bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive Symptoms Are Not Associated with Cognitive Performance in Post-Acute mTBI
Authors: Levy Arielle M , Saling Michael M , Anderson Jacqueline F I 
Published: August 2024

Abstract

Objective
Subjective cognitive symptoms are commonly reported after mild traumatic brain injury (mTBI) but are often not associated with objective cognitive performance. This may be due to limitations in traditional cognitive performance measures, which may not be sensitive to subtle variations in cognition in post-acute mTBI. This study explored associations between objective and subjective cognition using computer-based tasks of increasing cognitive load, proposed to be more sensitive to subtle differences in performance.

Method
Individuals with mTBI (n = 68) and trauma controls (n = 40) were prospectively recruited and assessed approximately 8 weeks post-injury. Participants completed measures of subjective symptom reporting, objective cognitive performance (including two computer-based tasks of increasing cognitive load), and psychological distress.

Results
There were no significant associations between subjective and objective cognition reporting in the mTBI group, both in bivariate correlations (|r| = 0.01–0.20, p &gt; .05) and when controlling for psychological distress (|r| = 0.00–0.17, p &gt; .05). A similar pattern of results was observed in trauma controls, suggesting that the limited relationships between objective and subjective cognition in mTBI may not be specific to this population.

Conclusions
Despite employing measures of cognitive performance proposed to be more sensitive than traditional tasks, no significant relationships were observed between objective and subjective cognition in post-acute mTBI, and estimated effect sizes were small to negligible. This provides further evidence that at a group level 8 weeks after mTBI subjective cognitive symptoms primarily reflect factors aside from objective cognition.
Benchmarking of AlphaFold2 accuracy self-estimates as indicators of empirical model quality and ranking: a comparison with independent model quality assessment programmes
Authors: Edmunds Nicholas S , Genc Ahmet G , McGuffin Liam J 
Published: August 2024

Abstract

Motivation
Despite an increase in protein modelling accuracy following the development of AlphaFold2, there remains an accuracy gap between predicted and observed model quality assessment (MQA) scores. In CASP15, variations in AlphaFold2 model accuracy prediction were noticed for quaternary models of very similar observed quality. In this study, we compare plDDT and pTM to their observed counterparts the local distance difference test (lDDT) and TM-score for both tertiary and quaternary models to examine whether reliability is retained across the scoring range under normal modelling conditions and in situations where AlphaFold2 functionality is customized. We also explore plDDT and pTM ranking accuracy in comparison with the published independent MQA programmes ModFOLD9 and ModFOLDdock.

Results
plDDT was found to be an accurate descriptor of tertiary model quality compared to observed lDDT-Cα scores (Pearson r = 0.97), and achieved a ranking agreement true positive rate (TPR) of 0.34 with observed scores, which ModFOLD9 could not improve. However, quaternary structure accuracy was reduced (plDDT r = 0.67, pTM r = 0.70) and significant overprediction was seen with both scores for some lower quality models. Additionally, ModFOLDdock was able to improve upon AF2-Multimer model ranking compared to TM-score (TPR 0.34) and oligo-lDDT score (TPR 0.43). Finally, evidence is presented for increased variability in plDDT and pTM when using custom template recycling, which is more pronounced for quaternary structures.

Availability and implementation
The ModFOLD9 and ModFOLDdock quality assessment servers are available at https://www.reading.ac.uk/bioinf/ModFOLD/ and https://www.reading.ac.uk/bioinf/ModFOLDdock/, respectively. A docker image is available at https://hub.docker.com/r/mcguffin/multifold.
Attention-based approach to predict drug–target interactions across seven target superfamilies
Authors: Schulman Aron , Rousu Juho , Aittokallio Tero , Tanoli Ziaurrehman 
Published: August 2024

Abstract

Motivation
Drug–target interactions (DTIs) hold a pivotal role in drug repurposing and elucidation of drug mechanisms of action. While single-targeted drugs have demonstrated clinical success, they often exhibit limited efficacy against complex diseases, such as cancers, whose development and treatment is dependent on several biological processes. Therefore, a comprehensive understanding of primary, secondary and even inactive targets becomes essential in the quest for effective and safe treatments for cancer and other indications. The human proteome offers over a thousand druggable targets, yet most FDA-approved drugs bind to only a small fraction of these targets.

Results
This study introduces an attention-based method (called as MMAtt-DTA) to predict drug–target bioactivities across human proteins within seven superfamilies. We meticulously examined nine different descriptor sets to identify optimal signature descriptors for predicting novel DTIs. Our testing results demonstrated Spearman correlations exceeding 0.72 (P &lt; 0.001) for six out of seven superfamilies. The proposed method outperformed fourteen state-of-the-art machine learning, deep learning and graph-based methods and maintained relatively high performance for most target superfamilies when tested with independent bioactivity data sources. We computationally validated 185 676 drug–target pairs from ChEMBL-V33 that were not available during model training, achieving a reasonable performance with Spearman correlation &gt;0.57 (P &lt; 0.001) for most superfamilies. This underscores the robustness of the proposed method for predicting novel DTIs. Finally, we applied our method to predict missing bioactivities among 3492 approved molecules in ChEMBL-V33, offering a valuable tool for advancing drug mechanism discovery and repurposing existing drugs for new indications.

Availability and implementation
https://github.com/AronSchulman/MMAtt-DTA.
Analysing the information content of the multimodal courtship display of a parasitoid wasp
Authors: Lang Sandra Regina , Conrad Taina , Steiger Sandra , Stökl Johannes 
Published: August 2024

Abstract
Courtship displays are generally composed of multiple signal components that are transmitted and perceived through different sensory modalities. However, previous studies on multimodal courtship displays have focused mainly on individual signals, thus failing to provide a full explanation of why these displays evolved despite the added costs involved. Therefore, it is essential to identify the purpose of each display component and link them to prevailing hypotheses on multimodal display function. Here, we study the multimodal courtship display of males of the parasitoid wasp Leptopilina heterotoma, which consists of wing fanning and a putative antennal pheromone, by determining the information conveyed about male quality through these two modalities. We found that a high wing-fanning frequency and a large body size led to a higher mating success, whereas we found no correlation of the pheromone composition with mating success. We conclude that the wing-fanning component conveys mate-assessment information, whereas the chemical display component, found to be species specific in a previous study, functions as a species-recognition mechanism but does not reflect the quality of a male. Altogether, our study suggests that the multimodal courtship display of L. heterotoma fits the multiple message hypothesis and might thus be a useful model for further studies.
Transcriptional profiling of mucus production in rhesus macaque endocervical cells under hormonal regulation
Authors: Rapp Katrina , Wei Shuhao , Roberts Mackenzie , Yao Shan , Fei Suzanne S , Gao Lina , Ray Karina , Wang Alexander , Godiah Rachelle , Han Leo 
Published: August 2024

Abstract

Objective
Endocervical mucus production is a key regulator of fertility throughout the menstrual cycle. With cycle-dependent variability in mucus quality and quantity, cervical mucus can either facilitate or block sperm ascension into the upper female reproductive tract. This study seeks to identify genes involved in the hormonal regulation of mucus production, modification, and regulation through profiling the transcriptome of endocervical cells from the non-human primate, the rhesus macaque (Macaca mulatta).

Intervention
We treated differentiated primary endocervical cultures with estradiol (E2) and progesterone (P4) to mimic peri-ovulatory and luteal-phase hormonal changes. Using RNA-sequencing, we identified differential expression of gene pathways and mucus-producing and mucus-modifying genes in cells treated with E2 compared to hormone-free conditions and E2 compared to E2-primed cells treated with P4.

Main Outcome Measures
We pursued differential gene expression analysis on RNA-sequenced cells. Sequence validation was done using quantitative PCR (qPCR).

Results
Our study identified 158 genes that show significant differential expression in E2-only conditions compared to hormone-free control and 250 genes that show significant differential expression in P4-treated conditions compared to E2-only conditions. From this list, we found hormone-induced changes in transcriptional profiles for genes across several classes of mucus production, including ion channels and enzymes involved in post-translational mucin modification that have not previously been described as hormonally regulated.

Conclusion
Our study is the first to use an in vitro culture system to create an epithelial cell–specific transcriptome of the endocervix. As a result, our study identifies new genes and pathways altered by sex steroids in cervical mucus production.

Summary Sentence
In vitro hormonal regulation of mucus production, modification, and secretion was profiled using primary epithelial endocervical cells.
578 - Cost per responder in Brazil (EASI-75, EASI90 and ΔNRS ≥4) of biologics and JAK inhibitors based on a network-meta-analysis of therapies for atopic dermatitis
Authors: Muzy Guilherme 
Published: August 2024

Abstract

Background
Atopic dermatitis (AD) poses a significant global health burden, affecting a substantial percentage of both pediatric and adult populations. Conventional systemic therapies exhibit limited efficacy and undesirable side effects, emphasizing the urgent need for more effective and economically viable treatment options.

Objective
This study aims to provide an updated analysis of the cost per response ratio for different systemic medications in monotherapy for moderate-to-severe AD, considering the unique Brazilian healthcare context. Additionally, it explores the number of successfully treated patients across various clinically meaningful endpoints.

Methods
The study includes biological therapies and JAK inhibitors approved by ANVISA up to January 2024. Efficacy was assessed using EASI and pruritus-NRS scores, aligning with HOME's Core Outcome Set for clinical trials. Costs were calculated based on each specific outcome, considering the factory price with an 18% increment for ICMS. Dosages and costs were derived from prescribing information and network meta-analyses.

Results
Upadacitinib 15 mg emerged as the most cost-effective therapy for achieving EASI-90, providing a substantial cost reduction compared to other medications. All JAK inhibitors demonstrated superior cost per response values for pruritus △NRS ≥ 4 compared to dupilumab.

Study limitations
This analysis was limited to the endpoints presented in the meta-analyses and other endpoints might offer different perspectives results.

Conclusion
This research contributes valuable insights into the cost-effectiveness of systemic therapies for AD in the Brazilian context. Despite not being obligatory, JAK inhibitors showcase notable cost-efficacy, providing an alternative to biological treatments. Decision-makers should leverage cost-effectiveness analyses for informed resource management and prioritize treatments that maximize clinical benefits and minimize costs.
628 - Clinical measures of improvement in atopic dermatitis are correlated with reductions in relevant biomarkers in patients treated with lebrikizumab
Authors: Guttman-Yassky Emma , Okragly Angela , Sun Zhe , Nickoloff Brian J , Natalie Chitra R , Gallo Gaia , Wolf Eric , Eyerich Kilian , Aparici Monica , Benschop Robert J 
Published: August 2024

Abstract

Introduction
In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), lebrikizumab demonstrated statistical superiority vs. placebo in patients with moderate-to-severe atopic dermatitis (AD). The objective of this analysis is to test for correlations between improvements in clinical outcomes and reductions in AD-relevant serum biomarkers during ADvocate1 and ADvocate2.

Objectives
To assess the correlation between clinical measures of atopic dermatitis (AD) and AD-specific biomarkers at baseline; and to assess the correlation between clinical measures of AD and changes in AD-specific biomarkers after treatment with lebrikizumab.

Methods
Full details of these studies were previously reported. Protein biomarkers were determined in available serum samples from patients receiving lebrikizumab 250 mg every 2 weeks (n=72) or placebo (n=36). Tested biomarkers included: IL-13 (baseline only), CCL2, CCL4, CCL11, CCL13, CCL17 (TARC), CCL22, CCL26 (eotaxin-3), CXCL10, total IgE, IL-4, IL-5, and periostin. Baseline biomarker levels and baseline clinical endpoints were compared using a Spearman correlation. A repeated measures correlation analysis was used to characterize paired measurement of within-patient biomarker levels and clinical endpoints at baseline, week 4, week 16, and week 52. Clinical measures of AD included Investigator’s Global Assessment (IGA), Eczema Area and Severity Index (EASI), and Pruritus Numeric Rating Scale (NRS).

Results
At baseline, EASI score was positively correlated with IL-13, periostin, IL-5, IgE, CCL13, CCL17, CCL22 and CCL26 (correlation coefficient&gt;0.3, p&lt;0.05), but not IL-4. During the studies, improvements in EASI, IGA, and Pruritus NRS were each correlated with reductions in periostin, CCL13, CCL17, CCL22, and CCL26 (correlation coefficient&gt;0.3, p&lt;0.05). Improvement in IGA was also correlated with a reduction in IgE (correlation coefficient&gt;0.3, p&lt;0.05).

Conclusions
Clinical measures of improvement in the signs and symptoms of AD are correlated with reductions in AD biomarkers in patients treated with lebrikizumab.
637 - ARQ-234: a high affinity CD200-Fc fusion protein for the treatment of atopic dermatitis
Authors: Sheridan Joseph , Heal Jonathan , Berk David R , Burnett Patrick , Blackbourn David J , Huxley Philip , Ashfield Rebecca 
Published: August 2024

Abstract

Background
Human CD200 receptor (CD200R, CD200R1), originally OX2R, is an inhibitory immune checkpoint receptor expressed on many myeloid cells, and lymphocyte populations including CD4 T and ILC2 cells, signaling via DOK2 and Erk/MAP kinases to inhibit the NFkB pathway and cytokine secretion. Its ligand, CD200, is expressed on the surface of tissues including endothelium, epithelia and neurons, where it moderates immune activation particularly at barrier sites including lung, skin and the GI tract. Published evidence, including GWAS studies, implicates dysregulation of the CD200 axis in many allergic, autoimmune and inflammatory diseases. Furthermore, a CD200R agonist antibody has demonstrated efficacy in an early phase clinical trial of moderate to severe atopic dermatitis patients.

Methods
We have engineered high affinity soluble CD200R agonists, comprising human CD200-Fc proteins with substantially increased (up to 130-fold) monomeric binding affinity for CD200R.

Results
High affinity human CD200-Fc a) out-performs wild type in inhibiting IL-6 release from a cell line expressing high levels of human CD200R, b) has superior potency to a CD200R agonist antibody in a humanized mouse model of contact hypersensitivity, and c) substantially reduces cell infiltrate in bronchoalveolar lavage fluid in a non-human primate model of airway inflammation. A high affinity murine CD200-Fc has been engineered for additional proof-of-concept studies, and is more potent than wild type in an in vivo model (collagen-induced arthritis). Finally, we describe ARQ-234, a high affinity CD200-Fc protein with antibody-like serum half-life in NHP, due to the introduction of mutations in the Fc domain which increase relative binding to the neonatal Fc receptor at low (endosomal) pH. ARQ-234 is currently in pre-clinical development as a therapeutic for atopic dermatitis.
640 - Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis
Authors: Bunick Christopher G , Bhatia Neal , Del Rosso James , Draelos Zoe D , Eichenfield Lawrence F , Kircik Leon H , Lebwohl Mark G , Gooderham Melinda , Green Lawrence J , Hebert Adelaide A , Vender Ronald B , Zirwas Matthew , Simpson Eric L , Gold Linda Stein , Seal Melissa , Snyder Scott , Osborne David W , Burnett Patrick , Higham Robert C , Chu David H , Berk David R 
Published: August 2024

Abstract

Background
Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd∼0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances.

Objective
We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR), seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2).

Methods
Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events.

Results
As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and &lt;1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials.

Conclusions
Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas.
649 - Safety of tralokinumab for the treatment of atopic dermatitis in patients with up to 4.5 years of treatment: an updated integrated analysis of eight clinical trials
Authors: Reich Kristian , Langley Richard G , Silvestre Juan Francisco , Staumont-Salle Delphine , Costanzo Antonio , Pink Andrew , Paller Amy , Katoh Norito , Wollenberg Andreas , Warren Richard B , Øland Christian Bjerregård , Tindberg Ann-Marie , Gjerum Le , Simpson Eric 
Published: August 2024

Abstract

Introduction/Background
Clinical trials of up to 52 weeks showed that tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, was efficacious and well-tolerated as monotherapy and combination with TCS.

Objectives
Here, we evaluate the long-term safety of tralokinumab in an integrated analysis of seven phase 3 parent trials (PTs) (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, NCT04587453), and the ongoing, up to 5-year extension study (ECZTEND; NCT03587805).

Methods
Two datasets were analyzed: placebo-controlled (initial 16-week period of the PTs), and all-tralokinumab combining PTs with ECZTEND including patients from first dose until end of tralokinumab exposure or data cut-off (April 30th, 2022). In the all-tralokinumab dataset, periods on placebo were disregarded. Treatment-emergent adverse events (AEs) were recorded. AEs of special interest (AESIs) were predefined. Proportions of patients with events and incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as time until first event or exposure end, whichever came first, and incidence was defined as first event.

Results
2693 patients (≥12 years) received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks in the all-tralokinumab dataset. Median age at baseline was 33.0 years (min-max; 12-92). 10.4% of patients were 12-17 years. 2307 patients experienced an AE (IR=202.0), most (97.3%) of which were mild-to-moderate. Serious AEs (SAEs) were reported in 226 patients (IR=4.5); SAEs were considered possibly or probably related by the investigator in 50 patients (IR=0.9). No preferred term level SAEs were reported with an IR≥0.1. Discontinuation of treatment due to AEs was low (IR=2.8). AEs leading to drug withdrawal with an IR&gt;0.1 were dermatitis atopic (IR=0.5) and injection site reaction (ISR) (IR=0.2). Frequently reported AEs in the all-tralokinumab dataset were consistent with the placebo-controlled dataset, including nasopharyngitis (IR=18.4), upper respiratory tract infection (IR=6.9), conjunctivitis (IR=5.0), ISR (IR=3.6), conjunctivitis allergic (IR=2.7), and injection site pain (IR=1.5). AESIs, including eye disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies, were observed in the all-tralokinumab dataset at rates similar to or lower than the placebo-controlled dataset.

Conclusion
Long-term use of tralokinumab, for up to 4.5 years, was well-tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period with no new safety signals identified.