy this, we investigated the virome of the European common frog (Rana temporaria) in the UK, utilizing high-throughput sequencing at six catch locations. De novo assembly revealed a coding-complete virus contig of a novel flavivirid ~11.2 kb in length. The virus encodes a single ORF of 3456 aa and 5′ and 3′ untranslated regions (UTRs) of 227 and 666 nt, respectively. We named this virus Rana tamanavirus (RaTV), as BLASTp analysis of the polyprotein showed the closest relationships to Tamana bat virus (TABV) and Cyclopterus lumpus virus from Pteronotus parnellii and Cyclopterus lumpus, respectively. Phylogenetic analysis of the RaTV polyprotein compared to Flavivirus and Flavivirus-like members indicated that RaTV was sufficiently divergent and basal to the vertebrate Tamanavirus clade. In addition to the Mitcham strain, partial but divergent RaTV, sharing 95.64–97.39 % pairwise nucleotide identity, were also obtained from the Poole and Deal samples, indicating that RaTV is widespread in UK frog samples. Bioinformatic analyses of predicted secondary structures in the 3′UTR of RaTV showed the presence of an exoribonuclease-resistant RNA (xrRNA) structure standard in flaviviruses and TABV. To examine this biochemically, we conducted an in vitro Xrn1 digestion assay showing that RaTV probably forms a functional Xrn1-resistant xrRNA.
Do You Know Your Daily Antibiotic Intake through Residues in Your Diet?
Authors: Seo Jegak , Kloprogge Frank , Smith Andrew M. , Karu Kersti , Ciric Lena
Published: December 2023

While the use of a wide range of antibiotics has been reported as extensive in the rearing of agricultural animals, extremely limited information is available on the antibiotic residues in animal products and the adverse impact consistent low-level exposure to antibiotics might have on the human body as well as its microbiome. The aim of this study was to estimate the possible antibiotic concentrations humans are exposed to via their diet using the concentration of antibiotics in animal food products and water, and an online survey on dietary habits. A total of 131 participants completed the dietary habits survey, the majority belonging to the omnivorous diet habit. Distinct dietary trends were observed into omnivorous and unknown groups eating food-producing animal products, with specific food types dominating each meal: pork (e.g. ham) and dairy products (e.g. milk, yoghurt) during breakfast, beef (e.g. burger) and chicken (e.g. chicken breast) products during lunch, and fish (e.g. salmon fillet) during dinner. 34 different animal-based food and drink products were tested for the presence of ten different antibiotics. Low levels of nine of the ten antibiotics were detected across the samples tested with amoxicillin and trimethoprim being the most frequently detected antibiotics from all samples with concentrations ranging from 216.7-6866.9 μg/kg and 55.2-461.7 μg/kg, respectively. Of all products tested, over 35% exceeded the acceptable daily intake antibiotic concentration for amoxicillin, ampicillin, and enrofloxacin.
ERG1A K+Channel Increases Intracellular Calcium Concentration through Modulation of Calsequestrin1 in C2C12Myotubes
Authors: Hockerman Gregory H. , Pratt Evan , Guha Shalini , LaVigne Emily , Whitmore Clayton , Khader Omar , McClure Natalie , Zampieri Sandra , Koran Jennifer , Wang W-H , Pond Amber L.
Published: December 2023

The ERG1A K+channel modulates the protein degradation that contributes to skeletal muscle atrophy by increasing intracellular calcium concentration ([Ca2+]i) and enhancing calpain activity, but the mechanism by which the channel regulates the [Ca2+]i is not known. Here, we have investigated the effect of human ERG1A (HERG) on [Ca2+]i in C2C12myotubes, using Fura-2 calcium assays, immunoblot, RT-qPCR, and electrophysiology. We hypothesized that HERG would modulate L-type calcium channel activity, specifically the Cav1.1 channel known to carry signal from the sarcoplasmic membrane of skeletal muscle to the sarcomeres of the myofibrils. However, we find that HERG has no effect on the amplitude of L-type channel current nor does it affect the mRNA levels nor protein abundance of the Cav1.1 channel. Instead we find that, although the rise in [Ca2+]i (induced by depolarization) is greater in myotubes over-expressing HERG relative to controls, the difference between the KCl-stimulated Ca2+increase in control and HERG over-expressing cells cannot be accounted for by L-type channel mediated Ca2+influx, which suggests that HERG could modulate excitation coupled calcium entry (ECCE). Indeed, the HERG-enhanced increase in [Ca2+]i induced by depolarization is blocked by 2-APB, an inhibitor of ECCE (and SOCE). Further, we show data suggesting that HERG also modulates the activity of ryanodine receptors, a component of ECCE, as well as store operated calcium entry (SOCE). Therefore, we investigated the effect of HERG on calsequestrin1, a calcium buffering/binding protein known to modulate ryanodine receptor 1 and store operated Ca2+entry activities. Indeed, we find that calsequestrin1 mRNA levels are decreased 0.83-fold (p<0.05) and the total protein abundance is lowered 77% (p<0.05) in myotubes over-expressing HERG relative to controls. In summary, the data show that ERG1A overexpression modulates [Ca2+]i in skeletal muscle cells by lowering the abundance of the calcium buffering/binding protein calsequestrin1.
TSpred: a robust prediction framework for TCR-epitope interactions based on an ensemble deep learning approach using paired chain TCR sequence data
Authors: Kim Ha Young , Kim Sungsik , Park Woong-Yang , Kim Dongsup
Published: December 2023

Prediction of T-cell receptor (TCR)-epitope interactions is important for many applications such as cancer immunotherapy. However, due to the scarcity of available data, it is known to be a challenging task particularly for novel epitopes. Here, we propose TSpred, a new ensemble deep learning approach for the pan-specific prediction of TCR binding specificity based on paired chain TCR data. This method combines the predictive power of CNN and the attention mechanism to capture the patterns underlying TCR-epitope interactions. In particular, we design a reciprocal attention mechanism which contributes to higher model generalizability to unseen epitopes. We perform a comprehensive evaluation of our model and observe that TSpred achieves state-of-the-art performances in both seen and unseen epitope specificity prediction tasks. Our model performs consistently well across both of the two widely used negative sampling strategies, while avoiding the potential bias associated with each strategy. Also, compared to other predictors, it is more robust to bias related to peptide imbalance in the dataset. In addition, the reciprocal attention component of our model allows for model interpretability by capturing structurally important binding regions. Results indicate that TSpred is a robust and reliable method for the task of TCR-epitope binding prediction.
Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations
Authors: Xu Weiling , Hong Yun Soo , Hu Bo , Comhair Suzy A. A. , Janocha Allison J. , Zein Joe G. , Chen Ruoying , Meyers Deborah A. , Mauger David T. , Ortega Victor E. , Bleecker Eugene R. , Castro Mario , Denlinger Loren C. , Fahy John V. , Israel Elliot , Levy Bruce D. , Jarjour Nizar N. , Moore Wendy C. , Wenzel Sally E. , Gaston Benjamin , Liu Chunyu , Arking Dan E. , Erzurum Serpil C. ,   the National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP),   TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: December 2023

Rationale

Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation.

Objectives

We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations.

Methods

We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations.

Measures and Main Results

In UK Biobank, asthmatics (n= 29,768) have lower mtDNA-CN compared to non-asthmatics (n= 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014],P= 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753],P= 0.007).

Conclusions

Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
Fluctuations in serum adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis
Authors: Bando Hironori , Yamamoto Masaaki , Urai Shin , Motomura Yuma , Sasaki Yuriko , Ohmachi Yuka , Kobatake Masaki , Tsujimoto Yasutaka , Oi-Yo Yuka , Suzuki Masaki , Yamamoto Naoki , Takahashi Michiko , Fukuoka Hidenori , Iguchi Genzo , Ogawa Wataru
Published: December 2023

Background

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in serum adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormones (thyroxine and triiodothyronine) in ICI-related thyroiditis. Here, we sought to test this hypothesis.

Methods

Patients who used ICI and had a history of measurement of serum ACTH and cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in serum ACTH and cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration [pre], maximum ACTH concentration [peak], and onset of ICI-RH) were analyzed to evaluate hormone fluctuations.

Results

A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in serum ACTH and cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 [29.9–48.3] (pre) to 64.4 [46.5–106.2] pg/mL (peak) (1.72–fold increase,p= 0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in serum ACTH and cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of serum ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of serum ACTH is a unique phenomenon in patients with ICI-RH.

Conclusions

Serum ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations can help predict the onset of ICI-RH.
Cost minimization analysis of treatments for metastatic HER2-positive breast cancer: Fixed-Dose combination of pertuzumab and trastuzumab for subcutaneous injections
Authors: Figallo Miguel , Delgado María F. , Gonzalez Mauricio , Arenas Adrián
Published: December 2023

The main objective of this study is to determine whether the employment of fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (or Phesgo) to treat metastatic HER2-positive breast cancer patients would minimize costs compared to the traditional treatment of separate intravenous doses of pertuzumab and trastuzumab in Peru. To achieve this, we used EsSalud (the social security health insurance) data and assessed it through a mixed strategy, which consisted of a quantitative and a qualitative approach. The first one aimed to calculate the direct (non-drug consumables, drugs, and healthcare professionals) and indirect costs of both treatments to develop a comparison, whilst the second aimed to validate information and internalize the procedure in an EsSalud context.

Overall, we found that the usage of Phesgo would be cost saving in EsSalud’s context. Specifically, we found three main insights. Firstly, the savings produced from switching from the traditional intravenous treatment to the subcutaneous one would allow EsSalud to afford full annual costs of 2 additional treatments, but without increasing their budget. This would cover 7% of the gap of 29 patients who do not have access to full treatment. Secondly, the result of a univariate sensitivity analysis in this work indicates that the price of Phesgo would have to increase by 16% so that both treatments cost the same. Thirdly, to increase the number of patients, the intravenous treatment would have to be totally replace by the Phesgo treatment, since the use of the latter requires less personnel and infrastructure.
Heart size disparity drives sex-specific response to cardiac resynchronization therapy: a post-hoc analysis of the MORE-MPP CRT trial
Authors: Wijesuriya Nadeev , Mehta Vishal , De Vere Felicity , Howell Sandra , Niederer Steven A , Burri Haran , Sperzel Johannes , Calo Leonardo , Thibault Bernard , Lin Wenjiao , Lee Kwangdeok , Grammatico Andrea , Varma Niraj , Gwechenberger Marianne , Leclercq Christophe , Rinaldi Christopher A
Published: December 2023

Background

Studies have reported that female sex predicts superior cardiac resynchronization therapy (CRT) response. One theory is that this association is related to smaller female heart size, thus increased “relative dyssynchrony” at given QRS durations (QRSd).

Objective

To investigate the mechanisms of sex-specific CRT response relating to heart size, relative dyssynchrony, cardiomyopathy type, QRS morphology, and other patient characteristics.

Methods

A post-hoc analysis of the MORE-CRT MPP trial (n=3739, 28% female), with a sub-group analysis of patients with non-ischaemic cardiomyopathy (NICM) and left bundle branch block (LBBB) (n=1308, 41% female) to control for confounding characteristics. A multivariable analysis examined predictors of response to 6 months of conventional CRT, including sex and relative dyssynchrony, measured by QRSd/LVEDV (left ventricular end-diastolic volume).

Results

Females had a higher CRT response rate than males (70.1% vs. 56.8%, p<0.0001).Subgroup analysis:Regression analysis of the NICM LBBB subgroup identified QRSd/LVEDV, but not sex, as a modifier of CRT response (p<0.0039). QRSd/LVEDV was significantly higher in females (0.919) versus males (0.708, p<0.001). CRT response was 78% for female patients with QRSd/LVEDV>median value, compared to 68% < median value (p=0.012). Association between CRT response and QRSd/LVEDV was strongest at QRSd<150ms.

Conclusions

In the NICM LBBB population, increased relative dyssynchrony in females, who have smaller heart sizes than their male counterparts, is a driver of sex-specific CRT response, particularly at QRSd <150ms. Females may benefit from CRT at a QRSd <130ms, opening the debate on whether sex-specific QRSd cut-offs or QRS/LVEDV measurement should be incorporated into clinical guidelines.
Proteome-wide Mendelian Randomization Analysis Identified Potential Drug Targets for Myocardial Infarction
Authors: Ye Xufeng , Wang Xinpei , Jia Jinzhu
Published: December 2023

Background

Myocardial infarction (MI) is a leading cause of global mortality. Finding effective drugs to treat MI is an urgent concern for clinicians. Proteome-wide Mendelian randomization (MR) analysis provides a new way to investigate invaluable therapeutic drug targets more efficiently.

Methods

Using a proteome-wide MR approach, we assessed the genetic predictive causality between thousands of plasma proteins and MI risk. First, by adopting several principles to judge genetic variants associated with plasma proteins and MI risk, we selected a series of suitable variants utilized as instrumental variables (IVs) for the latter Mendelian Randomization (MR) analysis. Second, we performed a proteome-wide MR analysis to select candidate proteins. Third, sensitivity tests including heterogeneity test, reverse causality test, and colocalization analyses were conducted to ensure the robustness of our selected protein. Last, we assessed the drugability of the identified potential drug targets for MI using databases including DrugBank, PharmGKB, and TTD.

Results

Of the identified IVs, 3,156 associated with 1,487 plasma proteins were validated. 15 proteins exhibited significant genetically predicted causal associations(P − value < 3.362∗10−5) with MI risk, including Plasmin, MSP, Apo B, TAGLN2, LRP4, C1s, Angiostatin, Apo C-III, PCSK9, ANGL4, FN1.4,Apo B, IL-6 sRa, SWAP70, FN, FN1.3. Sensitivity analyses pinpointed Plasmin and Angiostatin for heterogeneity and proteins MSP, Apo B, and Angiostatin for reverse causality effects. Colocalization analysis found several proteins sharing genetic variants with MI, notably Apo B, TAGLN2, LRP4, C1s, Apo C-III, PCSK9 and ANGL4. When the threshold was lowered to 0.7, additional variants SWAP70 could be contained. 7 potential drug targets for MI were identified: SWP70, TAGLN2, LRP4, C1s, Apo C-III, PCSK9, and ANGL4. Drugability assessment categorized these proteins into varying therapeutic potential categories, from successfully drugged targets to those only reported in the literature.

Conclusion

Our comprehensive study elucidated 7 promising drug targets offering profound insights into its molecular dynamics and presenting potential pathways for therapeutic interventions against MI.

Clinical Perspective

1) What Is New?

★ The analysis of thousands of proteins has identified 7 proteins that have a potential causal role in myocardial infarction risk.

★ Four of these ten proteins have drugs approved or in development that target them, and three 5 have not been previously reported to be associated with atrial fibrillation risk.

2) What Are the Clinical Implications?

★ The results of the present study demonstrate new potential drug/therapeutic targets for myocardial infarction.
Targeting the Histone Methyltransferase SETD7 Rescues Diabetes-induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin 3G
Authors: Mohammed Shafeeq A. , Gorica Era , Albiero Mattia , Karsai Gergely , Mengozzi Alessandro , Caravaggi Carlo Maria , Ambrosini Samuele , Masi Stefano , Vinci Maria Cristina , Spinetti Gaia , Rajagopalan Sanjay , El-Osta Assam , Pelisek Jaroslav , Ruschitzka Frank , Fadini Gian Paolo , Costantino Sarah , Paneni Francesco
Published: December 2023

Background

Peripheral artery disease (PAD) is highly prevalent in patients with diabetes (DM) and associates with a poor prognosis. Revascularization strategies failed to improve outcome, suggesting that new strategies to promote blood vessel growth are needed. Histone modifications have emerged as key modulators of gene expression, however their role in angiogenic response in DM remains poorly understood. Here we investigate the role of chromatin remodelling in DM-related impairment of angiogenic response.

Methodology

Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48 hours. Gene expression profiling was performed by RNA sequencing (RNA-seq). Cell migration and tube formation were employed to study angiogenic properties in HAECs. Levels of the histone methyltransferase SETD7 and its chromatin signature at histone 3 on lysine 4 (H3K4me1) were investigated by Western blot and chromatin immunoprecipitation (ChIP). Pharmacological blockade of SETD7 was achieved by using the selective inhibitor(R)-PFI-2 while the inactive enantiomer (S)-PFI-2 was used as a control. Mice with streptozotocin-induced DM were orally treated with (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation. Our experimental findings were translated in endothelial cells and gastrocnemius muscle samples obtained from DM patients with PAD.

Results

RNA-seq in HG-treated HAECs unveiled the histone methyltransferase SETD7 as the top-ranking transcript. SETD7 upregulation was associated with increased H3K4me1 levels as well as with impaired HAECs migration and tube formation. Both SETD7 silencing and inhibition by(R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-induced H3K4me1 enables the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA3G) by increasing chromatin accessibility to PPARγ. Moreover, SEMA3G overexpression mimicked the impairment of angiogenic response observed during hyperglycemia. In DM mice with hindlimb ischemia, (R)-PFI-2 improved limb perfusion by suppressing SEMA3G. Finally, RNAseq and immunofluorescence in vascular specimens from two cohorts of DM patients with PAD confirmed the upregulation of SETD7/SEMA3G signalling. Of note, (R)-PFI-2 restored angiogenic properties in HAECs collected from DM patients.

Conclusion

SETD7 is a druggable epigenetic target to promote neovascularization in DM.
Ancestry Specific Polygenic Risk Score, Dietary Patterns, Physical Activity, and Cardiovascular Disease
Authors: Hardy Dale S. , Garvin Jane T. , Mersha Tesfaye B.
Published: December 2023

Background

It is unknown whether the impact of high diet-quality and physical activity (PA) depends on the level of polygenic risk score (PRS) in different ancestries.

Objective

Determine the associations and interactions between high-risk PRSs, dietary patterns, and high PA with atherosclerotic cardiovascular disease (ASCVD) in European Americans (EAs) and African Americans (AAs). Another aim determined the molecular pathways of PRS-mapped genes and their relationships with dietary intake.

Methods

Cross-sectional analyses utilized de-identified data from 1987-2010 from 7-National Heart, Lung, and Blood Institute Candidate Gene Association Resource studies from the Database of Genotypes and Phenotypes studies for EAs (n=6,575) and AAs (n=1,606).

Results

The high-risk PRS increased ASCVD risk by 59% (Risk Ratio=1.59;95% Confidence Interval:1.16-2.17) in the highest tertile for AAs and by 15% (RR=1.15;1.13-1.30) and 18% (RR=1.18;1.04-1.35) in the second and highest tertiles compared to the lowest tertile in EAs. Within the highest PRS tertiles, high PA-diet combinations (Dietary Approaches to Stop High Blood Pressure (DASH), or Mediterranean, or Southern) reduced ASCVD risks by 9% (RR=0.91;0.85-0.96) to 15% (RR=0.85;0.80-0.90) in EAs; and by 13% (RR=0.87;0.78-0.97) and 18% (RR=0.82;0.72-0.95) for the DASH and Mediterranean diets, respectively in AAs. Top molecular pathways included fructose metabolism and catabolism linked to obesity, insulin resistance, and type 2 diabetes in both ancestries. Additional molecular pathways for AAs were Vitamin D linked to depression and aging acceleration; and death signaling associated with cancer.

Conclusions

Effects of high diet-quality and high PA can counterbalance the influences of genetically high-risk PRSs on ASCVD risk, especially in AAs.
Nanoscale Imaging and Microanalysis of Ice Age Bone Offers New Perspective on “Subfossils” and Fossilization
Authors: Anderson Landon A.
Published: December 2023

The 3-D structure and organization of type-1 collagen protein and vasculature for a set of ancient permafrost bones is extensively documented at the nanoscale (up to 150,000× magnification) for the first time. The chemical mapping technique ToF-SIMS is additionally used to directly localize chemical signal to these structures; C:N and isotope measurements are also reported for the bulk organic bone matrix. These analyses test the hypothesis that biomolecular histology of collagen and vasculature from the permafrost bones supports their taphonomic classification as “subfossils” rather than “fossils”. Results indicate the original collagenous scaffolding and vasculature are still present, the former of which is well-preserved, thus supporting the hypothesis. This study is the first to taphonomically classify a set of pre-Holocene bones as “subfossils” based on the preserved state of their biomolecular histology. These methods can be readily expanded to specimens of warmer thermal settings and earlier geologic strata. Doing so has potential to establish/formalize at what point a bone has been truly “fossilized”; that is, when it has transitioned from “subfossil” status to being a true “fossil” bone. This will elucidate the fossilization process for ancient vertebrates and lead to a deeper understanding of what it means to be a “fossil”.
Trait responsiveness to verbal suggestions predicts nocebo responding: A meta-analysis
Authors: Stein Madeline V. , Heller Monika , Chapman Sarah , Rubin James , Terhune Devin B.
Published: December 2023

Nocebo responding involves the experience of adverse health outcomes in response to contextual cues. These deleterious responses impact numerous features of mental and physical health but are characterized by pronounced heterogeneity. Suggestion is widely recognised as a contributing factor to nocebo responding but the moderating role of trait responsiveness to verbal suggestions (suggestibility) in nocebo responding remains poorly understood. We conducted a pre-registered meta-analysis (PROSPERO registration number CRD42023425605) to quantitatively synthesize available research on the relationship between suggestibility and nocebo responding. Four electronic databases were searched for original studies involving both the assessment of suggestibility and symptom reports in response to an inactive stimulus. Of 7,729 search results, 10 articles presenting 13 correlations between suggestibility and nocebo responding were analysed. A random-effects meta- analysis revealed a significant, albeit weak, positive correlation,r=0.21 [95% CI: 0.04, 0.37], between suggestibility and nocebo responses, such that more highly suggestible individuals displayed larger responses. Sensitivity and meta-regression analyses demonstrated that studies of higher methodological quality, including those that maintained experimenter blinding, exhibited stronger effect sizes. These results corroborate proposals that trait responsiveness to verbal suggestions confers greater response to nocebos and warrants renewed attention to the role of suggestibility in symptom induction and perception.
Item generation for a new patient-reported outcome measure: The non-traumatic anterior knee pain (AKP)-YOUTH scale
Authors: Nielsen Marie Germund , Lyng Kristian Damgaard , Holden Sinead , Johansen Simon Kristoffer , Winters Marinus , Rathleff Michael Skovdal
Published: December 2023

Question

Which domains are important to develop a preliminary item bank for a new patient-reported outcome measure relating to adolescents with non-traumatic anterior knee pain?

Design

Multiple methods: semi-structured interviews,

Participants

Twenty-one adolescents with anterior knee pain participated in semi-structured interviews which explored their experience of living with knee pain. Following thematic analysis, we generated an item bank based on the domains which emerged from the impact their knee pain had on their daily life. Ten clinical experts provided input on the preliminary item bank via an online survey. Cognitive interviews were conducted using the think-aloud approach with ten adolescents to evaluate the comprehensibility and face validity of the items.

Results

From the interviews we identified four overarching domains where adolescents were impacted by their knee pain: knee symptoms, limitations in physical activity/sport, limitations in social activities, and emotional impact of pain. Eighteen items was initially developed and expanded to 23 following clinical expert input. The cognitive interviews with adolescents demonstrated that the items were comprehensive, understandable, and relevant for adolescents.

Conclusion

This study developed an item bank of 23 items. These spanned four domains of impact for adolescents with anterior knee pain. The items had good face validity and were deemed relevant and understandable for adolescents with knee pain. Further steps are needed to validate and reduce the items for the non-traumatic anterior knee pain (AKP)-YOUTH scale.
Biases in hand perception are driven by somatosensory computations, not a distorted hand model
Authors: Peviani Valeria C , Miller Luke E , Medendorp W. Pieter
Published: December 2023

To sense and interact with objects in the environment, we effortlessly configure our fingertips at desired locations. It is therefore reasonable to assume the underlying control mechanisms rely on accurate knowledge about the structure and spatial dimensions of our hand and fingers. This intuition, however, is challenged by years of research showing drastic biases in the perception of finger geometry. This perceptual bias has been taken as evidence that the brain's internal representation of the body's geometry is distorted, leading to an apparent paradox with the skillfulness of our actions. Here, we propose an alternative explanation of the biases in hand perception: They are the result of the Bayesian integration of noisy, but unbiased somatosensory signals about finger geometry and posture. To address this hypothesis, we combined Bayesian reverse-engineering with behavioral experimentation on joint and fingertip localization of the index finger. We modelled the Bayesian integration either in sensory or in space-based coordinates, showing that the latter model variant led to biases in finger perception despite accurate representation of finger length. Behavioral measures of joint and fingertip localization responses showed similar biases, which were well-fitted by the space-based but not the sensory-based model variant. The space-based model variant also outperformed a distorted-hand model with built-in geometric biases. In total, our results suggest that perceptual distortions of finger geometry do not reflect a distorted hand model but originate from near-optimal Bayesian inference on somatosensory signals.
Unlocking the Full Potential of Nanopore Sequencing: Tips, Tricks, and Advanced Data Analysis Techniques
Authors: Meyer Daria , Goettsch Winfried , Spannenberg Jannes , Stieber Bettina , Krautwurst Sebastian , Hölzer Martin , Brandt Christian , Linde Jörg , Höner zu Siederdissen Christian , Srivastava Akash , Zarkovic Milena , Wollny Damian , Marz Manja
Published: December 2023

Nucleic acid sequencing is the process of identifying the sequence of DNA or RNA, with DNA used for genomes and RNA for transcriptomes. Deciphering this information has the potential to greatly advance our understanding of genomic features and cellular functions. In comparison to other available sequencing methods, nanopore sequencing stands out due to its unique advantages of processing long nucleic acid strands in real time, within a small portable device, enabling the rapid analysis of samples in diverse settings. Evolving over the past decade, nanopore sequencing remains in a state of ongoing development and refinement, resulting in persistent challenges in protocols and technology. This article employs an interdisciplinary approach, evaluating experimental and computational methods to address critical gaps in our understanding in order to maximize the information gain from this advancing technology. Here we present both overview and analysis of all aspects of nanopore sequencing by providing statistically supported insights. Thus, we aim to provide fresh perspectives on nanopore sequencing and give comprehensive guidelines for the diverse challenges that frequently impede optimal experimental outcomes.
Periodic diffraction from an aperiodic monohedral tiling
Authors: Kaplan Craig S. , O'Keeffe Michael , Treacy Michael M. J.
Published: December 2023

The diffraction pattern from the recently reported aperiodic `einstein', or `hat', monohedral tiling [Smith et al. (2023). arXiv:2303.10798v1] has been analyzed. The structure is the hexagonal mta net, a kite tiling, with aperiodic vertex deletions. A large model's diffraction pattern displays a robust sixfold periodicity in plane group p6. A repeating, roughly triangular motif of `diffused intensity' arises between the strongest Bragg peaks. The motif contains high-density regions of discrete `satellite' peaks, rather than continuous `diffuse scattering', breaking mirror symmetry, consistent with the chiral hat tiling.
Brand addiction and compulsive buying in female consumers' relationships with food brands
Authors: Hegner Sabrina , Schaumann Janina Magdalena , Francioni Barbara , Curina Ilaria
Published: December 2023

Purpose

The aim of this paper is to respond to the call for exploring and empirically testing both antecedents and outcomes of brand addiction and compulsive buying behaviour. The focus of the study is on the food habits of young female consumers.

Design/methodology/approach

To test the hypotheses, a survey design gathering cross-sectional primary data from 325 female Italian consumers and a structural equation modelling have been adopted.

Findings

Findings show that brand addiction is positively influenced by consumer resilience, leading to increased life happiness and self-esteem, while compulsive buying behaviour is negatively influenced by consumer resilience and positively influenced by impulsivity. Compulsive buying is also associated with brand addiction and emotional overeating. Emotional overeating is additionally influenced by impulsivity and the control variables of enjoyment of food and loneliness. Moreover, loneliness has a negative impact on life happiness and self-esteem.

Originality/value

The study applies the proposed theory by Mrad and Cui (2020) on the relationship between brand addiction and compulsive buying to food consumption. Furthermore, it expands on this research by investigating consumer characteristics as determinants and behavioural outcomes.
Enabling social change: a case study of complex adaptive leadership within an informal settlement in Iran
Authors: Shams Keyhan , Barahouei Mehrnegar , Priest Kerry L.
Published: December 2023

Purpose

This paper introduces a conceptual lens for leading social change in slums and informal settlements. In line with this aim, the purpose of this case study is to describe the public problem-solving approach of a social change organization situated in an informal settlement through the lens of adaptive leadership, complexity theory and social change leadership (SCL).

Design/methodology/approach

This paper follows an engaged reflection tradition. First, the author-practitioners describe an informal settlement case hereafter called ISC in southeast Iran where many people have historically remained undocumented and uneducated. Using complex adaptive systems theory, adaptive leadership and SCL as the conceptual lens, the paper analyzes ISC as a complex adaptive context in which the community and the government are in tension in solving problems, particularly illiteracy. The instrumental case study draws from participant observation and document analysis to describe and examine the endeavors of a community office operating within ISC. Through this reflective analysis, the authors illustrate how a social change organization can effectively tackle public issues like illiteracy within informal settlements.

Findings

This paper applies complexity leadership theory to a social context. The study illustrates how social change organizations can support the transformation of informal spaces into adaptive spaces to enact social change.

Originality/value

This paper reflects on engagement activity near the insecure borders of Iran, Afghanistan and Pakistan. By extending an organizational-level theory to the public sphere, this paper contributes theoretically to the complexity theory literature. Moreover, it provides a practical insight for community development and slum upgrading projects.
Dark side of decentralised finance: a call for enhanced AML regulation based on use cases of illicit activities
Authors: Benson Vladlena , Turksen Umut , Adamyk Bogdan
Published: December 2023

Purpose

This paper aims to focus on the need for an enhanced anti-money laundering (AML) regulation for decentralised finance (DeFi) to protect the integrity of global financial systems against illicit activities. Research highlights the requirement for a robust regulatory strategy for the fast-paced DeFi evolvement.

Design/methodology/approach

This study used doctrinal legal research by analysing legislation, which involved creating use cases to illustrate different aspects of potential illicit activities via the DeFi ecosystem. Various DeFi applications were assessed for the potential regulatory responses and outcomes.

Findings

This paper offers valuable insight into the regulatory challenges presented by DeFi. This study addresses the blind spots leveraged by criminals afforded by the DeFi’s decentralised nature. This paper offers a comprehensive examination of DeFi regulatory challenges based on use-case scenarios and provides recommendations for regulators on how to address them effectively.

Originality/value

This paper proposes measures for regulatory authorities to minimise money laundering risks through new channels such as decentralised exchanges, non-custodial wallets and cross-chain bridges. This study concludes with the future directions for DeFi regulation and AML compliance.