bluuebunny/crossref_metadata_2025_split huggingface dataset:
Site-specific cancer mortality after low-level exposure to ionizing radiation: findings from an update of the International Nuclear Workers Study (INWORKS)
Authors: Richardson David B , Laurier Dominique , Leuraud Klervi , Gillies Michael , Haylock Richard , Kelly-Reif Kaitlin , Bertke Stephen , Daniels Robert D , Thierry-Chef Isabelle , Moissonnier Monika , Kesminiene Ausrele , Schubauer-Berigan Mary K 
Published: August 2024

Abstract
A major update to the International Nuclear Workers Study was undertaken that allows us to report updated estimates of associations between radiation and site-specific solid cancer mortality. A cohort of 309 932 nuclear workers employed in France, the United Kingdom, and the United States were monitored for external radiation exposure. Associations of radiation with cancer mortality were quantified as the excess relative rate (ERR) per gray (Gy) using a maximum likelihood and a Markov chain Monte Carlo method (to stabilize estimates via a hierarchical regression). The analysis included 28 089 deaths due to solid cancer, the most common being lung, prostate, and colon cancer. Using maximum likelihood, positive estimates of ERR per Gy were obtained for stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura/mesothelioma, bone and connective tissue, skin, prostate, testis, bladder, kidney, thyroid, and residual cancers. Negative estimates of ERR per Gy were found cancers of oral cavity and pharynx, esophagus, and ovary. A hierarchical model stabilized site-specific estimates of association, including for lung (ERR per Gy = 0.65; 95% credible interval [CrI], 0.24-1.07), prostate (ERR per Gy = 0.44; 95% CrI, −0.06 to 0.91), and colon cancer (ERR per Gy = 0.53; 95% CrI, −0.07 to 1.11). The results contribute evidence regarding associations between low-dose radiation and cancer.
Nutritional convergence in plants growing on gypsum soils in two distinct climatic regions
Authors: Muller Clare T , Cera Andreu , Palacio Sara , Moore Michael J , Tejero Pablo , Mota Juan F , Drenovsky Rebecca E 
Published: August 2024

Abstract

Background and Aims
Soil endemics have long fascinated botanists owing to the insights they can provide about plant ecology and evolution. Often, these species have unique foliar nutrient composition patterns that reflect potential physiological adaptations to these harsh soil types. However, understanding global nutritional patterns to unique soil types can be complicated by the influence of recent and ancient evolutionary events. Our goal was to understand whether plant specialization to unique soils is a stronger determinant of nutrient composition of plants than climate or evolutionary constraints.

Methods
We worked on gypsum soils. We analysed whole-plant nutrient composition (leaves, stems, coarse roots and fine roots) of 36 native species of gypsophilous lineages from the Chihuahuan Desert (North America) and the Iberian Peninsula (Europe) regions, including widely distributed gypsum endemics, as specialists, and narrowly distributed endemics and non-endemics, as non-specialists. We evaluated the impact of evolutionary events and soil composition on the whole-plant composition, comparing the three categories of gypsum plants.

Key Results
Our findings reveal nutritional convergence of widely distributed gypsum endemics. These taxa displayed higher foliar sulphur and higher whole-plant magnesium than their non-endemic relatives, irrespective of geographical location or phylogenetic history. Sulphur and magnesium concentrations were mainly explained by non-phylogenetic variation among species related to gypsum specialization. Other nutrient concentrations were determined by more ancient evolutionary events. For example, Caryophyllales usually displayed high foliar calcium, whereas Poaceae did not. In contrast, plant concentrations of phosphorus were mainly explained by species-specific physiology not related to gypsum specialization or evolutionary constraints.

Conclusions
Plant specialization to a unique soil can strongly influence plant nutritional strategies, as we described for gypsophilous lineages. Taking a whole-plant perspective (all organs) within a phylogenetic framework has enabled us to gain a better understanding of plant adaptation to unique soils when studying taxa from distinct regions.
Anatomical Trajectory of the Corrugator Supercilii Muscle in Koreans: Implications for Aesthetic and Clinical Practices
Authors: Park Hyun Jin , Paulsen Friedrich , Kim Hongtae , Hur Mi-Sun 
Published: August 2024

Abstract

Background
Understanding the attachment patterns of the corrugator supercilii (CS) muscle is vital for treatments designed to improve facial symmetry and functionality.

Objectives
The aim of this research was to elucidate the anatomical trajectory and intricate relationships of the CS within the upper face and midface, specifically focusing on its connections with the frontalis (FT) and orbicularis oculi (OOc) muscles.

Methods
The CS was examined in 41 specimens of embalmed adult Korean cadavers with microdissection, histological analyses, and microcomputed tomography, performing an in-depth exploration of its anatomical positioning and the intricate interactions with adjacent muscles.

Results
Some lower fibers of the CS extended to the upper orbital part of the OOc in 59.5% of cases, while the CS interdigitated or blended exclusively with the FT in 40.5% of cases. The fibers of the CS demonstrated diverse extensions toward the upper face and midface, exhibiting varied trajectories and lengths. Additionally, lower fibers of the CS extended to significant anatomical landmarks such as the OOc, malaris muscle, and the superficial musculoaponeurotic system (SMAS).

Conclusions
In this study, we demonstrate that precise understanding of the CS and its relationship with the FT and OOc is crucial for optimizing invasive or noninvasive treatment like botulinum toxin injection, SMAS lifting, and browplasty surgery. The extension of lower fibers of the CS to significant anatomical landmarks indicates complex interactions with adjacent facial structures, highlighting the necessity of detailed anatomical knowledge for clinical applications.
Stochastic EM algorithm for partially observed stochastic epidemics with individual heterogeneity
Authors: Bu Fan , Aiello Allison E , Volfovsky Alexander , Xu Jason 
Published: August 2024

Summary
We develop a stochastic epidemic model progressing over dynamic networks, where infection rates are heterogeneous and may vary with individual-level covariates. The joint dynamics are modeled as a continuous-time Markov chain such that disease transmission is constrained by the contact network structure, and network evolution is in turn influenced by individual disease statuses. To accommodate partial epidemic observations commonly seen in real-world data, we propose a stochastic EM algorithm for inference, introducing key innovations that include efficient conditional samplers for imputing missing infection and recovery times which respect the dynamic contact network. Experiments on both synthetic and real datasets demonstrate that our inference method can accurately and efficiently recover model parameters and provide valuable insight at the presence of unobserved disease episodes in epidemic data.
603 - Ruxolitinib cream 1.5% twice daily for the treatment of extensive atopic dermatitis in children aged 2–11 years: 52 week results from a maximum-use trial
Authors: Bissonnette Robert , Lee Mark S , Forman Seth B , Gold Linda Stein , Kallender Howard , Angel Brett , Kuo Yutzu , Paller Amy S 
Published: August 2024

Abstract

Background
Eight-week safety and tolerability, efficacy, and limited systemic absorption of ruxolitinib cream 1.5% in an open-label, single-arm, maximum-use trial (MUsT) of children with moderate to severe atopic dermatitis (AD; NCT05034822) were previously described. This is the first report of longer-term data from the same study.

Objectives
Data on tolerability, safety, systemic exposure, and clinical and patient-reported outcomes are presented from the entire 52-week treatment period to assess whether clinical benefits and tolerability observed through Week 8 are sustained during the as-needed treatment long-term safety period through Week 52.

Methods
In this open-label, single-arm MUsT, patients 2-11 years old with AD ≥3 months, ≥35% affected body surface area (BSA), and Investigator’s Global Assessment (IGA) ≥3 applied twice-daily ruxolitinib cream 1.5% for 4 weeks to baseline lesions, then as-needed to active lesions for 4 weeks; patients could continue into the as-needed 44-week long-term safety period.

Results
This MUsT included 29 patients with moderate to severe AD. Treatment-emergent adverse events through Week 52 occurred in 31.0% of patients. One patient (3.4%) had 2 treatment-related application site reactions (paresthesia and folliculitis); no adverse events resulted in treatment interruption/discontinuation; none were serious or suggested systemic Janus kinase (JAK) inhibition. Through the 4-week continuous-use twice-daily treatment period, the mean (SD) application quantity was 8.5 (6.29) g/day, which was associated with a mean steady-state ruxolitinib plasma concentration of 98.2 nM, well below half-maximal concentration of JAK–mediated myelosuppression in adults (281 nM). From Week 8 to Week 52 (as-needed use), mean (SD) application quantity was 3.2 (2.79) g/day, consistent with lower, as-needed use in this long-term safety period. At Weeks 4 and 52 (assessed in n=26 and n=13 patients, respectively), 53.8%/53.8% achieved IGA–Treatment Success (IGA 0/1 with ≥2-grade improvement from baseline). Mean BSA decreased from 58.0% (range, 35.0%–92.0%) at baseline (n=29) to 11.4% at Week 4 and continued to decrease to 2.2% through Week 52 (n=26 and n=14, respectively). Patient-reported outcomes, such as the Patient-Oriented Eczema Measure, Children's Dermatology Life Quality Index, and Infants' Dermatitis Quality of Life Index, were collected through Week 52.

Conclusions
Ruxolitinib cream 1.5% demonstrated consistently good tolerability and safety over 52 weeks in children aged 2 to 11 years with extensive moderate to severe AD. Rapid lesion clearance over 4 weeks with twice-daily therapy, which was sustained with longer-term as-needed use associated with low quantities of ruxolitinib cream being applied, may address application burden concerns.
630 - Efficacy comparison of targeted systemic monotherapies including lebrikizumab for moderate-to-severe atopic dermatitis: a network meta-analysis
Authors: Silverberg Jonathan I , Bieber Thomas , Paller Amy , Beck Lisa A , Kamata Masahiro , Puig Luis , Wiseman Marni , Ezzedine Khaled , Foley Peter , Johansson Erin , Dossenbach Martin , Akmaz Bülent , Casillas Marta , Karlsson Andrei , Chovatiya Raj 
Published: August 2024

Abstract

Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 2–7% of adults globally, with 30% experiencing moderate-to-severe disease. Although several treatments for moderate-to-severe AD are available, the efficacy of many treatments has not been compared in head-to-head trials.

Objectives
Using a network meta-analysis (NMA), we evaluated the relative efficacy between lebrikizumab, an emerging biologic, and approved targeted systemic treatments for AD.

Methods
Double-blind, randomized, placebo-controlled clinical trials (systemic monotherapy-only) for moderate-to-severe AD in adults (≥18 years) and adolescents (≥12 years to ≤18 years) published before April 2023 were identified in a systematic literature review. Data were extracted for short-term (12–16 weeks) efficacy outcomes (Investigator’s Global Assessment [IGA] 0/1 with ≥2-point improvement from baseline and the Eczema Area and Severity Index [EASI]) and patient-reported outcomes (Pruritus Numeric Rating Scale [NRS] with ≥4-point improvement from baseline). Bayesian NMAs were performed using random-effects models, with baseline-risk adjustment. Key estimates from the NMAs included pairwise differences between all treatments and absolute response rates for each treatment.

Results
Twenty-two clinical trials were included. For % achieving IGA 0/1, at 12–16 weeks, the estimated response rates (posterior median and 95% credible interval) for each of the treatments were: upadacitinib 30 mg 55.8% (43.7–64.2%), upadacitinib 15 mg 41.3% (30.1–50.0%), abrocitinib 200 mg 39.0% (29.8–47.8%), dupilumab 300 mg 31.8% (23.1–38.7%), lebrikizumab 250 mg 31.4% (24.1–39.2%), abrocitinib 100 mg 24.5% (17.5–32.0%), tralokinumab 300 mg 17.3% (12.8–22.2%), baricitinib 4 mg 16.7% (9.8–25.5%), baricitinib 2 mg 15.5% (9.6–22.0%), and placebo 6.0% (4.3–7.3%). Similar trends were observed for the EASI and pruritus NRS responses at 12–16 weeks.

Conclusions
This 16-week NMA shows that lebrikizumab had a similar response rate to dupilumab, the most widely used targeted systemic therapy for AD, and may represent a valuable treatment option for moderate-to-severe AD.
634 - Patient-reported outcomes and safety in adolescent and adult atopic dermatitis patients treated with dupilumab: real-world insights one year into the GLOBOSTAD multinational prospective observational study
Authors: Murrell Dédée F , Ferrucci Silvia M , Foti Caterina , Perez-Garcia Bibiana , Lapeere Hilde , Calzavara-Pinton Piergiacomo , Fougerousse Anne-Claire , Wu Jiangming , Ardeleanu Marius , Bosman Kwinten 
Published: August 2024

Abstract

Introduction
The GLOBOSTAD study aims to capture long-term dupilumab effectiveness in real-world atopic dermatitis (AD) treatment.

Objective
To present patient-reported outcomes, that complement clinical AD assessments and guide healthcare decision-making, and a summary of adverse events one year after dupilumab initiation.

Methods
The GLOBOSTAD five-year, multinational, prospective, observational study (NCT03992417) enrolled patients aged ≥12 years with moderate-to-severe AD. Patients received dupilumab based on country-specific prescribing information. Assessments were performed at baseline, 3 months (M; ±1M), 6M (±2M), and 12M (±2M). Data are reported as observed for enrollment/safety (N = 955; data cutoff: March 2023) and follow-up (N = 903) populations.

Results
758/863/705 patients completed ≥1 follow-up assessment at 3M/6M/12M, respectively. During the study, patients reported rapid improvements in mean (SD) patient-oriented eczema measure from 19.7 (6.4) at baseline to 8.7 (6.6) at 3M to 7.1 (5.8) at end of observation period (12M); pruritus numerical rating scale from 6.3 (2.2) to 2.5 (2.4) to 1.7 (2.0); scoring of atopic dermatitis sleep loss score from 5.6 (3.0) to 1.7 (2.3) to 1.0 (1.8); dermatology life quality index (DLQI) from 13.7 (7.1) to 5.3 (5.1) to 3.9 (4.2); and children’s DLQI from 12.2 (6.2) to 2.7 (2.9) to 4.8 (4.8). Adverse events considered related to dupilumab by the investigator were reported in 187 (19.6%) patients. Adverse events leading to permanent dupilumab discontinuation were reported in 23 (2.4%) patients.

Conclusion
On initiating dupilumab treatment, patients reported rapid improvements in skin lesions, itch, sleep, and overall quality of life, from severe/very large effect scores to mild/small effect scores, which were sustained for up to one year. Safety data were consistent with previous studies.
641 - Pooled efficacy, patient-reported outcomes, and safety of roflumilast cream 0.15% from the INTEGUMENT-1 and INTEGUMENT-2 phase 3 trials of adults and children with atopic dermatitis
Authors: Simpson Eric , Boguniewicz Mark , Eichenfield Lawrence , Gonzales Mercedes E , Hebert Adelaide A , Prajapati Vimal H , Gooderham Melinda , Krupa David , Chu David H , Higham Robert C , Berk David R 
Published: August 2024

Abstract

Introduction
Roflumilast is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a nonsteroidal, once-daily cream for treatment of atopic dermatitis (AD).

Methods
We present pooled results from two identical phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600) of roflumilast cream 0.15%. Patients aged ≥6 years with mild to moderate AD were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) cream once-daily for 4 weeks. The primary endpoint was validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) Success (Clear/Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4. Patient-reported outcomes (PROs) were evaluated using the Worst Itch-Numeric Rating Scale (WI-NRS), SCORing AD (SCORAD), Patient-Oriented Eczema Measure, Dermatology Life Quality Index/Children’s Dermatology Life Quality Index, and the Dermatitis Family Impact questionnaire. Safety and tolerability were also evaluated.

Results
At Week 4, more roflumilast- than vehicle-treated patients achieved vIGA-AD Success (31.3% vs. 14.1%, P&lt;0.0001), WI-NRS Success (≥4-point improvement on WI-NRS in patients aged ≥12 years with baseline WI-NRS ≥4; 31.9% vs. 16.6%, P&lt;0.0001); and WI-NRS of 0/1 (in patients with baseline WI-NRS ≥2; 28.8% vs 18.5%, P=0.0087). At Week 4, roflumilast-treated patients improved more than vehicle-treated on the pruritus and sleep components of SCORAD (least squares mean percentage change −48.2% vs. −27.8%; [P&lt;0.0001] and −47.9% vs. −22.9% [P&lt;0.05], respectively). Differences favoring roflumilast were also seen for other secondary endpoints, including quality of life of the patient and family. Safety and local tolerability were favorable.

Conclusion
Once-daily, nonsteroidal roflumilast cream 0.15% improved PROs in patients with AD.
648 - Response to ritlecitinib with or without narrow band ultraviolet B (nbUVB) add-on therapy in patients with active non-segmental vitiligo (NSV)
Authors: Yamaguchi Yuji , Peeva Elena , Adiri Roni , Ghosh Pranab , Napatalung Lynne , Hamzavi Iltefat , Pandya Amit G , Shore Ronald N , Ezzedine Khaled , Guttman-Yassky Emma 
Published: August 2024

Abstract

Introduction/Background
Ritlecitinib, a JAK3/TEC family kinase inhibitor, demonstrated efficacy in a Phase 2b trial of patients with NSV.

Objectives
To evaluate the efficacy and tolerability of ritlecitinib with or without nbUVB add-on therapy in patients with NSV.

Methods
In a Phase 2b trial, following a 24-week placebo-controlled dose-ranging period, patients with NSV received ritlecitinib 200 mg for 4 weeks then 50 mg for 20 weeks, with or without nbUVB phototherapy 2x/week. Missing data were handled using observed case (OC) and last observation carried forward (LOCF).

Results
43 and 187 patients received ritlecitinib+nbUVB and ritlecitinib-monotherapy, respectively. Nine patients receiving ritlecitinib+nbUVB discontinued due to nbUVB group-specific efficacy criteria requiring &gt;10% improvement in %change from baseline (CFB) in Total-Vitiligo Area Scoring Index (T-VASI) at Week 12. At Week 24, mean (90% CI) %CFB in Facial-VASI (F-VASI) was -69.6 (-79.1, -60.1) vs -55.1 (-59.4, -50.7) (OC; P=0.009) and -57.0 (-65.3, -48.7) vs -51.5 (-55.9, -47.1) (LOCF; P=0.158), for ritlecitinib+nbUVB vs ritlecitinib-monotherapy, respectively. 60.9% (43.1%, 77.2%) vs 29.2% (22.8%, 35.9%) (OC; P=0.007) and 44.4% (30.2%, 59.1%) vs 27.4% (21.7%, 33.4%) (LOCF; P=0.081) of patients, respectively, achieved ≥75% improvement in F-VASI. Mean (90% CI) %CFB in T-VASI at Week 24 was -46.8 (-54.5, -39.2) vs -24.5 (-28.1, -21.0) (OC; P&lt;0.001) and -29.4 (-36.5, -22.2) vs -21.2 (-25.0, -17.4) (LOCF; P=0.043) for ritlecitinib+nbUVB vs ritlecitinib-monotherapy, respectively. 50.0% (33.3%, 66.7%) vs 15.2% (11.1%, 20.3%) (OC; P&lt;0.001) and 32.6% (22.1%, 44.7%) vs 14.4% (10.6%, 19.0%) (LOCF, P=0.014) of patients, respectively, achieved ≥50% improvement in T-VASI. nbUVB addition to ritlecitinib was well-tolerated with no new safety signals.

Conclusions
Ritlecitinib alone and with nbUVB therapy improved facial and total body repigmentation and was well-tolerated. nbUVB may improve ritlecitinib efficacy.
650 - Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis
Authors: Blauvelt Andrew , Chih-ho Hong H , Peris Ketty , Katoh Norito , Tauber Marie , Ameen Mahreen , Gooderham Melinda , Øland Christian Bjerregård , Tindberg Ann-Marie , Gjerum Le , Reich Kristian 
Published: August 2024

Abstract

Introduction/Background
To ensure minimal residual disease and to prevent relapses, recently published consensus reports have defined optimal long-term treatment targets for atopic dermatitis (AD).1,2 Tralokinumab, a monoclonal antibody specifically neutralizing interleukin-13, is approved for the treatment of moderate-to-severe AD. ECZTEND (NCT03587805) is an ongoing open-label, 5-year extension trial investigating the long-term safety and efficacy of tralokinumab 300 mg every other week (Q2W) plus optional topical corticosteroids (TCS).

Objectives
To determine the proportion of patients treated for up to 4 years with tralokinumab in AD clinical trials who: 1) exhibit stable improvement, with no or minimal fluctuations, in lesion extent and severity long-term (ie, response in ≥80% of attended visits), and 2) exhibit a stable long-term composite response (ie, up to 4 years of tralokinumab treatment and response in ≥80% of attended trial visits) in signs and symptoms of AD, and quality of life based on recent treat-to-target recommendations (EASI ≤7 and either DLQI ≤5 or Itch NRS ≤4).

Methods
This post hoc analysis included 347 patients who were continuously treated with tralokinumab for 52 weeks in the identically designed phase 3 monotherapy trials ECZTRA 1&2 and subsequently for up to 152 weeks in ECZTEND as of the April 30, 2022 data cutoff. Stability of long-term response, with no or minimal fluctuations, was defined as meeting the target endpoints at ≥80% of attended visits between Weeks 16-152 in ECZTEND. Endpoints analyzed were EASI ≤7, EASI ≤2, and a composite long-term treatment target: EASI ≤7 and either DLQI ≤5 or worst weekly pruritus NRS ≤4.

Results
A stable EASI ≤7 response (at ≥80% of attended visits) was observed in 70.2% (233/332) of tralokinumab-treated patients over Weeks 16-152 of ECZTEND. A stable EASI ≤2 response was observed in 34.0% (113/332) of patients, and a long-term optimal composite target, EASI ≤7 and either DLQI ≤5 or Itch NRS ≤4, was observed in 60.5% (201/332) of patients.

Conclusions
High proportions of clinical trial patients maintained stable responses, with no or minimal fluctuations in efficacy, with continued tralokinumab 300 mg Q2W plus optional TCS for up to 4 years of treatment.