bluuebunny/crossref_metadata_2025 huggingface dataset:
CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors
Authors: Wang Jiawan , Calizo Ana , Zhang Lindy , Pino James C. , Lyu Yang , Pollard Kai , Zhang Xiaochun , Larsson Alex T. , Conniff Eric , Llosa Nicolas J. , Wood David K. , Largaespada David A. , Moody Susan E. , Gosline Sara J. , Hirbe Angela C. , Pratilas Christine A.
Published: November 2023

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of
PTPN11
or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.
Anthropogenic warming induced intensification of summer monsoon frontal precipitation over East Asia
Authors: Moon Suyeon , Utsumi Nobuyuki , Jeong Jee-Hoon , Yoon Jin-Ho , Wang S.-Y. Simon , Shiogama Hideo , Kim Hyungjun
Published: November 2023

Summer monsoon frontal rainfall in East Asia (EA) is crucial for water resources and flood hazards in densely populated areas. Recent studies have documented the increasing intensity of summer frontal rainfall over recent decades. However, the extent of ongoing climate change on the intensification of the EA frontal precipitation system remains uncertain. Using an objective method for detecting frontal systems, we found a 17 ± 3% increase in observed frontal rainfall intensity during 1958 to 2015. Climate model simulations with and without greenhouse gases suggest that anthropogenic warming plays a key role in the intensification of EA summer frontal precipitation by 5.8% from 1991 to 2015. The analysis highlights that enhanced water vapor convergence and reinforced western North Pacific subtropical High collectively increased moisture transport to the region, resulting in intensified EA frontal precipitation. The results lend support to the anthropogenic warming–induced enhancement of the EA frontal precipitation and its persistence in the future.
Coherent light control of a metastable hidden state
Authors: Maklar Julian , Sarkar Jit , Dong Shuo , Gerasimenko Yaroslav A. , Pincelli Tommaso , Beaulieu Samuel , Kirchmann Patrick S. , Sobota Jonathan A. , Yang Shuolong , Leuenberger Dominik , Moore Robert G. , Shen Zhi-Xun , Wolf Martin , Mihailovic Dragan , Ernstorfer Ralph , Rettig Laurenz
Published: November 2023

Metastable phases present a promising route to expand the functionality of complex materials. Of particular interest are light-induced metastable phases that are inaccessible under equilibrium conditions, as they often host new, emergent properties switchable on ultrafast timescales. However, the processes governing the trajectories to such hidden phases remain largely unexplored. Here, using time- and angle-resolved photoemission spectroscopy, we investigate the ultrafast dynamics of the formation of a hidden quantum state in the layered dichalcogenide 1
T
-TaS
2
upon photoexcitation. Our results reveal the nonthermal character of the transition governed by a collective charge-density-wave excitation. Using a double-pulse excitation of the structural mode, we show vibrational coherent control of the phase-transition efficiency. Our demonstration of exceptional control, switching speed, and stability of the hidden state are key for device applications at the nexus of electronics and photonics.
Effect of body position on ventilation distribution in healthy newborn infants: an observational study
Authors: Rahtu Marika , Frerichs Inéz , Pokka Tytti , Becher Tobias , Peltoniemi Outi , Kallio Merja
Published: November 2023

Objectives

Newborn infants have unique respiratory physiology compared with older children and adults due to their lungs’ structural and functional immaturity and highly compliant chest wall. To date, ventilation distribution has seldom been studied in this age group. This study aims to assess the effect of body position on ventilation distribution in spontaneously breathing healthy neonates.

Design

Prospective observational study.

Setting

Maternity wards of Oulu University Hospital.

Patients

20 healthy, spontaneously breathing, newborn infants.

Interventions

Electrical impedance tomography data were recorded with a 32-electrode belt (Sentec AG, Landquart, Switzerland) in six different body positions in random order. Ventilation distribution was retrospectively assessed 10 minutes after each position change.

Main outcome measures

In each position, regional tidal impedance variation (ΔZ) and ventral-to-dorsal and right-to-left centre of ventilation were measured.

Results

The mean global ΔZ was the largest in supine position and it was smaller in prone and lateral positions. Yet, global ΔZ did not differ in supine positions, ventilation distribution was more directed towards the non-dependent lung region in supine tilted position (p<0.001). In prone, a reduction of global ΔZ was observed (p<0.05) corresponding to an amount of 10% of global tidal variation in supine position. In both lateral positions, tidal ventilation was distributed more to the corresponding non-dependent lung region.

Conclusions

Prone or lateral body positioning in healthy spontaneously breathing newborns leads to a redistribution of ventilation to the non-dependent lung regions and at the same time global tidal volume is reduced as compared with supine.
Responding to the ‘crowd’ of voices and opinions in the paediatric clinical space: an ethics perspective
Authors: Delany Clare , Moore Bryanna , Bhatia Neera , Burn Elise , Wimalasundera Neil , Preisz Anne
Published: November 2023

Ready access to the internet and online sources of information about child health and disease has allowed people more ‘distant’ from a child, family and paediatric clinician to inform and influence clinical decisions. It has also allowed parents to share aspects of their child’s health and illness to garner support or funding for treatment. As a consequence, paediatric clinicians must consider and incorporate the crowd of opinions and voices into their clinical and ethical reasoning.

We identify two key ethical principles and related ethics concepts foundational to this task. We then propose a series of exploratory ethics questions to assist paediatric clinicians to engage ethically with the multiple voices in the clinical encounter while keeping the child’s needs as a central focus. Using two clinical hypothetical case examples, we illustrate how our proposed ethics questions can assist paediatric clinicians to navigate the crowd in the room and bring moral reasoning to bear.

We highlight a need for specific practical interactional skills training to assist clinicians to ethically respond to the crowd in the room, including to identify and weigh up the harms and benefits of endorsing or going against proposed treatments for a child, and how to discuss social media and online sources of information with parents.
Assessment of large droplet fat in frozen sections of donor liver biopsies: utility and interobserver variability of the newly described Banff method compared to a simplified Average of Fields method
Authors: Kikuchi Alexander T , Akanuma Naoki , Choi Won-Tak , Gill Ryan M , Kakar Sanjay
Published: November 2023

Aims

There is great variability in the assessment and reporting of fat in frozen sections of donor liver biopsies. The Banff Working Group has proposed a novel method and definition for scoring large droplet fat (LDF) in donor liver biopsies. This study compares the Banff method with a simpler Average of Fields (AF) method and evaluates the impact of different LDF definitions.

Methods

Three pathologists assessed percentage of LDF (LDF%) in 10 donor liver biopsies using Banff and AF methods, applying the Banff LDF definition (cell distention with a single droplet larger than adjacent hepatocytes). Additionally, LDF% by the AF method was compared using two LDF definitions: Banff definition versus LDF definition 2 (single fat droplet occupying greater than half of a hepatocyte with nuclear displacement).

Results

Intraobserver concordance between the Banff and AF methods was similar for all three pathologists (kappa 0.76–1). Both methods exhibited 70% interobserver concordance, and there was substantial agreement (kappa 0.68) in the LDF% among the three pathologists for both methods. Comparing the two LDF definitions, results were significantly lower with the Banff definition; LDF >50% was observed in four cases with LDF definition 2 but none of the cases with the Banff definition.

Conclusions

There is high interobserver and intraobserver concordance of LDF% between the Banff and AF methods. LDF% determined by the Banff definition was lower than with LDF definition 2, and needs to be validated based on graft outcome before it can be recommended for clinical use.
Hepatitis B and hepatitis C testing outcomes among service users of Sexual Health London: an online sexually transmitted infection testing service for London residents
Authors: Day Sara Louise , McDonald Gemma , Kellett Chris
Published: November 2023

Objectives

The UK signed up to the 2016 global health strategy to eliminate viral hepatitis as a public health problem. Effective monitoring of hepatitis testing outcomes is required to track progress against targets. National reporting does not include hepatitis B and hepatitis C infections (HBV/HCV) detected by online sexually transmitted infection (STI) testing services (e-services). We identify HBV/HCV infection rates among individuals using Sexual Health London (SHL), a large e-service.

Methods

SHL e-records of individuals receiving reactive HBsAg and/or HepCAb screening results between 1 January 2021 and 1 January 2022 were reviewed. Only at-risk groups are offered HBV/HCV testing, with risks captured via an online triage/consultation. Roche Cobas e801 HBV/HCV screening assay uses a cut-off index of reactivity (COI) to categorise results: low reactive (COI >1–9) and reactive (COI ≥10). SHL refers individuals with any reactive result for confirmatory testing (CT) at a sexual health clinic that provides hepatitis outpatient management. Clinic staff performing the CT access the shared SHL e-record and electronically take over the patient’s care.

Results

67, 718 HBV and 61 064 HCV tests were performed, representing 16% of all kit returns. HBV reactivity was 1.4% (922/67 718): 474 low-reactive, 302 reactive and 146 unconfirmed-reactive. HCV reactivity was 0.3% (163/61 064): 53 low-reactive, 99 reactive and 11 unconfirmed-reactive.

Among individuals with reactive (COI ≥10) screening HBV results, 85% results confirmed, 12% negative and 3% unknown. For HCV, 79% results confirmed, 13% negative and 8% unknown. 57 out of 57 new HBV/HCV infections were electronically transferred. HBV prevalence was 299/67 718 (0.4%). The rate of previously undiagnosed cases detected was 40 out of 67 338 (0.06%) for HBV and 17 out of 61 016 (0.03%) for HCV.

Conclusions

16% of SHL service users received targeted testing for hepatitis in 2021. Testing volumes significantly exceeded and new HBV/HCV diagnosis rates were similar to those reported by sentinel laboratory surveillance. 100% new infections transitioned to care, demonstrating effective integration between online and local sexual health services.
Effect of sweet flavouring on the rewarding and reinforcing value of cigarillo use among young adults
Authors: Audrain-McGovern Janet , Manikandan Divya , Koita Fodie , Klapec Olivia , Pickworth Wallace B , Stone Matthew D
Published: November 2023

Introduction

Cigarillos dominate the US cigar market, and young adults largely drive use. While young adults prefer flavoured to non-flavoured cigarillos, especially those flavoured to taste like fruit or other sweets, the factors that underlie this preference have received little attention. We sought to determine if key indicators of abuse liability, the rewarding and reinforcing effects, are greater for sweet versus non-flavoured cigarillos.

Methods

Young adults (18–24 years old) completed three laboratory visits assessing the subjective rewarding value (exposure paradigm), relative reinforcing value (computerised choice task) and absolute reinforcing value (ad libitum cigarillo smoking session) of sweet-flavoured versus non-flavoured cigarillos. General linear regression models were fit with the appropriate family link for each outcome measure.

Results

Young adults rated sweet-flavoured cigarillos as more rewarding (estimated marginal mean (EMM) =4.52, 95% CI 4.00 to 5.03) than the non-flavoured cigarillo (EMM=3.31, 95% CI 2.80 to 3.83; B=1.20, 95% CI 0.80 to 1.60, p<0.001). The reinforcing value of sweet-flavoured cigarillos, measured by break point, was higher relative to non-flavoured cigarillos (6.34 out of 10), especially among young adults with a preference for flavoured cigarillos (B=1.94, 95% CI 0.71 to 3.18, p=0.003). Young adults took 1.9 times the number of puffs (35.75 vs 19.95) from sweet-flavoured cigarillos compared with non-flavoured cigarillos (Rate Ratio =1.94, 95% CI 1.30 to 2.90, p<0.001).

Conclusions

Sweet flavouring increases the abuse liability of cigarillos among young adults as reflected in greater liking, motivation to use and actual use. Banning sweet flavouring in cigarillos may diminish their use in young adults.

Trial registration number CT.gov (NCT05092919).
Discontinuity-Induced Bifurcations and Chaos in a Linear Ring Oscillator with a Piecewise Linear Reverse Coupling
Authors: Horikawa Yo
Published: November 2023

The bifurcations of periodic solutions and the generation of chaos in a ring of three unidirectionally coupled linear elements with a single reverse coupling through a piecewise linear function are considered. A discontinuous and a continuous piecewise linear function are employed for the reverse coupling. A chaotic attractor is generated immediately through a Hopf-like boundary equilibrium bifurcation of a focus in both cases. A chaotic attractor is also generated directly through a grazing bifurcation in the case of the discontinuous function, which is replaced with a cascade of period-doubling bifurcations in the case of the continuous function. A chaotic oscillation with the same form is also observed in an experiment on an analog circuit constructed with operational amplifiers. In a smooth version of the system, a ring of three unidirectionally coupled sigmoid neurons with a reverse coupling, the Hopf-like boundary equilibrium bifurcation is replaced with a period-doubling cascade following after the Hopf bifurcation.
Hong Kong Guangdong Rheumatology Meeting
Authors: MO Yingqian
Published: November 2023

Sjögren’s syndrome is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Hallmarks of the disease are a loss of salivary and lacrimal gland function as well as lymphocytic infiltration, elevated proinflammatory cytokines, and circulating autoantibodies. The effective treatments are limited. However, new therapies targeting specific immune pathways associated with Sjögren’s syndrome are being developed.

Gene transfer to the salivary glands has been considered a promising approach to treating the dysfunction. The application of this treatment on salivary gland injuries has been studied for decades, yet its clinical progress is delayed. This chapter provides a coup d’oeil into gene transfer methods and various gene/vector types for salivary glands.

AAV2-LAMP3-treated mice developed an SS-like phenotype with progressive salivary hypofunction and autoantibody production. To confirm the role of TLR4 in the induction of BMP6 following stimulation, AAV2-LAMP3–treated mice with established salivary hypofunction were treated i.p. with the TLR4 antagonist TAK242 for 10 days, and the effect of the drug on salivary gland protein expression and function was tested. We observed that treatment with TAK242 significantly decreased BMP6 expression and increased AQP5 expression in the salivary gland tissues. In agreement with this observation, the saliva flow rate of AAV2-LAMP3–treated mice also increased compared with that in vehicle control–treated mice.

Gene therapy using recombinant viruses as gene transfer vectors to deliver a water channel (aquaporin 1, AQP1) to restore membrane water permeability in the salivary gland was shown to be safe and resulted in some patients with radiation-induced xerostomia having a sustained increase in saliva flow. A clinical trial using AAV2 to transfer AQP1 to the salivary glands of radiation-induced xerostomia patients is ongoing (NCT02446249) and results from this study may support application of this treatment in Sjögren’s syndrome. Gene therapy could also be used to deliver immunomodulators locally to the salivary gland resulting in a higher local concentration within the gland that could deliver therapeutics levels of recombinant protein, while minimizing the side effects associated with the drugs.

Another study investigated whether a neurturin-expressing adenovirus could be used for gene therapy in vivo to protect parasympathetic neurons and prevent gland hypofunction after irradiation. The results suggest that in vivo neurturin gene therapy prior to irradiation protects parasympathetic function and prevents irradiation-induced hypofunction.
MRI Workshop for Axial Spondyloarthritis 2023 Interpretation of MRI Spine
Authors: CHUNG Ho Yin
Published: November 2023

Magnetic resonance imaging (MRI) of the spine is a frequent investigation for low back pain (LBP). Applications in axial spondyloarthritis (SpA) include diagnosis and assessment of disease activity. Sacroiliitis on MRI is a known diagnostic criterion. Other MRI lesions such as corner inflammatory lesions (CIL) and fatty corner lesions (FCL) may have potential roles in aiding diagnosis 1 , 2 and in predicting the formation of syndesmophytes. Facet joint and costovertebral lesions are associated with limited spinal mobility and functional impairment 3 . Other lesions described include discovertebral lesions (DVL), Modic type I and II lesions. Identification of individual lesions helps rheumatologists to understand disease progression and guide treatment.
MRI Workshop for Axial Spondyloarthritis 2023
Authors: LEE Victor
Published: November 2023

MRI sacroiliac joint is a sensitive imaging modality for evaluation of inflammation and the accompanying structural changes. Assessment of SpondyloArthritis international Society (ASAS) classification criteria incorporates active inflammation of the sacroiliac joint on MRI as one of the criteria of imaging arm of axial spondylarthritis. The current lecture would cover basic imaging anatomy of sacroiliac joints, typical imaging features of sacroiliac inflammation in axial spondyloarthritis and ‘red-flags’ suggesting alternative diagnosis. The supplementary role of structural changes on MRI in aiding diagnosis of axial spondyloarthritis will also be highlighted.
Symposium 5
Authors: IKEDA Kei
Published: November 2023

While magnetic resonance imaging (MRI) is the most established imaging modality to assess autoimmune myositis (AIM), there is a need for less expensive and more accessible tools. To analyze whether there is sufficient data from published literature to demonstrate that ultrasound presents good metric properties (truth, discrimination and feasibility) in AIM, the OMERACT ultrasound group for myositis performed a systematic literature review. The inclusion criteria required original research involving adult humans, reported in English, assessing ultrasound and elastography in patients with an AIM. Conference abstracts and computer-assisted diagnostics that focused on technique and not ultrasound domains were excluded. Approximately 2670 articles were identified. 41 full-text articles were included in the final analysis. There were 551 AIM patients studied. Eighteen studies (43.9%) had a control group, of which 15 (63.3%) were healthy controls. The age of participants (including controls) varied from 18 to 86 years, and most were females (59%). Diagnosis of AIM was largely biopsy-proven, although some were derived through clinical presentation, positive clinical imaging (ultrasound or otherwise) and/or electromyography and steroid responsiveness. The features examined with ultrasound in the 41 included articles consisted of: muscle echogenicity, bulk, atrophy, architecture, power Doppler, perfusion characteristics, shear wave modulus, shear wave velocity, elasticity index and fasciculations. 12 studies (29.2%) used quantitative methods to assess these characteristics, whilst others used semi-quantitative, dichotomous/binary and descriptive scoring systems. Criterion validity was met in 14 studies (12/14, 85.7%) and construct validity in 22 studies (22/25, 88.0%). Most published articles reported Level 3b to Level 5 evidence with varying degrees of bias. There was only one longitudinal study examining discrimination. Reliability and feasibility were under-reported. This was the first systematic review studying the utility of ultrasound in AIM, which suggested some evidence for criterion and construct validity. Further validation processes are underway.
Lunch Symposium
Authors: ØSTERGAARD Mikkel
Published: November 2023

The overall objectives of this session are to understand the patient burden of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) and to reflect on the role of tailored treatment strategies in the management of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).

The presentation will initially, for each of the 3 diseases, describe key disease characteristics and the clinical responses to different types of therapy, with emphasis on biological and targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs). Subsequently, the focus will be the gap between patients’ and physicians’ perspectives on the most important aspects of the diseases, and on the main goals of treatment. Thereafter, current international recommendations for RA, PsA and axSpA and the treat-to-target concept will be introduced and discussed, followed by a discussion, disease by disease, of whether prevention of radiographic progression should be an important the goal of treatment.

Finally, it will be discussed how the strategy for treating patients RA, PsA, and axSpA should be in the future, including the role of therapeutic strategies tailored for the individual patients.
Symposium 8
Authors: NASH Peter
Published: November 2023

Psoriatic arthritis (PsA) is a chronic inflammatory autoimmune condition characterized by inflamed joints. PsA often, but not always, occurs along with psoriasis (PsO), an autoimmune skin condition that results in scaly, red itchy patches. Biologics therapy has been a standard of treatment for moderate to severe PsA after the use of disease-modifying antirheumatic drugs (DMARDs). Traditionally PsA biologics targeted on inhibiting the tumor necrosis factor (TNF) or interleukin-17 (IL-17) pathway to suppress the inflammatory triggering cascade.

Recently biologics inhibiting the interleukin-23 (IL-23) pathway, such as guselkumab, is approved for the management of both PsA and PsO with promising efficacy in both skin and joint improvement. IL-23 inhibitors are included as recommended treatment option for peripheral and skin-involved PsA in the latest EULAR recommendations. With the availability of new mode of therapy, it is important to understand the characteristics and clinical evidence of different biologics modality and this lecture will demonstrate how to apply the various options to PsA patients presented with different disease profiles.
Abstract 14 — Comparison of the ASAS Health Index Between Radiographic Axial Spondyloarthritis and Non-Radiographic Spondyloarthritis in Singapore
Authors: Kwan Yu Heng , Woon Ting Hui , Wang Charmaine , Fong Warren
Published: November 2023

Background

Prior studies reported conflicting results regarding differences in Assessment of SpondyloArthritis (ASAS) Health Index (HI) scores between radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axial spondyloarthritis (nr-axSpA). Country-level variations in disease activity were also observed. Hence, this study aimed to compare the ASAS HI scores between r-axSpA and nr-axSpA in Singapore, and determine factors associated with poorer ASAS HI scores.

Methods

This was a cross-sectional evaluation of baseline data from a prospective cohort study in Singapore General Hospital, from January 2018 to March 2023. Patients aged 21 years and above who were clinically diagnosed with axial spondyloarthritis (axSpA) based on the 2009 ASAS criteria were included. Sociodemographic variables, clinical variables and patient-reported outcomes were collected. Univariable and multivariable linear regression were performed to identify variables associated with ASAS HI scores. Variables with p-value of <0.10 were included in the multivariable regression. A p-value of <0.05 was considered significant.

Results

Of the 331 patients, 265 (80.0%) and 66 (20.0%) had r-axSpA and nr-axSpA respectively. The median (IQR) age in r-axSpA was [40.0 (30.0-53.0) years], higher than nr-axSpA [34.0 (25.0-47.0) years], p<0.01. There was a higher proportion of males in r-axSpA (80.4%) than nr-axSpA (65.2%), p=0.01. Patients with r-axSpA had a longer disease duration [6.8 (1.8-14.0) years] than nr-axSpA [1.1 (0.2-5.4) years], p<0.01. More patients with r-axSpA (90.2%) were positive for HLA-B27 than nr-axSpA (69.7%), p<0.01. Differences in ASAS HI scores were not statistically significant between r-axSpA and nr-axSpA [4.0 (2.0-6.8) vs 5.5 (1.1-8.5), p=0.12]. Post multivariable regression, nr-axSpA ([Formula: see text]: 0.70, 95% CI: 0.09, 1.32, p=0.02), BASDAI ([Formula: see text]: 0.18, 95% CI: 0.01, 0.35, p=0.04), BASFI ([Formula: see text]: 0.47, 95% CI: 0.30, 0.65, p<0.01) and HADS-Depression scores ([Formula: see text]: 0.11, 95% CI: 0.01, 0.21, p=0.04) were positively associated with ASAS HI. Higher SF36-PCS ([Formula: see text]: −0.11, 95% CI: −0.14, −0.08, p<0.01) and SF36-MCS ([Formula: see text]: −0.07, 95% CI: −0.10, −0.04, p<0.01) were negatively associated with ASAS HI (Table 1).

Conclusion

Patients with nr-axSpA were associated with poorer overall health and functioning as compared to r-axSpA. Higher disease activity, poorer physical function, poorer mental health status and more depressive symptoms were associated with worse health and functioning.
Abstract 15 — Lupus Low Disease Activity State: An Underutilised Clinical Target that is Attainable and Protective against Lupus Nephritis Relapse
Authors: Cheung Chak Kwan , Lau Chak Sing , Chan Shirley Chiu Wai
Published: November 2023

Background

Lupus nephritis (LN) is a significant comorbidity affecting approximately 50-60% of patients with systemic lupus erythematosus (SLE). Complete and partial renal response (CRR/PRR) have been recommended as treatment targets in LN. Lupus low disease activity state (LLDAS) is also associated with favourable clinical outcomes. This study aims to investigate the LLDAS attainment rate and outcomes in patients with LN.

Methods

Patients with biopsy-proven LN during 2010-2020 in Queen Mary Hospital were included. Baseline demographics, blood parameters and urinalysis results were documented. Renal response and LLDAS attainment were assessed at 12 months after LN diagnosis. CRR was defined as proteinuria [Formula: see text]0.5g/day with a normal estimated glomerular filtration rate (eGFR); PRR was defined as a reduction in proteinuria by [Formula: see text]50% with near normal eGFR. A relapse was defined as a biopsy-proven active LN on histology after an initial treatment response of proteinuria reduction of [Formula: see text]50% or to sub-nephrotic range. Time-to-relapse survival analysis was performed to compare the significance of CRR/PRR and LLDAS attainment.

Results

143 LN patients were included, with a median follow-up duration of 10.4 years. At 12 months, 57 (40%), 14 (10%) and 69 (48%) patients achieved CRR, PRR and LLDAS, respectively. Although 39 (27%) patients attained both CRR/PRR and LLDAS, a significant number of 30 (21%) patients reached LLDAS without meeting CRR/PRR (Figure 1). Among 136 patients who achieved the pre-defined treatment response, 30 (22%) patients developed LN relapse after a median of 2.98 years. Patients reaching either CRR/PRR or LLDAS had a significantly lower risk of relapse (CRR/PRR: HR = 0.34, p = 0.02; LLDAS: HR = 0.28, p = 0.003). The attainment of both CRR/PRR and LLDAS was associated with the lowest risk of relapse (Figure 2).

Conclusion

We advocate LLDAS as a target for LN patients as attaining LLDAS reduces future LN relapse risks.
Abstract 17 — Overall Infection Risks of Tofacitinib in Patient with Rheumatoid Arthritis: A Meta-Analysis of Randomized Clinical Trials
Authors: Yusof Mohd Haidir Mohd , Jinih Marcel , Roos Nur Aishah Che , Yusof Ahmad Asmadi
Published: November 2023

Background

There is an ongoing controversy surrounding whether tofacitinib increases the risk of infections in patients with rheumatoid arthritis (RA). To address this issue, we conducted a meta-analysis using data from randomized clinical trials (RCTs) to assess the overall risk of infection in these patients.

Methods

We conducted a comprehensive systematic search in EMBASE, MEDLINE, and CENTRAL from their inception until December 2022 to identify relevant RCTs reporting the occurrence of infections in patients with RA who were treated with the standard clinical therapeutic dosage of tofacitinib (5mg twice daily orally). The primary outcomes of the included studies in this review focused on the incidence of total infections, serious infections, non-serious infections, and opportunistic infections (including herpes zoster and tuberculosis). Additionally, we examined secondary outcomes related to the incidence of various sites of infections, including the upper respiratory tract, lower respiratory tract, gastrointestinal tract, hepatobiliary system, urinary tract, skin and soft tissue, blood, dental and oral soft tissue, genital, reproductive tract, bone and joint, and central nervous system infections. Due to the expected anticipation of clinical and methodological heterogeneity across studies, the effect estimate was pooled with a random-effects model, to obtain the RRs and 95% CIs, using Mantel-Haenszel statistical method.

Results

Twelve eligible RCTs, involving a total of 6,056 patients, were included in the analysis. In comparison to the control group (placebo and other active treatments), tofacitinib exhibited a significant increase in the risk of total infections (RR, 1.21; 95% CI, 1.07-1.37; I2, 28%), serious infections (RR, 1.23; 95% CI, 1.02-1.48; I2, 0%), non-serious infections (RR, 1.20; 95% CI, 1.05-1.36; I2, 29%), and opportunistic infections (RR, 1.66; 95% CI, 1.40-1.97; I2, 0%). Secondary outcomes analyses revealed a significant increase in the risk of lower respiratory infections with tofacitinib (RR, 1.27; 95% CI, 1.10–1.47; I2, 0%).

Conclusion

Compared with placebo and other active treatments, tofacitinib significantly increased the overall risk of infections (total infections, serious infections, non-serious infections, and opportunistic infections). These findings can help clinicians assess the risk of infections in RA patients treated with tofacitinib.
Abstract 19 — Treat-to-Target in Spondyloarthritis (SpA): Are There Sex-Related Differential Responses?
Authors: Cheng Isaac T , So Ho , Yip Carson Chun Yin , Leung Ying Ying , Shin Kichul , Saeed Muhammad Ahmed , Chiowchanwisawakit Praveena , Hammoudeh Mohammed , Haroon Muhammad , Nallasivan Subramanian , Angkodjojo Stanley , Chung James Ho Yin , Kishimoto Mitsumasa , Wei James , Tam Lai Shan
Published: November 2023

Background:

Studies have reported that female patients with spondyloarthritis have different disease courses and treatment responses compared to male patients. Whether patients’ sex is associated with a different outcome after receiving one-year of tight control, treat-to-target (T2T) strategy remains uncertain. Thus, this study aimed to evaluate the differences in the clinical response between male and female patients from the APLAR SpA Registry.

Methods:

Patients who fulfilled the CASPAR 2006 classification criteria for PsA and 2009 ASAS classification for axSpA were recruited. They received 1 year of protocolized treatment aiming at 1) MDA or DAPSA-LDA for PsA patients, and 2) ASDAS-LDA for axSpA patients. Patients were assessed every 3-monthly and treatment was escalated if target was not reached.

Results:

Ninety-one male (age: 45.6±16.1, 43 PsA, 48 axSpA) and 52 female (age: 49.2±13.4, 36 PsA, 16 axSpA) patients were included. There was no significant difference between the 2 sexes at baseline, except a higher ESR and more severe enthesitis in female patients. During the study period, the use of csDMARDs and NSAIDs decreased slightly, whilst the use of bDMARDs significantly increased across both sexes (Fig. 1a). Considering the whole cohort, there were significant improvement in disease activity in PsA after 1-year and disease activity in axSpA remained low. Despite similar bDMARDs use at 1-year, female PsA patients had a lower MDA achievement rate (36% in female vs 51% in male). Female patients also remained to have a higher physician global assessment score (2.61±1.76 in female vs 1.98±1.57 in male, p=0.03), greater functional impairment (HAQ: 0.54±0.57 in female vs 0.32±0.46 in male, p=0.01) and more severe enthesitis (SPARCC: 0.83±1.67 in female vs 0.16±1.09 in male, p=0.005) at 1-year. There was also a trend of higher perceived disease burden and peripheral involvement in female (Fig. 1b).

Conclusion:

There may be differential treat-to-target responses between male and female SpA patients. The causes of such differential characteristics should be further explored to potentially implement a sex-specific treat-to-target strategy for spondyloarthritis.
Abstract 24 — Myricetin Impedes Tfh Cell Differentiation and Ameliorates the Tumorigenic Phenotype of Adjuvant-Induced Arthritis FLS in Rheumatoid Arthritis
Authors: Rasool Mahaboobkhan , Jose Ann Miriam
Published: November 2023

Background

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by destructive polyarthritis and extra-articular manifestations. Myricetin, a flavonoid, possesses several pharmacological benefits, including anti-arthritic effects. However, the specific role and molecular basis of myricetin in IL-21 mediated T follicular helper (Tfh) cell differentiation and activation of fibroblast-like synoviocytes (FLS) in RA remain unknown. In the present study, we decoded the therapeutic intervention of myricetin as an anti-arthritic small-molecule drug for impeding Tfh cell differentiation and for abrogating the RA-FLS-transformed aggressive phenotype.

Methods

In vivo experiments were conducted using an adjuvant-induced arthritis animal model to evaluate the effects of myricetin on Tfh cell differentiation, IL-21 production, choline kinase (ChoK) activation, and the JAK/STAT signaling pathway.

Results

In this study, myricetin was found to significantly inhibit the interaction between IL-21 and IL-21R, and at the molecular level, it suppressed JAK/STAT signaling and the downstream transcription factor Bcl-6, which decreased Tfh cell differentiation. Additionally, myricetin suppressed the IL-21-induced hyperproliferation of AIA-FLSs by downregulating the ChoK signaling cascade (Ras, Ral-GDS, and PI3K). Myricetin treatment reduced ChoK enzymatic activity and the proliferative, migratory, and invasive properties of AIA-FLS.

Conclusion

Taken together, our results demonstrated that myricetin is a promising therapeutic compound that abates IL-21-induced Tfh cell differentiation and the invasive behavior of AIA-FLS.
Abstract 25 — Remitting Seronegative Symmetric Synovitis with Pitting Edema (RS3PE) in Dialysis Patient
Authors: AlKindi Fatima , AlBashir Nihal , Chaaban Ahmad , George Abraham , Saad Mohamed , Hakim Mohammad Al , Budruddin Mohammed , Khan Imran , Boobes Yousef
Published: November 2023

Background

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by acute symmetrical synovitis, and pitting edema involving, the dorsal part of hands and feet. It affects more men aged more than 50 years. The inflammatory markers are usually elevated, with negative rheumatoid factor. The underlying etiology is not clear but has been associated with drugs exposure, infections, malignancy in 30% of cases, and coexist with other autoimmune diseases. The clinical course is benign with significant improvement to low-dose prednisolone therapy for 2 to 3 months. It has been rarely reported in dialysis patients.

Methods and case description

A 54 years old male, known to have long standing uncontrolled diabetes mellitus, hypertension, chronic kidney disease and diabetic retinopathy. Recently, he was treated for left foot cellulitis and advanced renal failure (813 micromol/L) initiated on hemodialysis. He presented one week later with progressive painful bilateral upper limb and lower limb pitting edema, with limited range of movement in hands and reduce urine output. He was resumed on hemodialysis for management of volume overload. Despite removal of almost 12 liters of fluids during consecutive dialysis sessions and improvement of lower limb edema, his bilateral hand edema was persistence with pain and limited movement. Further investigations were done to evaluate for rheumatological condition.

Results

Hand X ray was normal and ultrasound of the hand revealed features of synovitis, diffuse subcutaneous oedema and possible cellulitis. He was started on IV antibiotics without major improvement and blood culture was negative. CT chest showed left pleural effusion. The ESR was elevated 120, while serology for HBV. HCV, HIV, and parvovirus were negative. In addition, the autoimmune workup were negative (CCP, RF, ANA, ANCA, C3, C4, ACEI). He was diagnosed with remitting seronegative symmetric synovitis with pitting edema (RS3PE). He was treated with IV hydrocortisone once 100 mg, followed by oral prednisolone 10 mg for 5 days with dramatic improvement in bilateral hand edema and movement. He had hyperglycemia steroid related managed with adjustment of insulin therapy. At follow up in 1 week, patient regain full function of both hands, and he was on regular hemodialysis trice per week.

Conclusion

RS3PE is rare in hemodialysis patients, with favorable response to steroid therapy. We used shorter duration of 5 days steroid therapy with complete recovery and no recurrence at 1 year follow up. Screening for underlying autoimmune, infection or malignancy in RS3PE is essential.
One-Bit Supervision for Image Classification: Problem, Solution, and Beyond
Authors: Hu Hengtong , Xie Lingxi , Huo Xinyue , Hong Richang , Tian Qi
Published: November 2023

This article presents one-bit supervision, a novel setting of learning with fewer labels, for image classification. Instead of the training model using the accurate label of each sample, our setting requires the model to interact with the system by predicting the class label of each sample and learn from the answer whether the guess is correct, which provides one bit (yes or no) of information. An intriguing property of the setting is that the burden of annotation largely is alleviated in comparison to offering the accurate label. There are two keys to one-bit supervision: (i) improving the guess accuracy and (ii) making good use of the incorrect guesses. To achieve these goals, we propose a multi-stage training paradigm and incorporate negative label suppression into an off-the-shelf semi-supervised learning algorithm. Theoretical analysis shows that one-bit annotation is more efficient than full-bit annotation in most cases and gives the conditions of combining our approach with active learning. Inspired by this, we further integrate the one-bit supervision framework into the self-supervised learning algorithm, which yields an even more efficient training schedule. Different from training from scratch, when self-supervised learning is used for initialization, both hard example mining and class balance are verified to be effective in boosting the learning performance. However, these two frameworks still need full-bit labels in the initial stage. To cast off this burden, we utilize unsupervised domain adaptation to train the initial model and conduct pure one-bit annotations on the target dataset. In multiple benchmarks, the learning efficiency of the proposed approach surpasses that using full-bit, semi-supervised supervision.
Scalable and Accelerated Self-healing Control Circuit Using Evolvable Hardware
Authors: S. Deepanjali , Mahammad SK Noor
Published: November 2023

Controllers are mission-critical components of any electronic design. By sending control signals, they decide which and when other data path elements must operate. Faults, especially Single Event Upset (SEU) occurrence in these components, can lead to functional/mission failure of the system when deployed in harsh environments. Hence, competence to self-heal from SEU is highly required in the control path of the digital system. Reconfiguration is critical for recovering from a faulty state to a non-faulty state. Compared to native reconfiguration, the Virtual Reconfigurable Circuit (VRC) is an FPGA-generic reconfiguration mechanism. The non-partial reconfiguration in VRC and extensive architecture are considered hindrances in extending the VRC-based Evolvable Hardware (EHW) to real-time fault mitigation. To confront this challenge, we have proposed an intrinsic constrained evolution to improve the scalability and accelerate the evolution process for VRC-based fault mitigation in mission-critical applications. Experimentation is conducted on complex ACM/SIGDA benchmark circuits and real-time circuits used in space missions, which are not included in related works. In addition, a comparative study is made between existing and proposed methodologies for brushless DC motor control circuits. The hardware utilization in the multiplexer has been significantly reduced, resulting in up to a 77% reduction in the existing VRC architecture. The proposed methodology employs a fault localization approach to narrow the search space effectively. This approach has yielded an 87% improvement on average in convergence speed, as measured by the evolution time, compared to the existing work.
Fibroblasts under pressure: cardiac fibroblast responses to hypertension and antihypertensive therapies
Authors: Chalise Upendra , Hale Taben M.
Published: November 2023

Approximately 50% of Americans have hypertension, which significantly increases the risk of heart failure. In response to increased peripheral resistance in hypertension, intensified mechanical stretch in the myocardium induces cardiomyocyte hypertrophy and fibroblast activation to withstand increased pressure overload. This changes the structure and function of the heart, leading to pathological cardiac remodeling and eventual progression to heart failure. In the presence of hypertensive stimuli, cardiac fibroblasts activate and differentiate to myofibroblast phenotype capable of enhanced extracellular matrix secretion in coordination with other cell types, mainly cardiomyocytes. Both systemic and local renin-angiotensin-aldosterone system activation lead to increased angiotensin II stimulation of fibroblasts. Angiotensin II directly activates fibrotic signaling such as transforming growth factor β/SMAD and mitogen-activated protein kinase (MAPK) signaling to produce extracellular matrix comprised of collagens and matricellular proteins. With the advent of single-cell RNA sequencing techniques, heterogeneity in fibroblast populations has been identified in the left ventricle in models of hypertension and pressure overload. The various clusters of fibroblasts reveal a range of phenotypes and activation states. Select antihypertensive therapies have been shown to be effective in limiting fibrosis, with some having direct actions on cardiac fibroblasts. The present review focuses on the fibroblast-specific changes that occur in response to hypertension and pressure overload, the knowledge gained from single-cell analyses, and the effect of antihypertensive therapies. Understanding the dynamics of hypertensive fibroblast populations and their similarities and differences by sex is crucial for the advent of new targets and personalized medicine.
Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer
Authors: Mizrak Ikram , Lund Morten A. V. , Landgrebe Ann V. , Asserhøj Louise L. , Holstein-Rathlou Niels-Henrik , Greisen Gorm , Clausen Tine D. , Main Katharina M. , Vejlstrup Niels G. , Jensen Rikke B. , Pinborg Anja , Madsen Per L.
Published: November 2023

We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.
Gastrointestinal Effects on the Antioxidant and Immunomodulatory Properties of South African Fynbos Honey
Authors: Magoshi Innocentia Botlhale , Nekhumbe Anwani Wendy , Ibrahim Mohammed Auwal , Serem June Cheptoo , Bester Megan Jean
Published: November 2023

The Fynbos biome, Western Cape Province, South Africa, produces a unique honey from Apis mellifera capensis. The bioactivity of Fynbos (FB1-FB6) honeys and Manuka, unique manuka factor 15+ (MAN UMF15+) honey subjected to simulated in vitro digestion, was compared. The effect of each phase of digestion on the antioxidant properties and nitric oxide- (NO-) associated immunomodulatory effects was determined. The total phenolic content of MAN (UMF15+) was higher than that of FB honeys, and following digestion, the percentage bioaccessibility (BA) was 68.6% and

87.1
±
27.0
%

, respectively. With the Trolox equivalent antioxidant capacity assay, the activity of FB1 and FB6 was similar to MAN (UMF15+) but reduced for FB2, FB3, FB4, and FB5 with a %BA of 77.9% for MAN (UMF15+) and

78.2
±
13.4
%

for FB. The oxygen radical absorbance capacity of MAN (UMF15+) and FB honeys was similar and unaltered with digestion. In a cellular environment, using colon adenocarcinoma (Caco-2) cells, both undigested and the gastric digested honey reduced 2,2

′

-azobis-(2-amidinopropane) dihydrochloride- (AAPH-) mediated peroxyl radical formation. In contrast, following gastroduodenal digestion, the formation of reactive oxygen species (ROS) was increased. In murine macrophage (RAW 264.7) cells, all honeys induced different levels of NO which was significantly increased with digestion for MAN (UMF15+) and FB1. In LPS/IFN-γ stimulated RAW 264.7 macrophages, only undigested MAN (UMF15+) effectively reduced NO levels, and with digestion, NO scavenging activity of MAN (UMF15+) was reduced but increased for FB5 and FB6. In a noncellular environment, MAN (UMF15+), FB1, FB2, and FB6 scavenged NO, and with digestion, this activity was maintained. This study has identified that undigested and gastric-digested FB honey has antioxidant properties with strong potential anticancer effects following gastroduodenal digestion, related to ROS formation. MAN (UMF15+) had anti-inflammatory effects which were lost postdigestion, and in contrast, FB5 and FB6 had anti-inflammatory effects postdigestion.