bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zein nanoparticles stabilized by hydrophilic small molecule stabilizer matrine deliver curcumin effectively
Authors: Liu Hong , Wei Yongquan , Li Fu , Wang Xiang , Chen Yuxin , Huang Zenghui , Liang Pengyun , Wang Lisheng 
Published: June 2023

Abstract
Matrine (MAR), a quinolone alkaloid, was employed to augment the stability of zein nanoparticles. The incorporation of MAR into the hydrophobic shell of zein nanoparticles was primarily achieved through hydrogen bonding. Curcumin (CUR), a hydrophobic active substance, was encapsulated in the hydrophobic core of zein/matrine nanoparticles (ZMNPs). The preparation of ZMNPs and curcumin-loaded zein/matrine nanoparticles (CZMNPs) was accomplished using an antisolvent precipitation method. The encapsulation efficiency of curcumin in ZMNPs (zein/MAR = 8:1, 20 mg zein and 2.5 mg matrine) was significantly greater (52.64%) than that of nanoparticles produced from a single zein (2.50%). CZMNPs demonstrated a notable encapsulation efficiency and loading capacity (88.30% and 7.84%, respectively) upon the addition of 2 mg of curcumin, and were capable of sustained and gradual release of curcumin in simulated intestinal fluid. Furthermore, the stability of ZMNPs was observed to be favorable across a range of environmental conditions, including pH levels of 2–4 and 6–9, salt concentrations of ≤150 mM, temperatures of ≤90 °C, and storage at room temperature for a duration of 30 days. Additionally, the inherent anti-cancer properties of MAR make CZMNPs a more efficacious inhibitor of tumor cell proliferation in vitro. Moreover, the uptake of CZMNPs by A549 cells was significantly enhanced, potentially through the process of endocytosis. Therefore, the incorporation of matrine in zein-based nanoparticles confers anticancer properties to the resulting ZMNPs. These nanoparticles can serve as encapsulating agents for bioactive compounds in pharmaceutical formulations and as a novel delivery strategy for long-term cancer care. Specifically, matrine is anticipated to function as a potential stabilizer for other nanosystems.
Estimating the Effect of a Treatment When There Is Nonadherence in a Trial
Authors: Richardson David B , Dukes Oliver , Tchetgen Tchetgen Eric J 
Published: June 2023

Abstract
Randomized trials offer a powerful strategy for estimating the effect of a treatment on an outcome. However, interpretation of trial results can be complicated when study subjects do not take the treatment to which they were assigned; this is referred to as nonadherence. Prior authors have described instrumental variable approaches to analyze trial data with nonadherence; under their approaches, the initial assignment to treatment is used as an instrument. However, their approaches require the assumption that initial assignment to treatment has no direct effect on the outcome except via the actual treatment received (i.e., the exclusion restriction), which may be implausible. We propose an approach to identification of a causal effect of treatment in a trial with 1-sided nonadherence without assuming exclusion restriction. The proposed approach leverages the study subjects initially assigned to control status as an unexposed reference population; we then employ a bespoke instrumental variable analysis, where the key assumption is “partial exchangeability” of the association between a covariate and an outcome in the treatment and control arms. We provide a formal description of the conditions for identification of causal effects, illustrate the method using simulations, and provide an empirical application.
Preconception Periodontitis and Risk of Spontaneous Abortion in a Prospective Cohort Study
Authors: Bond Julia C , Wise Lauren A , Fox Matthew P , Garcia Raul I , Murray Eleanor J , White Katharine O , Rothman Kenneth J , Hatch Elizabeth E , Heaton Brenda 
Published: June 2023

Abstract
Few studies have evaluated the association between periodontitis and spontaneous abortion (SAB), and all had limitations. We used data from the Pregnancy Study Online (PRESTO), a prospective preconception cohort study of 3,444 pregnancy planners in the United States and Canada (2019–2022), to address this question. Participants provided self-reported data on periodontitis diagnosis, treatment, and symptoms of severity (i.e., loose teeth) via the enrollment questionnaire. SAB (pregnancy loss at &lt;20 weeks’ gestation) was assessed via bimonthly follow-up questionnaires. Participants contributed person-time from the date of a positive pregnancy test to the gestational week of SAB, loss to follow-up, or 20 weeks’ gestation, whichever came first. We fitted Cox regression models with weeks of gestation as the time scale to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), and we used inverse probability of treatment weighting to account for differential loss to follow-up. We used probabilistic quantitative bias analysis to estimate the magnitude and direction of the effect of exposure misclassification bias on results. In weighted multivariable models, we saw no appreciable association between preconception periodontitis diagnosis (HR = 0.97, 95% CI: 0.76, 1.23) or treatment (HR = 1.01, 95% CI: 0.79, 1.27) and SAB. A history of loose teeth was positively associated with SAB (HR = 1.38, 95% CI: 0.88, 2.14). Quantitative bias analysis indicated that our findings were biased towards the null but with considerable uncertainty in the bias-adjusted results.
Evaluating Model Specification When Using the Parametric G-Formula in the Presence of Censoring
Authors: Chiu Yu-Han , Wen Lan , McGrath Sean , Logan Roger , Dahabreh Issa J , Hernán Miguel A 
Published: June 2023

Abstract
The noniterative conditional expectation (NICE) parametric g-formula can be used to estimate the causal effect of sustained treatment strategies. In addition to identifiability conditions, the validity of the NICE parametric g-formula generally requires the correct specification of models for time-varying outcomes, treatments, and confounders at each follow-up time point. An informal approach for evaluating model specification is to compare the observed distributions of the outcome, treatments, and confounders with their parametric g-formula estimates under the “natural course.” In the presence of loss to follow-up, however, the observed and natural-course risks can differ even if the identifiability conditions of the parametric g-formula hold and there is no model misspecification. Here, we describe 2 approaches for evaluating model specification when using the parametric g-formula in the presence of censoring: 1) comparing factual risks estimated by the g-formula with nonparametric Kaplan-Meier estimates and 2) comparing natural-course risks estimated by inverse probability weighting with those estimated by the g-formula. We also describe how to correctly compute natural-course estimates of time-varying covariate means when using a computationally efficient g-formula algorithm. We evaluate the proposed methods via simulation and implement them to estimate the effects of dietary interventions in 2 cohort studies.
390 Efficacy and safety of roflumilast cream 0.15% in adults and children aged ≥6 years with mild to moderate atopic dermatitis in two phase 3 trials (INTEGUMENT-1 and INTEGUMENT-2)
Authors: Simpson Eric , Eichenfield Lawrence , Gooderham Melinda  , Gonzalez Mercedes E , Hebert Adelaide , Papp Kim , Prajapati Vimal , Krupa David , Burnett Patrick , Berk David , Higham Robert 
Published: June 2023

Abstract
Roflumilast is a selective, highly potent phosphodie­sterase 4 inhibitor under investigation as a nonsteroidal, once-daily cream for treatment of atopic dermatitis (AD). INTEGUMENT-1 (n = 654; NCT04773587) and INTEGUMENT-2 (n = 683; NCT04773600) were identical phase 3 randomized controlled trials conducted in patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of mild or moderate. Patients were randomized 2 : 1 to apply once-daily roflumilast cream 0.15% or vehicle for 4 weeks. The primary efficacy endpoint was vIGA-AD Success [defined as score of 0 (clear) or 1 (almost clear) with 2-grade improvement from baseline] at Week 4. Secondary endpoints included 75% improvement in EASI (EASI-75). At Week 4, significantly more roflumilast-treated than vehicle-treated patients achieved vIGA-AD Success (INTEGUMENT-1: 32.2% vs. 15.2%; P &lt; 0.0001; INTEGUMENT-2: 28.9% vs. 12.0%; P &lt; 0.0001) and EASI-75 (INTEGUMENT-1: 43.2% vs. 22.0%; P &lt; 0.0001; INTEGUMENT-2: 42.0% vs. 19.7%; P &lt; 0.0001). Incidence of treatment-emergent adverse events (AEs) was low in both arms, with most assessed as mild to moderate in severity. No AE occurred in more than 3.5% of patients in either arm with low rates of application site pain in both the roflumilast- and vehicle-treated patients (INTEGUMENT-1: 2.1% vs. 0.5%; INTEGUMENT-2: 0.9% vs. 0.9%). Local tolerability was favorable with &gt;90% of roflumilast-treated patients reporting no or mild sensation across arms in both trials at any timepoint. Once-daily roflumilast cream 0.15% improved AD across multiple efficacy endpoints while demonstrating favorable safety and tolerability in two phase 3 trials.
399 Pooled safety analysis of lebrikizumab in patients with uncontrolled asthma from three randomized clinical trials
Authors: Corren Jonathan , Szefler Stanley J , Armstrong April W   , Natalie Chitra R , Zitnik Ralph  , Zhao Fangyi , Siu Kimberly , Lio Peter A   , Mourey Robert J 
Published: June 2023

Abstract
LAVOLTA (L)I, LII and ACOUSTICS were randomized, placebo-controlled, double-blinded, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting interleukin-13, in patients with uncontrolled asthma (LI, NCT01867125; LII, NCT01868061; ACOUSTICS, NCT01875003). These studies failed to provide consistently significant efficacy results in uncontrolled asthma. This study aims to report pooled safety analysis of lebrikizumab in patients during the 52-week placebo-controlled period from the three clinical trials. Adults in LI and LII, adolescents (12–17 years) in ACOUSTICS, with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40–90% predicted and stable background therapy were randomized 1 : 1 : 1 to lebrikizumab 125 or 37·5 mg or placebo (PBO) subcutaneously once every 4 weeks. Safety analyses were based on all patients who received at least one dose of study drug, with patients grouped by assigned treatment. Safety was assessed using summary of adverse events (AEs). The proportions of patients who experienced treatment-emergent AEs [combined lebrikizumab doses (LEB), 1281 (77%) of 1661 patients vs. PBO, 650 (78%) of 883 patients], serious AEs (7.6% vs. 8.5%) and AEs leading to study drug discontinuation (3.4% vs. 3.6%) were similar between LEB and PBO. One death occurred in the PBO group. Similar frequencies of key safety events, including conjunctivitis (LEB, 1.6%; PBO, 1.7%), infections and infestations (LEB, 51.6%; PBO, 50.7%), and eosinophil-related disorders (LEB, 0.2%; PBO, 0.2%) were noted; higher frequency of eosinophilia (&gt;500 eosinophils/mm3) was reported (LEB, 1.1%; PBO, 0%). The safety profile was similar between lebrikizumab and placebo in adults and adolescents with uncontrolled asthma.
400 Efficacy of lebrikizumab in patients who did not achieve protocol-defined criteria for response after initial 16 weeks of therapy
Authors: Guttman-Yassky Emma , Rosmarin David , Thyssen Jacob P , Weidinger Stephan , Bieber Thomas  , Elmaraghy Hany , Atwater Amber Reck  , Pierce Evangeline , Xu Chenjia  , Gimeno Helena Agell , Simpson Eric , Mourey Robert J 
Published: June 2023

Abstract
Lebrikizumab demonstrated robust efficacy during the first 16 weeks of treatment in ADvocate1 and ADvocate2. This study aims to describe the 52-week results of lebrikizumab-treated patients who did not meet the protocol-defined criteria for response at 16 weeks of treatment. During the induction period, patients were randomized 2 : 1 to lebrikizumab 250 mg or placebo every 2 weeks (Q2W) for 16 weeks. Protocol-defined criteria for response were characterized as achieving a 75% Eczema Area and Severity Index (EASI75) or an Investigator’s Global Assessment of 0 or 1 (IGA 0,1) with a ≥2-point improvement and without rescue medication use. At Week 16, patients from the lebrikizumab treatment arm, who did not reach the criteria for response, were assigned to the Escape arm (n = 215). These patients continued to receive lebrikizumab 250 mg Q2W for an additional 36 weeks. Endpoints and measurements included at week 52 were EASI75, EASI90, IGA (0,1) and pruritus. Pruritus was assessed using an 11-point Pruritus Numeric Rating Scale (NRS). Data are presented as observed results with no imputation for missing data. Pooled results for patients who did not respond to lebrikizumab and entered the escape arm show 36.1% achieved IGA (0,1) with 2-point improvement at Week 52. In the same population, 75.5% achieved EASI75, 44.2% achieved EASI90 and 66.4% reported 4-point improvement in Pruritus NRS. These results suggest that patients, who do not achieve protocol-defined response at 16 weeks of treatment, can be slow responders and derive benefit from continuing long-term therapy with lebrikizumab.
401 Safety and efficacy of lebrikizumab in adolescent patients with moderate-to-severe atopic dermatitis: an open-label study
Authors: Paller Amy , Flohr Carsten , Eichenfield Lawrence F , Irvine Alan , Pinto-Correia Ana  , Natalie Chitra R , Pierce Evangeline  , Reifeis Sarah , Lima Renata Gontijo , Laquer Vivian , Weidinger Stephan  , Isho Nadine 
Published: June 2023

Abstract
Atopic dermatitis (AD) can greatly impact quality of life in adolescents, and improved management is needed. Lebrikizumab, a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in Phase 3 trials: ADvocate1, ADvocate2 and ADhere. This study aims to report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open label study of lebrikizumab in adolescent patients with moderate-to-severe AD. Eligible adolescents (n = 206) (≥12 to &lt;18 years; weighing ≥40 kg) received 500-mg loading doses at baseline and Week 2, and 250-mg lebrikizumab subcutaneous injections every 2-weeks (Q2W) for 52-weeks. Safety was monitored using adverse events (AEs), AEs leading to treatment discontinuation, vital signs and laboratory testing. Efficacy analyses included Investigator Global Assessment (IGA) and Eczema Area and Severity Index (EASI). A total of 172 patients completed the treatment period. Low frequencies of AEs leading to treatment discontinuation (2.4%) and SAEs (2.4%) were reported. Overall, 134 (65.0%) patients reported at least one treatment-emergent adverse event, most being mild or moderate in severity, including 14 (6.8%) conjunctivitis events. Efficacy was rapid, with 14.4% achieving IGA (0,1) at Week 4, increasing to 46.3% at Week 16 and 62.6% at Week 52. The EASI-75 was 28.6% at Week 4, 73.2% at Week 16, and 81.9% at Week 52. The mean percent improvement from baseline to Week 52 in EASI was 86.0%. Lebrikizumab open-label 250-mg Q2W had a safety profile in adolescents with moderate-to-severe AD, which was consistent with previous trials, with 2.4% treatment discontinuation due to AEs. Lebrikizumab demonstrated efficacy, with 81.9% of patients achieving EASI-75 and 62.6% achieving IGA (0,1) at Week 52.
409 Efficacy and safety of upadacitinib in adults and adolescents with moderate-to-severe atopic dermatitis: subgroup analysis of the Measure Up 1, Measure Up 2 and AD Up phase 3 clinical trials at 52 weeks
Authors: Paller Amy S , Mendes-Bastos Pedro , Eichenfield Lawrence F   , Soong Weily , Lio Peter  , Prajapati Vimal H , Platt Andrew M , Raymundo Eliza  , Liu John , Ladizinski Barry , Thyssen Jacob P 
Published: June 2023

Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous morphology and intense pruritus. Previous clinical trials have demonstrated that upadacitinib (UPA) was superior to placebo (PBO) in the treatment of moderate-to-severe AD. Here, we analyse the efficacy and safety of UPA across 52 weeks in adolescent and adult subgroups from three phase 3 studies. Patients were randomized to UPA 15 mg (UPA15), UPA 30 mg (UPA30) or PBO orally once daily, either alone or with concomitant topical corticosteroids. After 16 weeks, patients in the PBO group were randomized to the UPA15 or UPA30 groups. For both adolescent and adult subgroups at 52 weeks, the proportion of responders in the UPA15 and UPA30 groups was: ≥70% and 83% for EASI75, ≥31% and 47% for vIGA-AD 0/1 and ≥37% and 61% for Worst Pruritus Numeric Rating Scale improvement ≥4. Children’s Dermatology Life Quality Index (CDLQI) 0/1 was achieved by ≥15% (UPA15) and ≥28% (UPA30) of adolescents aged 12 to &lt;16 years; DLQI 0/1 was achieved by ≥18% (UPA15) and ≥38% (UPA30) of adolescents aged 16 to &lt;18 years and ≥30% (UPA15) and ≥45% (UPA30) of adults. Hospital Anxiety and Depression Scale (HADS-A and HADS-D) &lt;8 was achieved in ≥28% of adolescents and ≥45% of adults for both treatment groups. Rates of serious adverse events (AEs) and serious AEs leading to discontinuation at week 52 were similar for both adolescents and adults. UPA15 and UPA30 responses in moderate-to-severe AD across 52 weeks were similar between adolescents and adults, with acceptable safety outcomes in both populations.
Morphological traits explain the individual position within resource-consumer networks of a Neotropical marsupial
Authors: de Camargo Nícholas F , de Oliveira Hernani F M , Ribeiro Juliana F , de Camargo Amabílio J A , Vieira Emerson M 
Published: June 2023

Abstract
Knowledge regarding the influence of individual traits on interaction patterns in nature can help understand the topological role of individuals within a network of intrapopulation interactions. We tested hypotheses on the relationships between individuals’ positions within networks (specialization and centrality) of 4 populations of the mouse opossum Gracilinanus agilis and their traits (i.e., body length, body condition, tail length relative to body length, sex, reproductive condition, and botfly parasitism) and also seasonal effects in the Brazilian savanna. Individuals with lower body length, better body condition, and relatively shorter tail were more specialized (i.e., less connected within the network). Individuals were also more specialized and less connected during the warm-wet season. The relationship between individuals’ position in the network and body traits, however, was independent of season. We propose that specialization may arise not only as a result of preferred feeding strategies by more capable individuals (i.e., those with better body condition and potentially prone to defend and access high-quality food resources) but also because of morphological constraints. Smaller/younger individuals (consequently with less experience in foraging) and short-tailed individuals (less skilled to explore the vertical strata of the vegetation) would feed only on a subset of the available food resources and consequently become more specialized. Moreover, individuals are more specialized during the warm-wet season because of high competition (population-dense period) and higher ecological opportunities (resource-rich period). Therefore, our study reveals the relevance of individual traits in shaping interaction patterns and specialization in populations.
Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study
Authors: Sánchez-Cabo Fátima , Fuster Valentín , Silla-Castro Juan Carlos , González Gema , Lorenzo-Vivas Erika , Alvarez Rebeca , Callejas Sergio , Benguría Alberto , Gil Eduardo , Núñez Estefanía , Oliva Belén , Mendiguren José María , Cortes-Canteli Marta , Bueno Héctor , Andrés Vicente , Ordovás Jose María , Fernández-Friera Leticia , Quesada Antonio J , Garcia Jose Manuel , Rossello Xavier , Vázquez Jesús , Dopazo Ana , Fernández-Ortiz Antonio , Ibáñez Borja , Fuster Jose Javier , Lara-Pezzi Enrique 
Published: June 2023

Abstract

Aims
Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association.

Methods and results
Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration.

Conclusion
The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.
A Time of Healing: Can Social Engagement After Bereavement Reduce Trajectories of Depression After the Death of a Child?
Authors: Cha Hyungmin , Thomas Patricia A 
Published: June 2023

Abstract

Objectives
We work from a stress and life-course perspective to examine the mental health of parents who experienced the death of their child. We examine whether mental health eventually returns to pre-bereavement levels and how social engagement after bereavement may shape the recovery process of depressive symptoms.

Methods
We analyze discontinuous growth curve models to assess the association between a child’s death and trajectories of parents’ depressive symptoms from the 1998–2016 Health and Retirement Study. The sample includes 16,182 parents aged 50 years and older.

Results
Those who transitioned to bereavement experienced an elevation in depressive symptoms and a relatively long recovery time (e.g., 7 years) to their pre-bereavement mental health in our findings. However, when engaging in volunteer work after their loss, depressive symptoms reduce more quickly to their pre-bereavement levels. Volunteering offsets up to 3 years of the negative consequences of child loss.

Discussion
The death of a child is a traumatic event with extensive health consequences, but research should more fully examine the dynamic nature and potential mitigation of these health consequences over time. Our findings expand the temporal lens to encompass healing processes after bereavement, incorporating the importance of social engagement.