bluuebunny/crossref_metadata_2025_split huggingface dataset:
701 - Dupilumab efficacy and safety up to 2 years in children aged 6 months to 5 years with atopic dermatitis
Authors: Paller Amy S , Simpson Eric L , Siegfried Elaine C , Cork Michael J , Arkwright Peter D , Pinter Andreas , Dubost-Brama Ariane , Laws Elizabeth , Chen Zhen , Bansal Ashish , Prescilla Randy , Nguyen Tien V 
Published: August 2024

Abstract

Introduction/Background
While previous studies into continuous long-term dupilumab treatment for adults with moderate-to-severe atopic dermatitis (AD) demonstrated sustained efficacy, further study into long-term safety and efficacy data regarding dupilumab in children is needed.

Objectives
To evaluate the impact of treatment with dupilumab and low-potency topical corticosteroids (TCS) for up to 2 years on efficacy and safety measures in children aged 6 months to 5 years with moderate-to-severe AD.

Methods
Children aged 6 months to 5 years with moderate-to-severe AD, who had participated in prior dupilumab pediatric AD studies were enrolled in a phase 3 open label extension (OLE) study. Patients received subcutaneous dupilumab every 4 weeks; 200 mg for children weighing 5 to &lt;15 kg, 300mg for 15 to &lt;30 kg. Topical AD treatments were allowed. Efficacy outcomes assessed include the proportion of patients who achieved 75% improvement from baseline in Eczema Area and Severity Index (EASI-75) score and the proportion of patients who achieved an Investigator Global Assessment (IGA) score of 0/1 as observed from OLE baseline to 2 years. Safety was also evaluated.

Results
A total of 180 patients were included in the 6 month to 5 years cohort; mean (±SD) age at OLE baseline was 3.9 (1.3) years with mean (SD) duration of AD of 3.5 (1.3) years. At OLE baseline, 29.4% of patients achieved EASI-75, improving to 85.1% at 52 weeks and 92.1% at 104 weeks. Similarly, 12.8% of patients achieved IGA 0/1 at OLE baseline, improving to 36.0% at Week 52 and 40.6% at Week 104. Total treatment-emergent adverse events (TEAEs) were observed in 87.8% of patients (intensity: mild 24.4%, moderate 52.2%, severe 11.1%). TEAEs assessed as related to dupilumab by the study investigators were reported in 18.3% of patients; the most prevalent were conjunctivitis (2.8%), allergic conjunctivitis (1.7%), nasopharyngitis (1.7%) and urticaria (1.7%). Serious TEAEs assessed as related to dupilumab by the study investigators were observed in 0.6% of patients.

Conclusions
Treatment with dupilumab for up to 2 years in young children with moderate-to-severe AD demonstrated efficacy outcomes, with sustained improvement in clinical signs reported in a large proportion of patients. Results are consistent with the known safety profile for dupilumab.
711 - Prolonged half-life and sustained inhibition of key inflammatory biomarkers: a phase 1 study of APG777, a high-affinity humanized IgG1 monoclonal antibody targeting IL-13
Authors: Lim Xiu Qin , Winter Erica , Nograles Kristine , Thankamony Sai , Dillinger Lukas , Dambkowski Carl 
Published: August 2024

Abstract

Introduction
APG777 is a high-affinity humanized anti-IL-13 IgG1 monoclonal antibody (mAb) that blocks formation of the IL-13/IL-13Rα1/IL-4Rα complex, preventing receptor heterodimerization and downstream signaling. APG777 contains a triple amino acid modification, YTE, in the Fc region that extends half-life (t1/2) by increasing binding to neonatal Fc receptor.

Objectives
This is a report of initial results of the first study of APG777 in humans, including safety, pharmacokinetics (PK), and pharmacodynamics (PD).

Methods
This first-in-human, randomized, double-blind, placebo (PBO)-controlled trial evaluated safety, tolerability, PK, and PD of APG777 in healthy participants. The study was conducted in Australia and consisted of single ascending dose (SAD) and multiple dose (MD) cohorts. Participants received single subcutaneous (SC) doses up to 1200 mg in the SAD and repeat doses of 300 mg SC in the MD. Each cohort consisted of 8 participants randomized 6:2 to APG777 or PBO. Safety assessments were conducted throughout the study and blood draws for PK and PD were obtained at multiple timepoints.

Results
Forty participants were enrolled. To date, adverse events (AEs) were mild and generally unrelated to study drug. There were no serious AEs or dose-dependent trends. APG777 pharmacokinetics were dose proportional, with t1/2 of approximately 75 days. Single doses of APG777 resulted in sustained inhibition of pSTAT6 and TARC for 12 weeks, the longest available follow-up.

Conclusions
APG777 was well-tolerated at doses up to 1200 mg, similar to other IL-13-targeted mAbs. The t1/2 of APG777, due to its YTE modification, is approximately 3 times longer than currently available mAbs and PD assessments confirm sustained inhibition of key biomarkers of atopic dermatitis. The favorable safety profile and optimized PK of APG777 support the initiation of a phase 2 study in adults with moderate-to-severe atopic dermatitis where every 3- to 6-month maintenance dosing will be evaluated.
728 - Evaluation of risk factors for dupilumab-associated ocular sequelae in the treatment of atopic dermatitis
Authors: Reddy Varsha , Lum Alexa , Kitsios Katerina , Shil Swarna , Nattis Alanna 
Published: August 2024

Abstract

Background
Dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signaling. It is used in the treatment of moderate-to-severe atopic dermatitis in those 6 months or older who are uncontrolled on or cannot tolerate topical treatments. Ocular surface disease is a recognized adverse effect of dupilumab use that has been highlighted in previous studies. Few studies describe the risk factors for developing such ocular adverse effects.

Objectives
This study aims to highlight the risk factors associated with the development of dupilumab-associated ocular surface disease (DAOSD) described in the literature.

Methods
The PubMed and ScienceDirect databases were searched in April 2024 using key search terms including “dupilumab”, “demographics”, “risk factors”, “ocular”, “keratitis”, “conjunctivitis”, “side effects”, and “atopic dermatitis”. Nine articles were included after deduplication, title/abstract screening, full-text review, and quality appraisal. Studies were included if they were written in English and discussed risk factors for ocular side effects of dupilumab. Studies were excluded if they discussed other biologic agents or ocular conditions of other origins.

Results
Out of the nine studies analyzed, six described prior history of ocular disease as a risk factor for developing DAOSD. Severe atopic dermatitis was highlighted as a risk factor in five out of nine studies. Elevated total IgE levels and eosinophil count were described as risk factors in four out of nine studies. Three studies cited facial or eyelid eczema and two studies highlighted family history of atopy as having an association with the development of DAOSD. One study described high levels of chemokines, as well as personal history of other atopic conditions. At least one patient needing to discontinue treatment with dupilumab due to ocular side effects was mentioned in six out of nine studies. Seven out of nine studies included a recommendation for ophthalmological evaluation prior to or during treatment with dupilumab.

Conclusions
While the etiology of DAOSD is not fully understood, past studies have elucidated potential risk factors for its development. Patients being treated with dupilumab for atopic dermatitis have higher severity or refractory disease, and the discontinuation of treatment due to ocular side effects may have implications on the quality of life of these patients. Additional studies are needed to better understand the risk factors for DAOSD and prevent further complications. Limitations include small sample size and lack of control group in some studies, inclusion of studies in non-US countries, and lack of gender and racial representation in some studies.
733 - Nemolizumab elicits fast itch response in atopic dermatitis within 2 days: a post hoc analysis of ARCADIA 1 and 2 data
Authors: Silverberg Jonathan I , Stein-Gold Linda , Thaçi Diamant , Pink Andrew E , Papp Kim A , Legat Franz J , Laquer Vivian T , Cheong Soo Yeon , Ulianov Liliana , Ryzhkova Anna , Piketty Christophe 
Published: August 2024

Abstract

Background
Itch is the most burdensome symptom of atopic dermatitis (AD) that severely affects sleep and overall and quality of life.1,2 Rapid control of itch could be instrumental in minimizing disease symptoms and the associated burden for patients.3,4 Nemolizumab, an interleukin-31 (IL-31) alpha antagonist, inhibits the IL-31 pathway of itch and inflammation in AD.5

Objectives
To evaluate speed of onset of itch relief and sleep improvements with nemolizumab in moderate-to-severe AD.

Methods
ARCADIA-1 and ARCADIA-2 were two identical, randomized, double-blinded, placebo-controlled studies. Patients (≥12 years) with moderate-to-severe AD and inadequate response to topical corticosteroids (TCS) were randomized (2:1) to receive nemolizumab 30mg every 4 weeks (60mg baseline loading dose) or matching placebo, both with background TCS of low/medium potency with/without topical calcineurin inhibitors (TCI).

Results
Significant improvements in itch (least squares [LS] mean±standard error [SE] change from baseline [CFB] in Peak Pruritus Numeric Rating Scale [PP-NRS]) were noted in nemolizumab-treated vs placebo-treated patients by Day 1 in ARCADIA-1 (-0.9±0.08 vs -0.4±0.10) and ARCADIA-2 (-1.1±0.09 vs -0.4±0.12), reaching -2.4±0.08 vs -1.2±0.11 and -2.3 ±0.09 vs -0.9±0.12 respectively at Day 14 (p&lt;0.001 for all). Significantly greater proportions of nemolizumab-treated vs placebo-treated patients achieved ≥4-point improvement in PP-NRS by Day 2 in ARCADIA-1 (9.4% vs 3.4%, p&lt;0.01) and Day 1 in ARCADIA-2 (8.2% vs 1.9%, p&lt;0.001) and through Day 14 (ARCADIA-1: 22.7% vs 10.6%, p&lt;0.0001; ARCADIA-2: 23.4% vs 6.8%, p&lt;0.0001).

Conclusions
Treatment with nemolizumab plus TCS/TCI resulted in rapid, statistically and clinically significant improvements in itch in moderate-to-severe AD.
Non-contrast abbreviated MRI for the detection of hepatocellular carcinoma in patients with Liver Imaging Reporting and Data System LR-3 and LR-4 observations in MRI
Authors: Maung Soe Thiha , Tanpowpong Natthaporn , Satja Minchanat , Treeprasertsuk Sombat , Chaiteerakij Roongruedee 
Published: August 2024

Abstract

Background and aims
With ultrasound sensitivity limited in hepatocellular carcinoma (HCC) surveillance and few prospective studies on non-contrast abbreviated MRI (NC-AMRI), this study aimed to assess its diagnostic performance in detecting HCC.

Methods
This prospective study involved cirrhotic patients with contrast-enhanced MRI (CE-MRI) Liver Imaging Reporting and Data System (LI-RADS) LR-3 and LR-4 observations detected during HCC surveillance. Patients underwent average 3 complete CE-MRI rounds at 3-6 months interval, with approximately 12-month follow-up. NC-AMRI included diffusion-weighted (DWI), T2-weighted imaging (T2WI), and T1-weighted imaging (T1WI). NC-AMRI protocol images were analysed for diagnostic performance, with subgroup analyses. CE-MRI and NC-AMRI images were independently reviewed by 2 experienced radiologists, with inter-reader agreement assessed with Kappa coefficient. The reference standard was the American Association for the Study of Liver Diseases-defined presence of arterial hypervascularity and washout during the portal-venous or delayed phases on CE-MRI.

Results
In 166 CE-MRI follow-ups of 63 patients (median age: 63 years; 60.3% male, 39.7% female), 12 patients developed HCC, with average size of 19.6 mm. The NC-AMRI (DWI + T2WI + T1WI) showed 91.7% sensitivity (95%CI, 61.5-99.8) and 91.6% specificity (95%CI, 86.0-95.4), area under receiver operating characteristic 0.92 (95%CI, 0.83-1.00). Across different Body Mass Index categories, lesion size, Child-Turcotte-Pugh classes, Albumin-Bilirubin (ALBI) grades, and Model for End-Stage Liver Disease classes, sensitivity remained consistent. However, specificity differed significantly between ALBI grade 1 and 2 (86.7% vs. 98.4%, P = .010), and between viral and non-viral cirrhosis (93.8% vs. 80.8%, P = .010).

Conclusions
NC-AMRI proved clinically feasible, and exhibits high diagnostic performance in HCC detection.

Advances in knowledge
This study highlights efficacy of NC-AMRI in detecting HCC among cirrhotic patients with LR-3 and LR-4 observations, representing significant progress in HCC surveillance.
Dysfunction of the magnocellular subdivision of the visual thalamus in developmental dyslexia
Authors: Müller-Axt Christa , Kauffmann Louise , Eichner Cornelius , von Kriegstein Katharina 
Published: August 2024

Abstract
Developmental dyslexia (DD) is one of the most common learning disorders, affecting millions of children and adults worldwide. To date, scientific research has attempted to explain DD primarily based on pathophysiological alterations in the cerebral cortex. In contrast, several decades ago, pioneering research on five post-mortem human brains suggested that a core characteristic of DD might be morphological alterations in a specific subdivision of the visual thalamus—the magnocellular lateral geniculate nucleus (M-LGN). However, due to considerable technical challenges in investigating LGN subdivisions non-invasively in humans, this finding was never confirmed in vivo, and its relevance for DD pathology remained highly controversial.
Here, we leveraged recent advances in high resolution MRI at high field strength (7 T) to investigate the M-LGN in DD in vivo. Using a case-control design, we acquired data from a large sample of young adults with DD (n = 26; age 28 ± 7 years; 13 females) and matched control participants (n = 28; age 27 ± 6 years; 15 females). Each participant completed a comprehensive diagnostic behavioural test battery and participated in two MRI sessions, including three functional MRI experiments and one structural MRI acquisition. We measured blood oxygen level-dependent responses and longitudinal relaxation rates to compare both groups on LGN subdivision function and myelination. Based on previous research, we hypothesized that the M-LGN is altered in DD and that these alterations are associated with a key DD diagnostic score, i.e. rapid letter and number naming.
The results showed aberrant responses of the M-LGN in DD compared to controls, which was reflected in a different functional lateralization of this subdivision between groups. These alterations were associated with rapid letter and number naming performance, specifically in male DD. We also found lateralization differences in the longitudinal relaxation rates of the M-LGN in DD relative to controls. Conversely, the other main subdivision of the LGN, the parvocellular LGN (P-LGN), showed comparable blood oxygen level-dependent responses and longitudinal relaxation rates between groups.
The present study is the first to unequivocally show that M-LGN alterations are a hallmark of DD, affecting both the function and microstructure of this subdivision. It further provides a first functional interpretation of M-LGN alterations and a basis for a better understanding of sex-specific differences in DD with implications for prospective diagnostic and treatment strategies.
Synthesis of ɛ-NbN and δ-NbN by metathesis reaction of NaNbO3 and BN
Authors: Osaka Tenshin , Ikenobe Toshiya , Hiroi Zenji , Yamane Hisanori , Yamada Takahiro 
Published: August 2024

Abstract
δ-NbN powder with particles of ∼1 µm in size was obtained by heating a mixture of NaNbO3 and BN powders at 1373 K for 1 h, while agglomerates composed of ɛ-NbN platelet grains up to 50 µm in size were obtained by heating the mixture at the same temperature for 10 h. Metathesis reaction in which sodium borate was formed with replacement of the oxygen and nitrogen from NaNbO3 and BN occurred with the NbN formation. Wavelength-dispersive X-ray analysis showed that the molar ratios of Nb to N in the synthesized δ-NbN and ɛ-NbN were ∼1:1. Magnetic susceptibility measurements showed that the δ-NbN powder was a superconductor with a transition temperature of ∼16 K. In comparison, the ɛ-NbN agglomerates did not exhibit superconductivity above 2 K.
Single Monoclonal Antibodies Should Not Be Used for COVID-19 Therapy: A Call for Antiviral Stewardship
Authors: Casadevall Arturo , Focosi Daniele , Pirofski Liise-anne , Shoham Shmuel 
Published: August 2024

Abstract
The COVID-19 pandemic witnessed the greatest deployment of monoclonal antibody (mAb) therapies for an infectious disease, but all were defeated by SARS-CoV-2 evolution. As new mAbs are developed, the infectious disease community needs stewardship practices to reduce emergence of resistance.
Nuclear envelope lamin-related dilated cardiomyopathy: a case series including histopathology
Authors: O’Connor William , Arshia Asma , Prabakar Deipthan , Sabesan Vaishnavi , Spindel Jeffrey F 
Published: August 2024

Abstract

Background
Lamin A/C gene (LMNA) mutations cause myocardial fibrosis manifesting as arrhythmogenic, non-compaction, or dilated cardiomyopathies. Fibro-fatty replacement largely involves the conduction system and conduction disease commonly occurs prior to contractile dysfunction.

Case summary
Two young, unrelated Caucasian males, aged 34 and 25, were referred to our centre for treatment of advanced heart failure. Both patients had a family history of heart failure and sudden cardiac death among their first-degree relatives and were diagnosed with Lamin A/C mutations, but they had not been screened prior to disease onset. Although the initial phenotypes were dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy, both patients’ disease progressed rapidly to include ventricular arrhythmias, severe global left ventricular hypokinesis, and dependence on outpatient milrinone to complete activities of daily living. Both patients received heart transplantation within 2 years of initial disease onset. The surgical pathology of the explanted hearts revealed characteristic findings of fibro-fatty degeneration of the conduction system, and using light microscopy, they were found to have nuclear membrane thinning, bubbling, and convolution throughout all areas sampled.

Discussion
Lamin A/C–related cardiomyopathy is associated with sudden cardiac death early in the disease course, warranting early consideration of implantable cardioverter defibrillator implantation, and rapid progression to end-stage cardiomyopathy refractory to standard medical therapies, necessitating early referral to an advanced heart failure centre. We report a newly observed and recorded finding of morphologic nuclear alterations in late-stage disease using high-power light microscopy. These alterations underscore the pathophysiology of Lamin A/C–related cardiomyopathy and provide a basis for future research into disease-specific therapies.
Acute type B aortic dissection following transcatheter mitral valve edge-to-edge repair: a case report
Authors: Ma Guizhou , Zhou Linjie , Cai Dianyu , Wang Ying , Cai Zhixiong 
Published: August 2024

Abstract

Background
Transoesophageal echocardiography is rarely reported as a possible cause of aortic dissection during the transcatheter edge-to-edge repair procedure. Herein, we present a case of type B aortic dissection following the transcatheter mitral valve edge-to-edge repair procedure, most likely related to the transoesophageal echocardiography probe.

Case summary
A 68-year-old Chinese man complained of exertional dyspnoea lasting over 2 years and had been diagnosed with severe mitral regurgitation. He was admitted to our hospital for the treatment of severe mitral regurgitation with transcatheter edge-to-edge repair. One MitraClip XTR (Abbott Vascular) was successfully implanted under the guidance of active transoesophageal echocardiography, and the mitral regurgitation became trace. However, the patient complained of persistent back pain after the treatment, and computed tomography angiography revealed a type B aortic dissection in the descending aorta. After 2 weeks of unsuccessful conservative treatment, he successfully underwent endovascular stenting and was discharged from the hospital. The patient recovered well and remained event free during the 6-month follow-up.

Discussion
Herein, we presented a rare complication following transcatheter mitral valve edge-to-edge repair that was most likely related to the transoesophageal echocardiography probe—type B aortic dissection. We postulated that repetitive flexion of the transoesophageal echocardiography probe led to compression-induced injury to the descending aorta wall at the mid-oesophageal level, which was the most probable aetiology of type B aortic dissection. Although this complication is rare, it is potentially fatal and therefore needs attention.
Clinical and genetic associations of asymmetric apical and septal left ventricular hypertrophy
Authors: Yuan Victoria , Vukadinovic Milos , Kwan Alan C , Rader Florian , Li Debiao , Ouyang David 
Published: August 2024

Abstract

Aims
Increased left ventricular mass has been associated with adverse cardiovascular outcomes including incident cardiomyopathy and atrial fibrillation. Such associations have been studied in relation to total left ventricular hypertrophy, while the regional distribution of myocardial hypertrophy is extremely variable. The clinically significant and genetic associations of such variability require further study.

Methods and results
Here, we use deep learning–derived phenotypes of disproportionate patterns of hypertrophy, namely, apical and septal hypertrophy, to study genome-wide and clinical associations in addition to and independent from total left ventricular mass within 35 268 UK Biobank participants. Using polygenic risk score and Cox regression, we quantified the relationship between incident cardiovascular outcomes and genetically determined phenotypes in the UK Biobank. Adjusting for total left ventricular mass, apical hypertrophy is associated with elevated risk for cardiomyopathy and atrial fibrillation. Cardiomyopathy risk was increased for subjects with increased apical or septal mass, even in the absence of global hypertrophy. We identified 17 genome-wide associations for left ventricular mass, 3 unique associations with increased apical mass, and 3 additional unique associations with increased septal mass. An elevated polygenic risk score for apical mass corresponded with an increased risk of cardiomyopathy and implantable cardioverter-defibrillator implantation.

Conclusion
Apical and septal mass may be driven by genes distinct from total left ventricular mass, suggesting unique genetic profiles for patterns of hypertrophy. Focal hypertrophy confers independent and additive risk to incident cardiovascular disease. Our findings emphasize the significance of characterizing distinct subtypes of left ventricular hypertrophy. Further studies are needed in multi-ethnic cohorts.