bluuebunny/crossref_metadata_2025_split huggingface dataset:
638 - Long-term safety and efficacy of roflumilast cream 0.15% in adults and children aged ≥6 years with mild to moderate atopic dermatitis: a 52-week, phase 3, open-label extension trial
Authors: Simpson Eric L , Eichenfield Lawrence F , Papp Kim A , Forman Seth , Hebert Adelaide A , Gonzalez Mercedes E , Gooderham Melinda , Chih-ho Hong H , Prajapati Vimal H , Guttman Emma , Silverberg Jonathan , Seal Melissa , Krupa David , Burnett Patrick , Synder Scott , Chu David H , Higham Robert C , Berk David R 
Published: August 2024

Abstract

Background
Roflumilast, a highly potent phosphodiesterase-4 inhibitor, is being investigated as a non-steroidal, once-daily cream for atopic dermatitis (AD).

Methods
INTEGUMENT-OLE (NCT04804605) was an open-label 52-week safety trial. Patients (N=658) with mild to moderate AD who completed a 4-week randomized vehicle-controlled phase 3 trial of roflumilast cream continued or switched to once-daily roflumilast cream 0.15% in this open-label extension trial. Starting at Week 4, patients achieving Validated Investigator Global Assessment for AD (vIGA-AD) score of 0 (Clear) switched to twice-weekly (BIW) maintenance dosing. The primary endpoint was safety; secondary endpoints included vIGA-AD, Worst Itch-Numeric Rating Scale (WI-NRS), and Eczema Area and Severity Index (EASI). “Disease control” was defined as duration of vIGA-AD=0/1 on BIW dosing following achievement of vIGA-AD=0.

Results
With cumulative treatment up to 56 weeks, 36.7% of patients reported treatment-emergent adverse events (AEs); most were mild to moderate in severity. Overall, 4.7% of patients had AEs deemed treatment-related and 3.0% discontinued due to AEs. The most common AEs (&gt;2%) were COVID-19, upper respiratory tract infection, nasopharyngitis, and headache. At Week 52, 55.7%, 61.1%, and 53.6% of patients achieved vIGA-AD=0/1 (Clear/Almost Clear), ≥75% reduction in EASI, and ≥4-point reduction in WI-NRS (among patients aged ≥12 years with baseline WI-NRS ≥4), respectively. Of the 130 (19.8%) patients who achieved disease control, 50% maintained “disease control” for at least 281 days.

Conclusion
Treatment with roflumilast cream 0.15% demonstrated long-term safety in patients with AD consistent with parent trials and durable efficacy through 52 weeks, including patients who switched to BIW dosing.
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

Abstract

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

Abstract

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&lt;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&lt;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

Abstract

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&lt;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&lt;0.0001) at Week 16, itch-free/nearly itch-free state (defined as PP-NRS&lt;2) was achieved in 34.6% of nemolizumab- vs 5.9% of placebo-treated patients (P&lt;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&lt;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

Abstract

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

Abstract

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 &lt; 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 &lt; 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

Abstract

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

Abstract
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

Abstract
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

Abstract
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.