bluuebunny/crossref_metadata_2025 huggingface dataset:
628 - Clinical measures of improvement in atopic dermatitis are correlated with reductions in relevant biomarkers in patients treated with lebrikizumab
Authors: Guttman-Yassky Emma , Okragly Angela , Sun Zhe , Nickoloff Brian J , Natalie Chitra R , Gallo Gaia , Wolf Eric , Eyerich Kilian , Aparici Monica , Benschop Robert J
Published: August 2024

Introduction

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

Objectives

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Background

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

Objective

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

Methods

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

Results

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

Conclusions

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

Introduction/Background

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

Objectives

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

Methods

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

Results

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

Conclusion

Long-term use of tralokinumab, for up to 4.5 years, was well-tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period with no new safety signals identified.
652 - Tralokinumab real-world use in adults with atopic dermatitis: baseline characteristics of the first 100 patients recruited to the TRACE study in the United States
Authors: Armstrong April W , Rubin Cory , Jarell Abel , Nguyen Tien , Bagel Jerry , Stinson John , Schneider Shannon , Anastasiadou Dimitra M , Rodriguez Adrian
Published: August 2024

Introduction/Background

Tralokinumab is a fully human, high-affinity, monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD) pathogenesis. Numerous clinical studies have established that tralokinumab is an efficacious treatment for patients with moderate-to-severe AD, along with having a favorable safety profile. However, there is a lack of evidence on tralokinumab use in routine clinical practice, where patient management may differ from that defined by clinical trial protocols.

Objectives

TRACE is a global, real-world study that aims to better understand the effectiveness, safety, and clinical use of tralokinumab in patients with AD in daily practice.

Methods

TRACE is a global, observational, prospective, single-cohort study of tralokinumab-treated adults with moderate-to-severe AD. Overall, 11 countries across Europe, North America and the Middle East are participating. The primary objective of TRACE is to assess changes in clinical signs and symptoms of AD in patients treated with tralokinumab according to the nationally approved labels. Secondary objectives include safety, quality of life, patient-reported outcomes and treatment adherence. For this interim analysis, the objective was to report the baseline characteristics of the first 100 US patients.

Results

Overall, 55% of the first 100 US patients initiated on tralokinumab in the TRACE study were female; the majority (54%) were White, followed by 18% Black or African American and 12% Asian. Mean (standard deviation [SD]) age was 46.4 years (18.2) and body mass index was 28.6 kg/m2 (7.7). Patients had a mean disease duration of 13.9 years (SD 16.5), with 46% being biologic-naïve and 54% biologic-experienced. Most patients (88%) had moderate-to-severe AD, with a mean Investigator’s Global Assessment score of 3.2 (SD 0.8); mean Eczema Area and Severity Index was 15.4 (SD 7.9). A heavy symptomatic burden of disease was evident, with a mean eczema-related sleep numerical rating scale (NRS) of 4.2 (SD 3.3) and mean worst daily pruritus NRS of 6.1 (SD 2.6). Patients also reported a substantial impact of AD on quality of life; mean Dermatology Life Quality Index was 13.2 (SD 8.5). Almost one quarter (24%) of patients reported ≥1 atopic comorbidity, with asthma (12%), cardiovascular disease (8%) and autoimmune disease (6%) being the most frequent; 3% of patients had psychiatric illness.

Conclusions

Initial findings showed that tralokinumab is being prescribed as a first-line biologic treatment option in the US in accordance with the label. Treated patients had a heavy burden of disease with considerable impact on quality of life.
655 - Long-term safety and efficacy of delgocitinib cream for up to 36 weeks in adults with chronic hand eczema: results of the phase 3 open-label extension DELTA-3 trial
Authors: Gooderham Melinda , Molin Sonja , Bissonnette Robert , Worm Margitta , Crépy Marie-Noëlle , Stingeni Luca , Warren Richard B , Schliemann Sibylle , Balita-Crisostomo Cherry Lou , Oesterdal Marie Louise , Agner Tove
Published: August 2024

Introduction/Background

In patients with moderate to severe Chronic Hand Eczema (CHE), delgocitinib cream, a topical pan-Janus kinase inhibitor, was well tolerated and demonstrated significant improvement in all efficacy endpoints in DELTA-1 and -2.

Objectives

The objectives of this study were to evaluate the long-term safety and efficacy of twice-daily applications of delgocitinib cream 20 mg/g as needed for up to 36 weeks in adults with CHE in the Phase 3 open-label DELTA-3 trial (NCT04949841), an extension trial of the 16-week DELTA-1 (NCT04871711) and DELTA-2 (NCT04872101) trials.

Methods

In DELTA-3, subjects who completed the 16-week (W) treatment period in DELTA-1 and DELTA-2 were treated on an as-needed basis with twice-daily delgocitinib cream 20 mg/g for 36 weeks (n=801). Subjects with Investigator's Global Assessment for CHE (IGA-CHE) ≥2 received delgocitinib cream until symptoms resolved (i.e., IGA-CHE 0/1 [clear/almost clear]). Primary endpoint was number of treatment-emergent adverse events (TEAEs). Key secondary endpoints were IGA-CHE 0/1 and ≥75%/≥90% improvement in Hand Eczema Severity Index (HECSI-75/90) scores; Hand Eczema Symptom eDiary captured patient-reported worst severity of itch/pain over the past 24 hours.

Results

No safety concerns were identified during delgocitinib cream treatment in DELTA-1 (n=325; R=305.4; PYO=100.9), DELTA-2 (n=313; R=280.6; PYO=95.9) and DELTA-3 (n=801; R=231.1; PYO=535.7). In DELTA-3, the most frequent TEAEs were COVID-19 and nasopharyngitis. In DELTA-3, IGA-CHE 0/1, HECSI-75, HECSI-90 and ≥4-point itch/pain reduction were maintained from baseline (24.6%, 51.8%, 31.8%, and 50.6%/51.9%, respectively) to W36 (30.0%, 58.6%, 36.6%, and 52.4%/55.4%, respectively) among delgocitinib cream-treated subjects in the parent trials. Among those treated with cream vehicle in parent trials, response rates improved from baseline (9.1%, 23.7%, 12.0%, and 26.3%/32.3%, respectively) to W36 (29.5%, 51.5%, 35.7%, and 41.3%/43.3%, respectively).

Conclusions

Overall, with delgocitinib cream 20 mg/g treatment no safety concerns were identified and efficacy further improved, supporting the benefit of long-term as-needed use of delgocitinib cream in patients with moderate to severe CHE.
679 - Rocatinlimab significantly improves clinical responses in patients with moderate-to-severe atopic dermatitis by week 2 in a randomized double-blind placebo-controlled phase 2b study
Authors: Guttman-Yassky Emma , Esfandiari Ehsanollah , Mano Hirotaka , Arai Takahiro , Kabashima Kenji
Published: August 2024

Introduction/Background

Moderate-to-severe atopic dermatitis (msAD) can cause chronic cycles of pruritus and scratching, impacting quality of life.

Objectives

To evaluate rocatinlimab for the treatment of msAD To investigate the onset of action of rocatinlimab on pruritis Numerical Rating scale (pNRS) and Eczema Area and Severity Index (EASI) in adults with msAD

Methods

A multicenter, randomized, double-blind, placebo-controlled Phase 2b trial (NCT03703102) evaluated rocatinlimab (anti-OX40 monoclonal antibody) for msAD. Primary endpoint achievement (Percent change from baseline to week 16 in EASI) has been presented. Randomized patients (1:1:1:1:1) received subcutaneous rocatinlimab 150mg/600mg every 4 weeks (Q4W) or 300mg/600mg every 2 weeks (Q2W) for 36 weeks, or placebo (Weeks 0–18) followed by rocatinlimab (600mg Q2W Weeks 18–36). All cohorts had 20-week off-treatment follow-up.

Results

Clinical response onset with rocatinlimab was evaluated post-hoc (N=267; rocatinlimab: n=210; placebo: n=57) by investigating pNRS and EASI between baseline and Week 16. Difference in least squares mean of percent change from baseline between rocatinlimab cohorts and placebo were assessed. Pruritus was significantly improved with rocatinlimab by Week 2 in all cohorts (−18.40% to −21.96%; p≤0.018) except 600mg Q4W (−9.66%; p=0.208), and in all cohorts by Week 4 (−15.70% to −27.19%; p≤0.045); EASI improvements were significant in all rocatinlimab cohorts by Week 6 (−20.50% to −32.13%; p≤0.001) compared with placebo, and the 300mg and 600mg Q2W cohorts by Week 2 (−13.27% and −13.66%; p≤0.028). Further improvements with rocatinlimab continued to Week 16 compared with placebo; improvements from baseline continued in all active cohorts to Week 36 and were maintained for 20 weeks off-treatment, suggesting rocatinlimab may have potential for disease modification in adults with msAD.

Conclusion

Rocatinlimab improved pNRS and EASI by Week 2; improvements continued and were maintained off-treatment until the end of study.
722 - Efficacy of povorcitinib for the treatment of vitiligo by patient demographics and baseline clinical characteristics: week 52 subgroup analysis from a randomized, placebo-controlled, phase 2b clinical trial
Authors: Pandya Amit G , Passeron Thierry , Blauvelt Andrew , van Geel Nanja , Brown Kurt , Erskine Lois , Xue Zhenyi , Ezzedine Khaled
Published: August 2024

Introduction/Background

Povorcitinib—an oral, small-molecule, selective Janus kinase 1 inhibitor—was statistically superior to placebo at Week 24 in patients with nonsegmental vitiligo in a phase 2b clinical trial (NCT04818346).

Objectives

To evaluate the efficacy of povorcitinib in subgroups of patients with nonsegmental vitiligo defined by demographics and baseline clinical characteristics.

Methods

Adults with nonsegmental vitiligo affecting ≥0.5%/≥8% facial/total body surface area (F-BSA/T-BSA) were randomized 1:1:1:1 to once-daily povorcitinib 15/45/75 mg or placebo for 24 weeks; subsequently, patients received povorcitinib 45/75 mg for an additional 28 weeks. The percentage of patients achieving ≥50% reduction from baseline in total Vitiligo Area Scoring Index (T-VASI50) and ≥50% and ≥75% reduction in facial-VASI (F-VASI50 and F-VASI75, respectively) were assessed by demographics and baseline characteristics. Data were analyzed using descriptive statistics; missing values were considered nonresponders.

Results

In total, 171 patients were randomized; at baseline, median (range) age was 50 (23–74) years, mean (SD) disease duration was 19.4 (14.0) years, and mean (SD) T-VASI was 25.5 (19.1). Subgroup analyses were conducted among the 103 patients who received any dose of povorcitinib from Day 1. At Week 52, 35/103 (34.0%) evaluable patients who received povorcitinib 15/45/75 mg achieved T-VASI50, 63/103 (61.2%) achieved F-VASI50, and 47/103 (45.6%) achieved F-VASI75. T-VASI50 responses were consistent within subgroups defined by age (≤40/>40 years, 42.9%/30.7%), sex (male/female, 23.8%/41.0%), race (White/Non-White, 31.6%/41.7%), Fitzpatrick skin type (I–III/IV–VI, 31.4%/39.4%), F-BSA (≤1.5%/>1.5%, 30.4%/41.2%), T-BSA (≤20%/>20%, 35.4%/32.7%), autoimmune comorbidities (Yes/No, 37.9%/32.4%), disease duration (≤10/10–20/>20 years, 41.7%/13.0%/38.6%), and previous therapy (Yes/No, 34.4%/30.0%). Similar findings were observed for F-VASI50 and F-VASI75.

Conclusions

Patients receiving povorcitinib achieved T-VASI50, F-VASI50, and F-VASI75 responses regardless of demographics or baseline clinical characteristics. Results should be confirmed in larger populations.
725 - The TCS/TCI-free rate remains high and stable while on lebrikizumab for treatment of moderate-to-severe atopic dermatitis over 1 year
Authors: Del Rosso James , Nosbaum Audrey , Golant Alexandra , Nakahara Takeshi , Murase Jenny E , Pink Andrew , Montmayeur Sonia , Qiao Meihua , Chen Sherry , Pau-Charles Ignasi , Bieber Thomas
Published: August 2024

Background

The ADvocate1 and ADvocate2 phase 3 trials investigated lebrikizumab (LEB), a monoclonal antibody selectively targeting interleukin-13, for the treatment of patients with moderate-to-severe atopic dermatitis (AD). Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) are commonly used as concomitant treatment for AD. However, long term use can result in side effects. Thus, remaining free of TCS/TCI usage is important for evaluating the benefit of systemic AD therapies.

Objectives

To summarize and assess the proportion of patients without TCS or TCI usage over the course of the maintenance period based on pooled ADvocate1 and ADvocate2 studies.

Methods

This study consisted of pooled ADvocate1 and ADvocate2 data for patients responding to LEB at week 16 (induction period). Responders (N = 291) were re-randomized in a 2:2:1 ratio to receive 250 mg LEB every 2 weeks (Q2W; N = 113), 250 mg LEB every 4 weeks (Q4W; N = 118), or placebo every 2 weeks (LEB withdrawal/PBO; N = 60) for 36 weeks (maintenance period). Lack of TCS/TCI use was interpreted as an advantageous outcome of LEB treatment. Data are presented as observed data.

Results

Across the maintenance period, high proportions of patients in all groups (Q2W – 90.3%; Q4W – 88.1%; PBO – 86.7%) did not use TCS. Higher proportions (Q2W – 96.5%; Q4W – 98.3%; PBO – 95%) did not use TCI. Importantly, 88.5% of Q2W, 86.4% of Q4W, and 81.7% of PBO, did not use either TCS or TCI. This high TCS/TCI free rate remained stable over the course of the maintenance period.

Conclusions

Most patients with moderate-to-severe AD responding to LEB remained free of TCS, TCI, and TCS/TCI use throughout the first year of treatment.
Total mesorectal excision quality in rectal cancer surgery affects local recurrence rate but not distant recurrence and survival: population-based cohort study
Authors: Collin Åsa , Dahlbäck Cecilia , Folkesson Joakim , Buchwald Pamela
Published: August 2024

Background

The quality of the total mesorectal excision specimen in rectal cancer surgery is assessed with a three-tier grade (mesorectal, intramesorectal and muscularis propria). This study aimed to analyse the prognostic impact of the total mesorectal excision grade on survival, and to identify risk factors for intramesorectal and muscularis propria resection in a population-based setting.

Methods

All patients in the Swedish Colorectal Cancer Registry with rectal cancer stage I–III ≤ 10 cm from the anal verge, diagnosed 2015–2019, undergoing total mesorectal excision were analysed. Clinical, surgical and pathological data were retrieved and analysed for the following primary outcomes: local and distant recurrence and overall and relative survival; secondary outcomes were risk factors for total mesorectal excision grading (intramesorectal or muscularis propria resection). Of note, postoperative death < 30 days or recurrence within 90 days were exclusion criteria for survival and recurrence analysis. Recurrence-free patients with less than 3 years follow-up, and patients lacking data regarding recurrence, were also excluded from recurrence analyses.

Results

Overall, of 7979 patients treated during the study interval, 1499 patients were eligible for recurrence, 2441 patients for survival and 2476 patients for risk-factor analyses, of which 75% were graded mesorectal, 17% intramesorectal and 8% muscularis propria. Median follow-up for survival was 42 (1–77) months. The worst total mesorectal excision grading (muscularis propria resection) was an independent risk factor for local recurrence in multivariable analysis (HR 2.73, 95% c.i. 1.07 to 7.0, P = 0.036). Total mesorectal excision grade had no impact on distant recurrence or survival. Female sex, tumour level <5 cm, abdominoperineal resection, minimally invasive surgery (laparoscopic and robotic), high blood loss, long duration of surgery and intraoperative perforation were independent risk factors for worse total mesorectal excision grading (intramesorectal and/or muscularis propria resection) in multivariable analyses.

Conclusion

Muscularis propria resection increases the risk of local recurrence but does not seem to affect distant recurrence or survival.
Examining cognition and brain networks using magnetoencephalography in paediatric autoimmune encephalitis and acute disseminated encephalomyelitis: a preliminary study
Authors: Billaud Charly H A , Wood Amanda G , Griffiths-King Daniel , Kessler Klaus , Wassmer Evangeline , Foley Elaine , Wright Sukhvir K
Published: August 2024

Paediatric autoimmune encephalitis, including acute disseminated encephalomyelitis, are inflammatory brain diseases presenting with cognitive deficits, psychiatric symptoms, seizures, MRI and EEG abnormalities. Despite improvements in disease recognition and early immunotherapy, long-term outcomes in paediatric autoimmune encephalitis remain poor. Our aim was to understand functional connectivity changes that could be associated with negative developmental outcomes across different types of paediatric autoimmune encephalitis using magnetoencephalography. Participants were children diagnosed with paediatric autoimmune encephalitis at least 18 months before testing and typically developing children. All completed magnetoencephalography recording at rest, T1 MRI scans and neuropsychology testing. Brain connectivity (specifically in delta and theta) was estimated with amplitude envelope correlation, and network efficiency was measured using graph measures (global efficiency, local efficiency and modularity). Twelve children with paediatric autoimmune encephalitis (11.2 ± 3.5 years, interquartile range 9 years; 5M:7F) and 12 typically developing controls (10.6 ± 3.2 years, interquartile range 7 years; 8M:4F) participated. Children with paediatric autoimmune encephalitis did not differ from controls in working memory (t(21) = 1.449; P = 0.162; d = 0.605) but had significantly lower processing speed (t(21) = 2.463; P = 0.023; Cohen’s d = 1.028). Groups did not differ in theta network topology measures. The paediatric autoimmune encephalitis group had a significantly lower delta local efficiency across all thresholds tested (d = −1.60 at network threshold 14%). Theta modularity was associated with lower working memory (β = −0.781; t(8) = −2.588, P = 0.032); this effect did not survive correction for multiple comparisons (P(corr) = 0.224). Magnetoencephalography was able to capture specific network alterations in paediatric autoimmune encephalitis patients. This preliminary study demonstrates that magnetoencephalography is an appropriate tool for assessing children with paediatric autoimmune encephalitis and could be associated with cognitive outcomes.
Interaction of the dorsolateral prefrontal cortex with the precuneal medial parietal cortex for the monitoring of information in working memory in the macaque monkey
Authors: Petrides Michael , Lefebvre Sarah , Novek Jennifer , Zlatkina Veronika
Published: August 2024

The executive control process of monitoring information in working memory depends on the mid-dorsolateral prefrontal cortical region (cytoarchitectonic areas 46 and 9/46) in interaction with the hippocampal memory system. Anatomical studies demonstrated strong connectivity between the mid-dorsolateral prefrontal cortex and the medial parietal area PGm that lies on the precuneus. Area PGm is also strongly connected with the attentional system on the lateral inferior parietal lobule (area PG) and the limbic retrosplenial/posterior cingulate region that interacts with the hippocampal memory system. Thus, in terms of anatomical connectivity, area PGm appears to be a critical node for the integration of executive control processing from the prefrontal cortex with the online attentional and memory related processing. This hypothesis was tested in macaque monkeys with the crossed unilateral lesion methodology. A unilateral lesion in the mid-dorsolateral prefrontal cortex was combined with a unilateral lesion in area PGm in the opposite hemisphere. The results demonstrated an impairment on the externally ordered working memory task that assesses the monitoring of information in working memory. Thus, the medial parietal area PGm is a critical node in mediating the functional interaction between the prefrontal region for the executive control process of monitoring information and the memory system.
Spatiotemporal whole-brain activity and functional connectivity of melodies recognition
Authors: Bonetti Leonardo , Brattico Elvira , Carlomagno Francesco , Cabral Joana , Stevner Angus , Deco Gustavo , Whybrow Peter C , Pearce Marcus , Pantazis Dimitrios , Vuust Peter , Kringelbach Morten L
Published: August 2024

Music is a non-verbal human language, built on logical, hierarchical structures, that offers excellent opportunities to explore how the brain processes complex spatiotemporal auditory sequences. Using the high temporal resolution of magnetoencephalography, we investigated the unfolding brain dynamics of 70 participants during the recognition of previously memorized musical sequences compared to novel sequences matched in terms of entropy and information content. Measures of both whole-brain activity and functional connectivity revealed a widespread brain network underlying the recognition of the memorized auditory sequences, which comprised primary auditory cortex, superior temporal gyrus, insula, frontal operculum, cingulate gyrus, orbitofrontal cortex, basal ganglia, thalamus, and hippocampus. Furthermore, while the auditory cortex responded mainly to the first tones of the sequences, the activity of higher-order brain areas such as the cingulate gyrus, frontal operculum, hippocampus, and orbitofrontal cortex largely increased over time during the recognition of the memorized versus novel musical sequences. In conclusion, using a wide range of analytical techniques spanning from decoding to functional connectivity and building on previous works, our study provided new insights into the spatiotemporal whole-brain mechanisms for conscious recognition of auditory sequences.
Goal-directed learning is multidimensional and accompanied by diverse and widespread changes in neocortical signaling
Authors: Marrero Krista , Aruljothi Krithiga , Delgadillo Christian , Kabbara Sarah , Swatch Lovleen , Zagha Edward
Published: August 2024

New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus–response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of response-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.
Precise synthesis of ligand-protected metal nanoclusters for electrochemical/photoelectrochemical applications
Authors: Kawawaki Tokuhisa , Negishi Yuichi
Published: August 2024

Ligand-protected metal nanoclusters (NCs) represent a significant advancement in the field of catalysis due to their unique size-specific electronic and geometric structures. These properties are highly dependent on the metal species, number of constituent atoms, and geometric structure of the metal NC. We discuss on the synthesis, stability, structural characterization, and electrocatalytic/photocatalytic applications of these fascinating materials, emphasizing their superior performance over conventional catalysts. In this study, we have obtained a deeper understanding of the interaction between the metal core and the organic ligands protecting the metal NCs, as well as the desorption behavior of the ligands under calcination, which is crucial for the application of metal NCs as heterogeneous catalysts. Based on this understanding, we have demonstrated that metal NC–supported catalysts with appropriate pretreatment exhibit higher activity as photocatalysts compared to conventional catalysts. Moreover, by suppressing oxygen poisoning through the use of sulfur species in the ligands, Pt NCs showed high activity as cocatalysts for photocatalytic hydrogen evolution in water splitting. Additionally, atomically precised phosphine-protected Pt NCs exhibited high activity as cathode electrocatalysts for fuel cells. These findings are expected to significantly contribute to the development of more diverse catalysts based on metal NCs, including those with varying metal species, numbers of constituent atoms, and geometric structures.
Evolution of Intangible Property to Crypto Assets: Legal Pragmatism in Anglo-American Common Law and Chinese Civil Law
Authors: Hung Alvin Hoi-Chun
Published: August 2024

The emergence of crypto assets, a novel category of assets, has posed significant challenges to property law across various legal systems. The integration of these intangible assets into property law frameworks proves to be complicated for many civil law jurisdictions, which tend to adhere to dogmatic approaches. In contrast, Anglo-American common law and Chinese civil law systems, despite their divergent origins, have exhibited legally pragmatic responses to intangible property, including crypto assets. By examining the development of their property laws concerning property conceptualization and the treatment of emerging intangible assets, this article explores how the historical foundations of Anglo-American common law in feudal tradition and Chinese civil law in communist ideologies have fostered adaptable and flexible notions of property. This adaptability is argued to be a strength within both the Anglo-American common law and Chinese civil law systems, enabling them to accommodate innovative intangible assets more easily compared to their civilian counterparts.
The impact of management on the fecal microbiome of endangered greater sage-grouse (Centrocercus urophasianus) in a zoo-based conservation program
Authors: Vaasjo Emma , Stothart Mason R , Black Sandra R , Poissant Jocelyn , Whiteside Douglas P
Published: August 2024

Greater sage-grouse (Centrocercus urophasianus) are a critically endangered species in Canada with fewer than 140 individuals remaining on native habitats in southern Alberta and Saskatchewan. In 2014, the Wilder Institute/Calgary Zoo initiated North America’s only zoo-based conservation breeding program for this species to bolster declining wild populations through conservation reintroductions. Within the managed population of sage-grouse, morbidity and mortality have primarily been associated with intestinal bacterial infections. As a preliminary study to assess the gastrointestinal health of this species in managed care, the fecal bacterial microbiome of adult and juvenile captive sage-grouse was characterized with 16S rRNA sequencing. The composition of the microbiome at the phylum level in greater sage-grouse is consistent with previous studies of the avian microbiome, with Bacillota as the most abundant phyla, and Actinomycetota, Bacteroidota and Pseudomonadota also being highly abundant. Antibiotic use and sex did not have a significant impact on the diversity or composition of the microbiome, but the management of juvenile sage-grouse did influence the development of the microbiome. Juveniles that were raised outdoors under maternal care developed a microbiome much more similar to adults when compared to chicks that were incubated and hand-raised. The local environment and parental care appear to be important factors influencing the diversity and composition of the gastrointestinal microbiome in this species.
Type A aortic dissection during transoesophageal echocardiography: a case report
Authors: Lee Chung-Yen , Chiang Kuang-Chien , Lee Wen-Jeng , Chan Chih-Yang , Yang Li-Tan
Published: August 2024

Background

The occurrence of type A aortic dissection (TAAD) during transoesophageal echocardiography (TEE) has only been reported once. We present another case of pre-procedural type B AD with retrograde TAAD or de novo TAAD during the TEE procedure.

Case summary

An 81-year-old man with a pre-existing infrarenal abdominal aortic aneurysm and highly tortuous aorta was referred to our ward for acute decompensated heart failure (ADHF) with New York Heart Association functional class II. On hospital Day 2, the patient complained of intermittent dull pain over chest and back; ADHF or acute coronary syndrome was suspected. On Day 3, we transferred the patient to the intensive care unit due to ADHF with cardiogenic shock attributed to fluid overload, atrial fibrillation with rapid ventricular response, and severe mitral regurgitation with severely impaired left ventricular ejection fraction. Given the heightened surgical risk, TEE was performed to evaluate the eligibility of mitral transcatheter edge-to-edge repair. The first mid-oesophageal long-axis view showed no evidence of dissection. After 20 min, the same view showed the occurrence of TAAD. Urgent contrast CT confirmed a TAAD extending from the aortic root to the infrarenal abdominal aorta. Due to the prohibitive risk for surgical repair of TAAD, the patient received palliative care and unfortunately passed away on hospital Day 6.

Discussion

Albeit rare, TAAD could progress or de novo occur during TEE, especially in high-risk patients. Therefore, high alertness during TEE procedures is imperative. Moreover, in patients with AD and poor renal function, the risk of using TEE as an alternative diagnostic modality should be carefully considered.
Time to reap the fruits of EU-SILC’s new way of measuring unmet needs
Authors: Ingleby David , Guidi Caterina F
Published: August 2024

A change in the methodology of the EU-SILC questionnaire on health needs, implemented from 2015 onwards, made it possible to distinguish the probability of a person saying they needed care from the probability that they received it. However, datasets taking advantage of this change were not published by Eurostat until the end of 2023 and offered only limited possibilities for disaggregation. In this article, we show how useful these results can be, despite their limitations. In order to facilitate more and better research into health inequalities in Europe, Eurostat should give priority to publishing more datasets as soon as possible.
Asymmetric mate preference and reproductive interference mediate climate-induced changes in mate availability in a small mammal hybrid zone
Authors: Matocq Marjorie D , Hunter Elizabeth A , Murphy Peter J , Adkins Casey L , Shoemaker Kevin T
Published: August 2024

Range expansion and contraction are among the most common biotic responses to changing environmental conditions, yet much is to be learned about the mechanisms that underlie range-edge population dynamics, especially when those areas are points of secondary contact between closely related species. Here, we present field-measured parentage data that document the reproductive outcomes of changes in mate availability at a secondary contact zone between two species of woodrat in the genus Neotoma. Changes in mate availability resulted from drought-driven differential survival between the species and their hybrids. As the availability of conspecific mates declined, rates of hybridization increased, leading to the accumulation of admixed individuals in the zone of contact. Patterns of reproductive success in the wild appear to be the result of a combination of both pre-mating isolation and post-zygotic selection resulting from genomic incompatibilities between the parental lineages. Evidence of asymmetric mate preference between the parental lineages came from both skewed reproductive output in the field and laboratory preference trials. Moreover, partial genomic incompatibility was evident from the near-zero reproductive success of F1 males and because nearly all surviving hybrids had one pure parent. Nonetheless, the high reproductive success of F1 females and backcrossing in both parental directions allow for introgression between the parental species. These findings reveal how climate change may alter evolutionary outcomes for species at the edge of their ranges through an interplay of behavioral, demographic, and genetic mechanisms.
Genome reduction in novel, obligately methyl-reducing Methanosarcinales isolated from arthropod guts (Methanolapillus gen. nov. and Methanimicrococcus)
Authors: Protasov Evgenii , Reeh Hanna , Liu Pengfei , Poehlein Anja , Platt Katja , Heimerl Thomas , Hervé Vincent , Daniel Rolf , Brune Andreas
Published: August 2024

Recent metagenomic studies have identified numerous lineages of hydrogen-dependent, obligately methyl-reducing methanogens. Yet, only a few representatives have been isolated in pure culture. Here, we describe six new species with this capability in the family Methanosarcinaceae (order Methanosarcinales), which makes up a substantial fraction of the methanogenic community in arthropod guts. Phylogenomic analysis placed the isolates from cockroach hindguts into the genus Methanimicrococcus (M. hacksteinii, M. hongohii, and M. stummii) and the isolates from millipede hindguts into a new genus, Methanolapillus (M. africanus, M. millepedarum, and M. ohkumae). Members of this intestinal clade, which includes also uncultured representatives from termites and vertebrates, have substantially smaller genomes (1.6–2.2 Mbp) than other Methanosarcinales. Genome reduction was accompanied by the loss of the upper part of the Wood–Ljungdahl pathway, several energy-converting membrane complexes (Fpo, Ech, and Rnf), and various biosynthetic pathways. However, genes involved in the protection against reactive oxygen species (catalase and superoxide reductase) were conserved in all genomes, including cytochrome bd (CydAB), a high-affinity terminal oxidase that may confer the capacity for microaerobic respiration. Since host-associated Methanosarcinales are nested within omnivorous lineages, we conclude that the specialization on methyl groups is an adaptation to the intestinal environment.
Cross-species transcriptomics reveals differential regulation of essential photosynthesis genes in Hirschfeldia incana
Authors: Garassino Francesco , Bengoa Luoni Sofia , Cumerlato Tommaso , Reyes Marquez Francisca , Harbinson Jeremy , Aarts Mark G M , Nijveen Harm , Smit Sandra
Published: August 2024

Photosynthesis is the only yield-related trait not yet substantially improved by plant breeding. Previously, we have established H. incana as the model plant for high photosynthetic light-use efficiency (LUE). Now we aim to unravel the genetic basis of this trait in H. incana, potentially contributing to the improvement of photosynthetic LUE in other species. Here, we compare its transcriptomic response to high light with that of Arabidopsis thaliana, Brassica rapa, and Brassica nigra, 3 fellow Brassicaceae members with lower photosynthetic LUE. We built a high-light, high-uniformity growing environment, in which the plants developed normally without signs of stress. We compared gene expression in contrasting light conditions across species, utilizing a panproteome to identify orthologous proteins. In-depth analysis of 3 key photosynthetic pathways showed a general trend of lower gene expression under high-light conditions for all 4 species. However, several photosynthesis-related genes in H. incana break this trend. We observed cases of constitutive higher expression (like antenna protein LHCB8), treatment-dependent differential expression (as for PSBE), and cumulative higher expression through simultaneous expression of multiple gene copies (like LHCA6). Thus, H. incana shows differential regulation of essential photosynthesis genes, with the light-harvesting complex as the first point of deviation. The effect of these expression differences on protein abundance and turnover, and ultimately the high photosynthetic LUE phenotype is relevant for further investigation. Furthermore, this transcriptomic resource of plants fully grown under, rather than briefly exposed to, a very high irradiance, will support the development of highly efficient photosynthesis in crops.
Tools and methods for cell ablation and cell inhibition in Caenorhabditis elegans
Authors: Rentsch Dennis , Bergs Amelie , Shao Jiajie , Elvers Nora , Ruse Christiane , Seidenthal Marius , Aoki Ichiro , Gottschalk Alexander
Published: August 2024

To understand the function of cells such as neurons within an organism, it can be instrumental to inhibit cellular function, or to remove the cell (type) from the organism, and thus to observe the consequences on organismic and/or circuit function and animal behavior. A range of approaches and tools were developed and used over the past few decades that act either constitutively or acutely and reversibly, in systemic or local fashion. These approaches make use of either drugs or genetically encoded tools. Also, there are acutely acting inhibitory tools that require an exogenous trigger like light. Here, we give an overview of such methods developed and used in the nematode Caenorhabditis elegans.