bluuebunny/crossref_metadata_2025 huggingface dataset:
656 - Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe chronic hand eczema in the phase 3 DELTA-2 trial
Authors: Gooderham Melinda , Thaçi Diamant , Damgaard Tina , Madsen Daniel , Soehoel Anders , Bissonnette Robert
Published: August 2024

Introduction/Background

In the DELTA-2 (NCT04872101) Phase 3 trial, delgocitinib cream 20 mg/g, a topical pan-Janus kinase inhibitor, was well-tolerated and demonstrated significant improvement in all efficacy endpoints versus cream vehicle in adults with moderate to severe chronic hand eczema (CHE).

Objectives

The objectives of this analysis were (1) to examine systemic exposure of delgocitinib cream 20 mg/g in adults with moderate to severe CHE in the randomized, double-blind, vehicle-controlled DELTA-2 trial (2) to compare the DELTA-2 systemic exposure with corresponding data following oral administration of delgocitinib in a Phase 1 trial, (3) to present a summary of safety related to delgocitinib cream from the randomized, double-blind, vehicle-controlled DELTA-2 trial.

Methods

Pharmacokinetic blood sampling in DELTA-2 was performed 2-6 hours after delgocitinib application at Weeks 1, 4, and 16 using a liquid chromatography/mass spectrometry-based method (lower limit of quantitation: 5 pg/ml). In the Phase 1 trial (NCT05050279), single oral doses of delgocitinib were tested in healthy volunteers with sampling performed for up to 24-hours post-administration.

Results

In DELTA-2, minimal systemic exposure was recorded in 313 delgocitinib-treated patients, with the highest geometric mean plasma concentration being 0.21 ng/ml at Week 1 (n=286). In the Phase 1 trial, the lowest oral delgocitinib dose tested (1.5 mg; n=8) is regarded as subtherapeutic and showed a peak systemic exposure (geometric mean Cmax) of 7.2 ng/ml. In DELTA-2, adverse events (AEs) were reported by 45.7% (n=143/313; delgocitinib cream) and 44.7% (n=71/159; cream vehicle) of patients, with COVID-19 being most common (11.5% vs 12.6%, respectively). The rate of possibly or probably related AEs was low and similar between delgocitinib cream and cream vehicle. No deaths were reported. Few serious AEs were reported with none assessed as related to the study drug.

Conclusions

The DELTA-2 trial demonstrated minimal systemic exposure in association with a favorable safety profile, supporting a lack of meaningful systemic effect from twice-daily applications of delgocitinib cream in patients with moderate to severe CHE.
671 - Rapid and early onset of itch relief with tapinarof cream 1% once daily in two pivotal phase 3 trials in adults and children down to two years of age with atopic dermatitis
Authors: Simpson Eric , Silverberg Jonathan I , Bissonnette Robert , Gold Linda Stein , Armstrong April W , Hebert Adelaide A , Serrao Rocco T , Jakus Jeannette R , Brown Philip M , Rubenstein David S , Piscitelli Stephen C , Tallman Anna M , Eichenfield Lawrence F
Published: August 2024

Introduction

Itch is the most bothersome symptom for patients with atopic dermatitis (AD), and has a significant negative impact on health-related quality of life. Rapid onset of pruritus relief with sustained efficacy is a key outcome for AD therapies. In ADORING 1 and 2, two identical pivotal phase 3, double-blind, vehicle-controlled trials, tapinarof cream 1% once daily (QD) demonstrated efficacy and was well tolerated in adults and children down to 2 years of age with AD.

Objective

Here, we evaluate time to onset of itch relief in the pivotal phase 3 trials.

Methods

In ADORING 1 and 2, patients with a Validated Investigator Global Assessment for Atopic DermatitisTM score of ≥3 (moderate or severe), an Eczema Area and Severity Index score of ≥6, and body surface area involvement of 5–35% were randomized 2:1 to tapinarof cream or vehicle QD for 8 weeks. Itch relief was assessed by changes in Peak Pruritus Numerical Rating Scale (PP-NRS) score, daily and by visit, from baseline through Week 8. PP-NRS considers itch over the past 24 hours; lower scores indicate less pruritus.

Results

407 and 406 patients were randomized in ADORING 1 and 2. At baseline, mean PP-NRS scores were 6.7 and 6.8 in both trials, respectively. For daily evaluations of itch from baseline, greater reductions in mean PP-NRS scores for tapinarof versus vehicle were observed as early as Day 1, 24 hours after initial application in ADORING 1 (–1.2 vs –0.9), and Day 2 in ADORING 2 (–1.6 vs –1.4). Daily itch improvements continued through Week 8 in both trials. Statistically significant reductions in mean weekly PP-NRS scores occurred as early as Week 1 (earliest assessment) with tapinarof versus vehicle (–2.0 vs –1.2 [P<0.0001]) and (–2.0 vs –1.3 [P=0.0010]) in ADORING 1 and 2, respectively. Significantly greater reductions in mean PP-NRS scores with tapinarof versus vehicle were seen for all visits through Week 8 (–4.1 vs –2.6 and –4.1 vs –2.4 [both P<0.0001]).

Conclusions

Tapinarof cream 1% QD demonstrated rapid, significant, and clinically meaningful pruritus relief from 24 hours after initial application, with improvements increasing through Week 8 in both trials in adults and children down to 2 years with AD.
672 - Nemolizumab monotherapy improves itch, sleep disturbance, and skin lesions in patients with moderate-to-severe prurigo nodularis: Pooled analyses from OLYMPIA 1 and OLYMPIA 2 phase 3 studies
Authors: Yosipovitch Gil , Ständer Sonja , Metz Martin , Pink Andrew E , Silverberg Jonathan I , Sofen Howard , Ahmed Faiz , Noda Aliene , Jabbar Lopez Zarif K , Piketty Christophe , Kwatra Shawn G
Published: August 2024

Introduction

Nemolizumab demonstrated clinically and statistically significant improvements in itch, sleep disturbance, and skin lesions in adults with moderate-to-severe prurigo nodularis (PN) in two phase 3 pivotal studies (OLYMPIA 1 [NCT04501666]1 and OLYMPIA 2 [NCT04501679]2).

Objectives

To report pooled efficacy and safety from two phase 3 studies of nemolizumab in the treatment of PN.

Materials & Methods

A pooled analysis of two phase 3 pivotal studies in adults with moderate-to-severe PN, randomized (2:1) to receive either nemolizumab (initial 60 mg subcutaneous dose followed by 30 mg or 60 mg [depending on a baseline weight below or ≥90 kg, respectively]) or matching placebo every 4 weeks (Q4W).

Results

Nemolizumab significantly improved all pre-specified efficacy endpoints vs placebo. At Week 16, a ≥4-point improvement from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) was achieved in 57.4% of nemolizumab- vs 18.7% placebo-treated patients (P<0.0001), an Investigator’s Global Assessment score of 0/1 [clear/almost clear skin] with ≥2-point reduction from baseline was achieved in 31.9% of nemolizumab- vs 9.1% of placebo-treated patients (P<0.0001) at Week 16, itch-free/nearly itch-free state (defined as PP-NRS<2) was achieved in 34.6% of nemolizumab- vs 5.9% of placebo-treated patients (P<0.0001) and a ≥4-point improvement from baseline in weekly average Sleep Disturbance NRS was achieved in 50.9% of nemolizumab- vs 16.0% of placebo-treated patients (P<0.0001). Treatment-emergent adverse events (TEAEs) were reported in 66.5% of patients (nemolizumab) and 59.1% (placebo). Of these patients, the majority in each treatment group experienced that were considered mild or moderate in severity.

Conclusion

Nemolizumab monotherapy administered Q4W was well-tolerated and led to rapid and sustained clinically meaningful improvements in itch intensity and sleep disturbance along with improvement in skin lesions. Pooled results were consistent with those observed in individual pivotal phase 3 studies.2,3
678 - Patient-reported outcomes for GSK1070806, an anti-IL-18 monoclonal antibody: a phase 1b, randomised, double-blind, parallel-group placebo-controlled study of patients with atopic dermatitis
Authors: Ghafoori Parima , Fortunato Lea , Patel Dharm S , Ellis Joanne , Wong Gabriel , Kelly John B , Birch Helen , Chen Wen-Hung , Uings Iain
Published: August 2024

Introduction/Background

Administration of GSK1070806, an anti–IL-18 monoclonal antibody, in patients with atopic dermatitis (AD) resulted in significant clinical improvements versus placebo after 12 weeks.

Objectives

Assessment of patient-reported outcomes (PROs) for patients with AD receiving GSK1070806.

Methods

In this multicentre, randomised, double-blind, parallel-group study (NCT04975438), adults (≥18 years) with confirmed AD diagnosis for ≥6 months and moderate-to-severe disease (Eczema Area and Severity Index ≥16; Investigator’s Global Assessment score ≥3) received 2 mg/kg GSK1070806 or placebo (single one-hour intravenous infusion). PRO measures included Peak Pruritis Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI), Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS-SD 8b), Brief Fatigue Inventory Item 3 (BFI-Item 3), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). PROs were assessed at baseline and either daily (PP-NRS and BFI-Item 3) or a combination of weekly (up to Week 4) and biweekly (after Week 4) (PROMIS-SD, DLQI and FACIT-F) for up to 24 weeks. Changes from baseline (CFB) in PP-NRS and DLQI scores at Week 12 were analysed using a Bayesian repeated measures model with all other PROs analysed descriptively.

Results

Of 34 enrolled patients (53% female, mean [standard deviation] age 44.8 [16.9] years), 23 received GSK1070806 and 11 received placebo. Posterior median of difference (95% credible interval) CFB at Week 12 in PP-NRS were -4.6 (-5.5, -3.7; GSK1070806) and -0.5 (-1.7, 0.7; placebo), and for DLQI were -6.1 (-8.8, -3.4; GSK1070806) and -0.01 (-4.3, 4.1; placebo). Observed mean PROMIS-SD 8b, BFI-Item 3 and FACIT-F scores also indicated improvements among patients who received GSK1070806 versus placebo.

Conclusions

Patients with moderate-to-severe AD who received GSK1070806 experienced positive improvements across all PROs versus placebo. These results provide further evidence of GSK1070806 benefit in patients with moderate-to-severe AD.
704 - Effectiveness of atopic dermatitis patient education programs – a systematic review and meta-analysis
Authors: Andrade Luis F , Abdi Parsa , Mashoudy Kayla D , Kooner Amritpal , Egler Ashley , Urbonas Rebecca , Smith Aaron , Yosipovitch Gil
Published: August 2024

Background

Patient education in atopic dermatitis (AD) has worked in parallel to the gold standard of pharmacological treatment as a foundational component of therapeutic regimens. In addition to improving patient education, past investigations of educational interventions have demonstrated profound reductions in disease severity for patients living with AD. However, prior meta-analytical work has focused mostly on specific patient groups (e.g pediatric education), and there is limited data on the impact of said educational interventions across different AD severity scales, adult populations, and virtual platforms.

Objective

In this study, we conducted a systematic review of the literature to determine the effectiveness of online programming in AD education compared to in-person interventions.

Methods

A comprehensive search was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions 2019. Studies were retrieved based on articles published up to 04 April 2023. Adherence to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement guided the reportage process for this systematic review and meta-analysis. The primary outcome of our meta-analysis was the effect of various educational modalities on atopic dermatitis severity as measured by multiple scales across the studies, the most common including SCORAD, Dermatology Life Quality Index (DLQI), Patient Oriented Eczema Measure (POEM), and Eczema Area and Severity Index (EASI).

Results

Our study found significant differences in various disease severity and patient-reported indexes for those enrolled in educational experimental compared to control including SCORAD (standard mean difference [SMD] = 0.65, 95% Confidence Intervals (CI): 0.45–0.86), P < 0.00001), QOL (SMD= 0.36 ,95% CI: 0.18–0.54, P = 0.0002), POEM (SMD = 0.28, 95% CI: 0.07–0.49, P = 0.009), and EASI (SMD = 0.80, 95% CI: 0.54–1.06, P < 0.00001).

Conclusion

Our pooled analyses showed that targeted educational programs are an effective method of improving quality of life and reducing disease severity in AD. Moreover, virtual interventions can be employed as constructive tools for reducing barriers of access to patient education. Future research on educational interventions should utilize various methodologies to encourage individual learning preferences with a focus on adult cohorts.
712 - Positive 52-week maintenance data observed with rademikibart in patients with moderate-to-severe atopic dermatitis (S

EASI

DE CHINA)
Authors: Zhang Jianzhong , Silverberg Jonathan I , Guo Jiawang , Yun Jili , Pan Wuban , Wei Zheng , Collazo Raúl
Published: August 2024

Introduction/Background

Rademikibart (formally, CBP-201) is a next-generation optimized monoclonal antibody targeting the IL-4Rα subunit. Rademikibart achieved all Week 16 primary and secondary endpoints in a global Phase 2 atopic dermatitis (AD) trial (WW001; NCT04444752) and a pivotal trial in China (SEASIDE CHINA or CN002; NCT05017480)1 in patients with moderate-to-severe AD.

Objectives

Long-term treatment of atopic dermatitis is essential for continued symptom management, prevention of complications, and improvments in the patient's quality of life. In this report, we now report Stage 2, long-term 52-week data from the SEASIDE CHINA pivotal trial.

Methods

Adults (n=318) and adolescents (n=12) (IGA ≥3, EASI ≥16, BSA ≥10%, PP-NRS ≥4) were randomized (2:1) to rademikibart (300mg Q2W) or placebo for 16 weeks (Stage-1). EASI-50 responders, regardless of Stage-1 treatment, were re-randomized to Q2W (n=113) or Q4W rademikibart (n=112). Non-responders received open-label Q2W rademikibart (n=86).

Results

Initial baseline mean EASI was 29.3 (range, 16.0–72.0) with 54.7% IGA4 for Stage 1 responders and 23.7 (16.0-66.6) with 51.2% respectively for non-responders. In patients who achieved IGA 0/1, 76.0% (Q2W) and 87.2% (Q4W) maintained their response at Week 52. Similarly, 91.7% (Q2W) and 91.9% (Q4W) maintained their EASI-75 response. From Week 16 to Week 52, 28.2% (Q2W/Q2W; n=91) and 20.8% (Q2W/Q4W; n=91) additional patients achieved IGA 0/1, and 16.3% (Q2W/Q2W) and 11.0% (Q2W/Q4W) additional patients achieved EASI-75.

Of patients with ≥4-point reduction in PP-NRS, 81.6% (Q2W) and 95.2% (Q4W) maintained that response at Week 52. A ≥5-point reduction on the DLQI was maintained by 93.4% (Q2W) and 90.0% (Q4W). For 26 rademikibart non-responders (Stage-1), EASI scores improved by 45% with 51.4% acheiving EASI-75 by Week 52. Treatment with rademikibart was generally well tolerated.

Conclusion

Maintenance data with rademikibart are compelling and build upon strong results shown in Stage 11. High rates of maintained efficacy with Q4W dosing, additional gains in efficacy with continued treatment, and maintenance of ciniically meaningful changes in pruitis and QOL were observed.
Lemierre’s syndrome presenting with arterial and Central nervous system involvement
Authors: Simons Brandon , Williams Mason , Hayes Laura , Gupta Kanika , Chandra Tushar
Published: August 2024

A 17-year-old male presented with acute onset right-sided facial swelling, trismus, pharyngitis, and sepsis. An initial CT abdomen and pelvis revealed multifocal bilateral nodular cavitary lung lesions. CT soft tissue neck with contrast demonstrated a parapharyngeal abscess and thrombophlebitis of the right internal jugular vein. The patient was subsequently diagnosed with Lemierre’s syndrome. On the following day, the patient’s neurological status markedly declined. Brain MRI/MRA/MRV showed right internal carotid artery narrowing, multiple areas of acute and subacute infarctions secondary to vasculitis, meningitis, venous sinus thrombosis, and intracerebral abscesses. Workup for primary causes of intracranial vasculitis was negative. Although commonly presented as venous disease, this case highlights a rare presentation of Lemierre’s syndrome with arterial involvement and significant intracranial complications. Clinicians should consider vasculitis and central nervous system involvement as potential complications of Lemierre’s syndrome rather than searching for separate aetiologies.
Drosophila appear resistant to trans-synaptic tau propagation
Authors: Catterson James H , Mouofo Edmond N , López De Toledo Soler Inés , Lean Gillian , Dlamini Stella , Liddell Phoebe , Voong Graham , Katsinelos Taxiarchis , Wang Yu-Chun , Schoovaerts Nils , Verstreken Patrik , Spires-Jones Tara L , Durrant Claire S
Published: August 2024

Alzheimer’s disease is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of Alzheimer’s disease is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models, and indirect evidence for tau spread via synapses has been observed in human Alzheimer’s disease. Halting tau propagation is a promising therapeutic target for Alzheimer’s disease; thus, a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau in Drosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing four different human tau constructs in two distinct neuronal populations reveals a robust resistance in Drosophila to the trans-synaptic spread of human tau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global human tau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.
Hippocampal adenosine-to-inosine RNA editing in sepsis: dynamic changes and influencing factors
Authors: Jin Yun-Yun , Liang Ya-Ping , Wei Zhi-Yuan , Sui Wei-Jia , Chen Jian-Huan
Published: August 2024

Sepsis-associated encephalopathy is a diffuse brain dysfunction secondary to infection. It has been established that factors such as age and sex can significantly contribute to the development of sepsis-associated encephalopathy. Our recent study implicated a possible link between adenosine-to-inosine RNA editing and sepsis-associated encephalopathy, yet the dynamics of adenosine-to-inosine RNA editing during sepsis-associated encephalopathy and how it could be influenced by factors such as age, sex and antidepressants remain uninvestigated. Our current study analysed and validated transcriptome-wide changes in adenosine-to-inosine RNA editing in the hippocampus of different septic mouse models. Seventy-four sites in 64 genes showed significant differential RNA editing over time in septic mice induced by caecal ligation and perforation. The differential RNA editing might contribute to the RNA expression regulation of the edited genes, with 42.2% differentially expressed. These differentially edited genes, especially those with missense editing, such as glutamate receptor, ionotropic, kainate 2 (Grik2, p.M620V), filamin A (Flna, p.S2331G) and capicua transcriptional repressor (Cic, p.E2270G), were mainly involved in abnormal social behaviour and neurodevelopmental and psychiatric disorders. Significant effects of age and sex were also observed on sepsis-associated RNA editing. Further comparison highlighted 40 common differential RNA editing sites that caecal ligation and perforation-induced and lipopolysaccharide-induced septic mouse models shared. Interestingly, these findings demonstrate temporal dynamics of adenosine-to-inosine RNA editing in the mouse hippocampus during sepsis, add to the understanding of age and sex differences in the disease and underscore the role of the epigenetic process in sepsis-associated encephalopathy.
The interplay of cognitive control and feature integration: insights from theta oscillatory dynamics during conflict processing
Authors: Pastötter Bernhard , Haciahmet Céline C , Beste Christian , Münchau Alexander , Frings Christian
Published: August 2024

Adaptive behavior is fundamental to cognitive control and executive functioning. This study investigates how cognitive control mechanisms and episodic feature retrieval interact to influence adaptiveness, focusing particularly on theta (4 to 8 Hz) oscillatory dynamics. We conducted two variations of the Simon task, incorporating response-incompatible, response-compatible, and neutral trials. Experiment 1 demonstrated that cognitive adjustments—specifically, cognitive shielding following incompatible trials and cognitive relaxation following compatible ones—are reflected in midfrontal theta power modulations associated with the Simon effect. Experiment 2 showed that reducing feature overlap between trials leads to less pronounced sequential modulations in behavior and midfrontal theta activity, supporting the hypothesis that cognitive control and feature integration share a common neural mechanism. These findings highlight the interaction of cognitive control processes and episodic feature integration in modulating behavior. The results advocate for hybrid models that combine top–down and bottom–up processes as a comprehensive framework to understand cognitive control dynamics and adaptive behavior.
Antipredator decisions of male Trinidadian guppies (Poecilia reticulata) depend on social cues from females
Authors: Brusseau Alix J P , Feyten Laurence E A , Crane Adam L , Ramnarine Indar W , Ferrari Maud C O , Brown Grant E
Published: August 2024

Many prey species rely on publicly available personal and social information regarding local predation threats to assess risks and make context-appropriate behavioral decisions. However, in sexually dimorphic species, males and females are expected to differ in the perceived costs and/or benefits associated with predator avoidance decisions. Recent studies suggest that male Trinidadian guppies (Poecilia reticulata) show reduced or absent responses to acute personal information cues, placing them at greater risk of predation relative to females. Our goal here was to test the hypothesis that adult (reproductively active) male guppies rely on social information to limit potential costs associated with their lack of response to risky personal cues. Adult male guppies were exposed to personal chemosensory cues (either conspecific alarm cues (AC), a novel odor, or a water control) in the presence of a shoal of three females inside a holding container that allowed the transmission of visual but not chemical cues. At the same time, we exposed females to either risk from AC or no risk, resulting in the display of a range of female behavior, from calm to alarmed, available as social information for males. Alarmed females caused male fright activity to increase and male interest in females to decrease, regardless of the personal cue treatment. These results indicate that male guppies rely more on female information regarding predation risk than their own personal information, probably to balance trade-offs between reproduction and predator avoidance.
The overview of the BioRED (Biomedical Relation Extraction Dataset) track at BioCreative VIII
Authors: Islamaj Rezarta , Lai Po-Ting , Wei Chih-Hsuan , Luo Ling , Almeida Tiago , Jonker Richard A. A , Conceição Sofia I. R , Sousa Diana F , Phan Cong-Phuoc , Chiang Jung-Hsien , Li Jiru , Pan Dinghao , Meesawad Wilailack , Tsai Richard Tzong-Han , Sarol M. Janina , Hong Gibong , Valiev Airat , Tutubalina Elena , Lee Shao-Man , Hsu Yi-Yu , Li Mingjie , Verspoor Karin , Lu Zhiyong
Published: August 2024

The BioRED track at BioCreative VIII calls for a community effort to identify, semantically categorize, and highlight the novelty factor of the relationships between biomedical entities in unstructured text. Relation extraction is crucial for many biomedical natural language processing (NLP) applications, from drug discovery to custom medical solutions. The BioRED track simulates a real-world application of biomedical relationship extraction, and as such, considers multiple biomedical entity types, normalized to their specific corresponding database identifiers, as well as defines relationships between them in the documents. The challenge consisted of two subtasks: (i) in Subtask 1, participants were given the article text and human expert annotated entities, and were asked to extract the relation pairs, identify their semantic type and the novelty factor, and (ii) in Subtask 2, participants were given only the article text, and were asked to build an end-to-end system that could identify and categorize the relationships and their novelty. We received a total of 94 submissions from 14 teams worldwide. The highest F-score performances achieved for the Subtask 1 were: 77.17% for relation pair identification, 58.95% for relation type identification, 59.22% for novelty identification, and 44.55% when evaluating all of the above aspects of the comprehensive relation extraction. The highest F-score performances achieved for the Subtask 2 were: 55.84% for relation pair, 43.03% for relation type, 42.74% for novelty, and 32.75% for comprehensive relation extraction. The entire BioRED track dataset and other challenge materials are available at https://ftp.ncbi.nlm.nih.gov/pub/lu/BC8-BioRED-track/ and https://codalab.lisn.upsaclay.fr/competitions/13377 and https://codalab.lisn.upsaclay.fr/competitions/13378.

Database URL: https://ftp.ncbi.nlm.nih.gov/pub/lu/BC8-BioRED-track/https://codalab.lisn.upsaclay.fr/competitions/13377https://codalab.lisn.upsaclay.fr/competitions/13378
Propagation path of a flowering cherry (Cerasus × yedoensis) cultivar ‘Somei-Yoshino’ traced by somatic mutations
Authors: Shirasawa Kenta , Esumi Tomoya , Itai Akihiro , Hatakeyama Katsunori , Takashina Tadashi , Yakuwa Takuji , Sumitomo Katsuhiko , Kurokura Takeshi , Fukai Eigo , Sato Keiichi , Shimada Takehiko , Shiratake Katsuhiro , Hosokawa Munetaka , Monden Yuki , Kusaba Makoto , Ikegami Hidetoshi , Isobe Sachiko
Published: August 2024

In the long history of human relations with flowering cherry trees in Japan, ‘Somei-Yoshino’ occupies an exceptional position among a variety of flowering trees: it is a self-incompatible interspecific hybrid but has been enthusiastically planted by grafting throughout Japan, due most likely to its flamboyant appearance upon full bloom. Thus, ‘Somei-Yoshino’ gives us a rare opportunity to trace and investigate the occurrence and distribution of somatic mutations within a single plant species through analysis of the genomes of the clonally propagated trees grown under a variety of geographical and artificial environments. In the studies presented here, a total of 46 samples of ‘Somei-Yoshino’ trees were collected and their genomes were analysed. We identified 684 single nucleotide mutations, of which 71 were present in more than two samples. Clustering analysis of the mutations indicated that the 46 samples were classified into eight groups, four of which included 36 of the 46 samples analysed. Interestingly, all the four tree samples collected in Ueno Park of Tokyo were members of the four groups mentioned above. Based on comparative analysis of their mutations, one of the four trees growing in Ueno Park was concluded to be the closest to the original ancestor. We propose that somatic mutations may be used as tracers to establish the ancestral relationship amongst clonally propagated individuals.
Cardiac fibromas in adult patients: a case series focusing on rhythmology and radiographic features
Authors: Finke Karl , Gietzen Thorsten , Steven Daniel , Baldus Stephan , ten Freyhaus Henrik , Maintz David , Pennig Lenhard , Gietzen Carsten
Published: August 2024

Background

Fibromas are rare primary benign cardiac tumours that can become symptomatic due to expansive growth, ventricular rhythm disturbances, and sudden cardiac death. Distinguishing fibromas from other (malign) cardiac masses is essential for accurate diagnosis and treatment. While there is some experience in management of cardiac fibromas in children, management of adult patients is unknown.

Case summary

We present three cases of cardiac fibroma in adult patients diagnosed by echocardiography, cardiovascular magnetic resonance (CMR), and computed tomography (CT): (1) a 55-year-old male with a left ventricular fibroma leading to reduced left ventricular ejection fraction and mitral regurgitation. He had family history of sudden cardiac death, showed premature ventricular contractions (PVCs), and was treated with a primary preventive subcutaneous implantable cardiac defibrillator (S-ICD); (2) a 39-year-old male with right ventricular fibroma as an incidental finding. He complained of episodes of PVC. Due to a low PVC burden, decision was made against ablation and the patient was planned for follow-up; and (3) an 18-year-old female with left ventricular apex fibroma detected by CMR shortly after birth and confirmed by surgical biopsy. Being asymptomatic, conservative management was pursued and follow-up by CMR planned.

Discussion

Cardiac fibromas can show various clinical presentations and hence being detected late in life. Given potential complications of surgical biopsy, diagnosis of cardiac fibromas is primarily based on echocardiography, CT, and CMR. Rhythm disturbances as PVCs are common. Due to association with ventricular arrhythmias and sudden cardiac death, preventive ICD placement might be appropriate on an individual basis.
The prognostic impact of unplanned invasive coronary angiography following coronary artery bypass grafting
Authors: Heuts Samuel , Bova Roberto , Romeo Jamie L R , Vriesendorp Pieter A , van der Horst Iwan C C , Segers Patrique , Maessen Jos G , Gollmann-Tepeköylü Can , van 't Hof Arnoud W J , Bidar Elham , Lux Arpad
Published: August 2024

OBJECTIVES

Myocardial ischaemia following coronary artery bypass grafting (CABG) is a potentially devastating complication. Nevertheless, the incidence, aetiology and prognostic relevance of unplanned coronary angiography (uCAG) remain understudied. We aimed to investigate the prevalence and outcome of patients undergoing urgent, uCAG in the postoperative period following CABG.

METHODS

We screened all patients undergoing isolated elective CABG in an academic referral centre between 2016 and 2021 and identified patients undergoing uCAG within 30 days of surgery. For uCAG patients, a distinction was made between patients undergoing re-revascularization (REV) and patients receiving conservative management (CON). The primary outcomes were 30-day mortality and unadjusted and adjusted long-term survival. Secondary outcomes were the indication for and prevalence of uCAG and urgent revascularization.

RESULTS

Of the 1918 patients undergoing isolated CABG, 78 individuals needed uCAG (4.1%), of whom 45 underwent immediate revascularization (REV group; 2.3% overall, 57% within the uCAG group, median age 69.9 years) and 33 were treated conservatively (CONS group; 1.7% overall, 42% within the uCAG group, median age 69.1 years). Patients undergoing uCAG (n = 78) had a higher 30-day mortality than patients not undergoing uCAG (n = 1840, 30-day mortality: 9.0% vs 0.4%, P < 0.001). Long-term survival was significantly decreased in patients undergoing uCAG in both unadjusted (hazard ratio 2.20, 95% confidence interval 1.30–3.73) and EuroSCORE-, age- and sex-adjusted models (hazard ratio uCAG 2.03, 95% confidence interval 1.16–3.56).

CONCLUSIONS

Unplanned postoperative coronary angiography is performed in 4.1% of isolated CABG procedures, and patients in need of such urgent invasive evaluation are subjected to decreased short- and long-term survival.
The association of haemoglobin A1c variability with adverse outcomes in patients with atrial fibrillation prescribed anticoagulants
Authors: Huang Jia-Yi , Cai An-Ping , Tsang Christopher Tze Wei , Wu Mei-Zhen , Gu Wen-Li , Guo Ran , Zhang Jing-Nan , Zhu Ching-Yan , Hung Yik-Ming , Lip Gregory Y H , Yiu Kai-Hang
Published: August 2024

Aims

The association of haemoglobin A1c (HbA1c) variability with the risk of adverse outcomes in patients with atrial fibrillation (AF) prescribed anticoagulants remains unclear. This study aimed to evaluate the association of HbA1c variability with the risk of ischaemic stroke (IS)/systemic embolism (SE) and all-cause mortality among patients with non-valvular AF prescribed anticoagulants.

Methods and results

Patients newly diagnosed with AF from 2013 to 2018 were included. Variability in HbA1c, indexed by the coefficient of variation (CV), was determined for those with at least three HbA1c measurements available from the time of study enrolment to the end of follow-up. To evaluate whether prevalent diabetes would modify the relationship between HbA1c variability and outcomes, participants were divided into diabetes and non-diabetes groups. The study included 8790 patients (mean age 72.7% and 48.5% female). Over a median follow-up of 5.5 years (interquartile range 5.2, 5.8), the incident rate was 3.74 per 100 person-years for IS/SE and 4.89 for all-cause mortality in the diabetes group. The corresponding incident rates in the non-diabetes group were 2.41 and 2.42 per 100 person-years. In the diabetes group, after adjusting for covariates including mean HbA1c, greater HbA1c variability was significantly associated with increased risk of IS/SE [hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.27–2.13) and all-cause mortality (HR = 1.24, 95% CI: 1.05–1.47) compared with the lowest CV tertile. A similar pattern was evident in the non-diabetes group (IS/SE: HR = 1.58, 95% CI: 1.23–2.02; all-cause mortality: HR = 1.35, 95% CI: 1.10–1.64).

Conclusion

Greater HbA1c variability was independently associated with increased risk of IS/SE and all-cause mortality among patients with AF, regardless of diabetic status.
Hypnotic use and the risk of cardiovascular diseases in insomnia patients
Authors: Xie Yao , Zhu Shiyu , Wu Shuang , Liu Chang , Shen Jian , Jin Chunna , Ma Hong , Xiang Meixiang
Published: August 2024

Aims

We aimed to examine the association between hypnotic agents and cardiovascular outcomes in general individuals with insomnia.

Methods and results

In a propensity score matched cohort of UK Biobank (UKB) participants with insomnia, Cox proportional hazard model was used to estimate the association between regular use of hypnotic agents and predetermined cardiovascular outcomes including incident coronary heart diseases (CHD), heart failure (HF), stroke, and cardiovascular death. Inverse probability of treatment weighting, competing risk models, and shared frailty models were further performed during sensitivity analysis. Drug-target Mendelian randomization (MR) analyses were employed for further evaluation of the association between therapeutic targets of hypnotics and cardiovascular diseases. During a median follow-up of 14.3 years, the matched cohort documented a total of 929 CHD cases, 360 HF cases, 262 stroke cases, and 180 cardiovascular deaths. No significant association was detected between Z-meds and CHD, stroke, and cardiovascular mortality. Benzodiazepine use was significantly associated with the increased risk of CHD, HF, and cardiovascular mortality. The inverse probability of treatment weighting, competing risk models, and shared frailty models didn’t alter the above associations. Moreover, drug-target MR analyses corroborated the safety of Z-meds in the general population regarding cardiovascular health.

Conclusion

Our findings suggested the heterogeneous associations between different categories of hypnotics and incident cardiovascular events in individuals with insomnia. Both observational and genetic evidence raised safety concerns regarding the cardiovascular impact of benzodiazepines. No cardiovascular hazard of Z-meds was discovered in the UKB population with insomnia.
Adaptive radiation despite conserved modularity patterns in San Salvador Island Cyprinodon pupfishes and their hybrids
Authors: Chan HoWan , Colaco Emma , Martin Christopher H , Evans Kory M
Published: August 2024

Adaptive radiations are striking examples of rapid speciation along ecological lines. In adaptive radiations, fast rates of lineage diversification often pair with rapid rates of morphological diversification. Such diversification has often been documented through the lens of ecological drivers, overlooking the intrinsic structural constraints that may also have a key role in configuring patterns of trait diversification. Covariation within and between traits has been hypothesized to govern the axes of trait evolution, either by increasing the degree of covariation between traits (i.e. integration), which promotes morphological coordination, or by strengthening the degree of covariation within traits (i.e. modularity), which allows organisms to explore novel trait combinations and different regions of morphospace. Here, we study the modularity of the skull within an adaptive radiation of pupfishes that is endemic to San Salvador Island, Bahamas. This radiation exhibits divergent craniofacial morphologies, including generalist, snail-eating specialist, and scale-eating specialist species. We assessed morphological disparity, integration strength, and modularity patterns across the sympatric San Salvador Island pupfish radiation, lab-reared hybrids, and closely related outgroup species. Our findings revealed an unexpected uniformity in the pattern of modularity across diverse species, supporting a five-module functional hypothesis comprising the oral jaw, pharyngeal jaw, neurocranium, hyoid apparatus, and hyomandibula. Despite this conserved modularity pattern, all species exhibited weak but significantly varying strengths of overall between-module integration and significant disparity across all cranial regions. Our results suggest rapid morphological diversification can occur even with conserved patterns of modularity. We propose that broadscale patterns of modularity are more conserved while between-module associations are more evolvable between species.
Metabolic reprogramming in the food-borne pathogen Listeria monocytogenes as a critical defence against acid stress
Authors: Wu Jialun , Wang Chuhan , O'Byrne Conor
Published: August 2024

The ability to sense and respond effectively to acidic stress is important for microorganisms to survive and proliferate in fluctuating environments. As specific metabolic activities can serve to buffer the cytoplasmic pH, microorganisms rewire their metabolism to favour these reactions and thereby mitigate acid stress. The orally acquired pathogen Listeria monocytogenes exploits alternative metabolic activities to overcome the acidic stress encountered in the human stomach or food products. In this minireview, we discuss the metabolic processes in L. monocytogenes that mitigate acid stress, with an emphasis on the proton-depleting reactions, including glutamate decarboxylation, arginine/agmatine deimination, and fermentative acetoin production. We also summarize the recent findings on regulatory mechanisms that control the expression of genes that are responsible for these metabolic activities, including the general stress response regulator SigB, arginine repressor ArgR, and the recently discovered RofA-like transcriptional regulatory GadR. We further discuss the importance of this metabolic reprogramming in the context of food products and within the host. Finally, we highlight some outstanding challenges in the field, including an understanding of acid-sensing mechanisms, the role of intraspecies heterogeneity in acid resistance, and how a fundamental understanding of acid stress response can be exploited for food formulation to improve food safety and reduce food waste.
Loss of genetic variation and ancestral sex determination system in North American northern pike characterized by whole-genome resequencing
Authors: Johnson Hollie A , Rondeau Eric B , Sutherland Ben J G , Minkley David R , Leong Jong S , Whitehead Joanne , Despins Cody A , Gowen Brent E , Collyard Brian J , Whipps Christopher M , Farrell John M , Koop Ben F
Published: August 2024

The northern pike Esox lucius is a freshwater fish with low genetic diversity but ecological success throughout the Northern Hemisphere. Here, we generate an annotated chromosome-level genome assembly of 941 Mbp in length with 25 chromosome-length scaffolds. We then genotype 47 northern pike from Alaska through New Jersey at a genome-wide scale and characterize a striking decrease in genetic diversity along the sampling range. Individuals west of the North American Continental Divide have substantially higher diversity than those to the east (e.g. Interior Alaska and St. Lawrence River have on average 181 and 64K heterozygous SNPs per individual, or a heterozygous SNP every 5.2 and 14.6 kbp, respectively). Individuals clustered within each population with strong support, with numerous private alleles observed within each population. Evidence for recent population expansion was observed for a Manitoba hatchery and the St. Lawrence population (Tajima's D = −1.07 and −1.30, respectively). Several chromosomes have large regions with elevated diversity, including LG24, which holds amhby, the ancestral sex determining gene. As expected amhby was largely male-specific in Alaska and the Yukon and absent southeast to these populations, but we document some amhby(−) males in Alaska and amhby(+) males in the Columbia River, providing evidence for a patchwork of presence of this system in the western region. These results support the theory that northern pike recolonized North America from refugia in Alaska and expanded following deglaciation from west to east, with probable founder effects resulting in loss of both neutral and functional diversity (e.g. amhby).
Association Between Adverse Early Life Factors and Telomere Length in Middle and Late Life
Authors: Lin Fengyu , Luo Jiefeng , Zhu Yiqun , Liang Huaying , Li Dianwu , Han Duoduo , Chang Qinyu , Pan Pinhua , Zhang Yan
Published: August 2024

Background and Objectives

Telomere length (TL) has been acknowledged as biomarker of biological aging. Numerous investigations have examined associations between individual early life factors and leukocyte TL; however, the findings were far from consistent.

Research Design and Methods

We evaluated the relationship between individual and combined early life factors and leukocytes TL in middle and late life using data from the UK Biobank. The early life factors (eg, maternal smoking, breastfeeding, birth weight, and comparative body size and height to peers at age 10) were measured. The regression coefficients (β) and 95% confidence interval (CI) were applied to assess the link of the early life factors and TL in adulthood. Flexible parametric survival models incorporated age to calculate the relationship between early life factors and life expectancy.

Results

Exposure to maternal smoking, lack of breastfeeding, low birth weight, and shorter height compared to peers at age 10 were identified to be associated with shorter TL in middle and older age according to the large population-based study with 197 504 participants. Individuals who experienced more than 3 adverse early life factors had the shortest TL in middle and late life (β = −0.053; 95% CI = −0.069 to −0.038; p < .0001), as well as an average of 0.54 years of life loss at the age of 45 and 0.49 years of life loss at the age of 60, compared to those who were not exposed to any early life risk factors.

Discussion and Implications

Early life factors including maternal smoking, non-breastfed, low birth weight, and shorter height compared to peers at age 10 were associated with shorter TL in later life. In addition, an increased number of the aforementioned factors was associated with a greater likelihood of shorter TL in adulthood, as well as a reduced life expectancy.
Dual-Alpha: a large EEG study for dual-frequency SSVEP brain–computer interface
Authors: Sun Yike , Liang Liyan , Li Yuhan , Chen Xiaogang , Gao Xiaorong
Published: August 2024

Background

The domain of brain–computer interface (BCI) technology has experienced significant expansion in recent years. However, the field continues to face a pivotal challenge due to the dearth of high-quality datasets. This lack of robust datasets serves as a bottleneck, constraining the progression of algorithmic innovations and, by extension, the maturation of the BCI field.

Findings

This study details the acquisition and compilation of electroencephalogram data across 3 distinct dual-frequency steady-state visual evoked potential (SSVEP) paradigms, encompassing over 100 participants. Each experimental condition featured 40 individual targets with 5 repetitions per target, culminating in a comprehensive dataset consisting of 21,000 trials of dual-frequency SSVEP recordings. We performed an exhaustive validation of the dataset through signal-to-noise ratio analyses and task-related component analysis, thereby substantiating its reliability and effectiveness for classification tasks.

Conclusions

The extensive dataset presented is set to be a catalyst for the accelerated development of BCI technologies. Its significance extends beyond the BCI sphere and holds considerable promise for propelling research in psychology and neuroscience. The dataset is particularly invaluable for discerning the complex dynamics of binocular visual resource distribution.
Efficient phylogenetic tree inference for massive taxonomic datasets: harnessing the power of a server to analyze 1 million taxa
Authors: Piñeiro César , Pichel Juan C
Published: August 2024

Background

Phylogenies play a crucial role in biological research. Unfortunately, the search for the optimal phylogenetic tree incurs significant computational costs, and most of the existing state-of-the-art tools cannot deal with extremely large datasets in reasonable times.

Results

In this work, we introduce the new VeryFastTree code (version 4.0), which is able to construct a tree on 1 server using single-precision arithmetic from a massive 1 million alignment dataset in only 36 hours, which is 3 times and 3.2 times faster than its previous version and FastTree-2, respectively. This new version further boosts performance by parallelizing all tree traversal operations during the tree construction process, including subtree pruning and regrafting moves. Additionally, it introduces significant new features such as support for new and compressed file formats, enhanced compatibility across a broader range of operating systems, and the integration of disk computing functionality. The latter feature is particularly advantageous for users without access to high-end servers, as it allows them to manage very large datasets, albeit with an increase in computing time.

Conclusions

Experimental results establish VeryFastTree as the fastest tool in the state-of-the-art for maximum likelihood phylogeny estimation. It is publicly available at https://github.com/citiususc/veryfasttree. In addition, VeryFastTree is included as a package in Bioconda, MacPorts, and all Debian-based Linux distributions.