Search

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination., Methods: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses., Results: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) ( p < 0.001)., Conclusion: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

Pseudouridylation, the conversion of uridine (U) to pseudouridine (Ѱ), is one of the most prevalent and evolutionary conserved RNA modifications, which is catalyzed by pseudouridine synthase (PUS) enzymes. Ѱs play a crucial epitranscriptomic role by regulating attributes of cellular RNAs across diverse organisms. However, the precise biological functions of PUSs in plants remain largely elusive. In this study, we identified and characterized 21 members in the rice PUS family which were categorized into six distinct subfamilies, with RluA and TruA emerging as the most extensive. A comprehensive analysis of domain structures, motifs, and homology modeling revealed that OsPUSs possess all canonical features of true PUS proteins, essential for substrate recognition and catalysis. The exploration of OsPUS promoters revealed presence of cis-acting regulatory elements associated with hormone and abiotic stress responses. Expression analysis of OsPUS genes showed differential expression at developmental stages and under stress conditions. Notably, OsTruB3 displayed high expression in salt, heat, and drought stresses. Several OsRluA members showed induction in heat stress, while a significant decline in expression was observed for various OsTruA members in drought and salinity. Furthermore, miRNAs predicted to target OsPUS s were themselves responsive to variable stresses, adding an additional layer of regulatory complexity of OsPUSs. Study of protein-protein interaction networks provided substantial support for the potential regulatory role of OsPUSs in numerous cellular and stress response pathways. Conclusively, our study provides functional insights into the OsPUS family, contributing to a better understanding of their crucial roles in shaping the development and stress adaptation in rice., Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01396-4., Competing Interests: Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Prof. H.S. Srivastava Foundation for Science and Society 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

This research article explores the distinct TADF efficiency of three donor-acceptor based regio-isomers: DPAOCN ( ortho -isomer), DPAMCN ( meta -isomer), and DPAPCN ( para -isomer). DPAPCN exhibits maximum TADF efficiency in both solution and solid-state with an impressive reverse inter-system crossing (RISC) rate of ∼10 6 s -1 ; the underlying cause being the minimum singlet-triplet splitting energy or Δ E ST and maximum SOC (spin-orbit coupling) between the S 1 & T 1 states. Apart from TADF, differences in crystal packing of the regio-isomers result in intriguing bulk phase properties. DPAOCN, with its non-centrosymmetric P 2 1 2 1 2 1 space group and substantial crystal void volume, exhibits reversible tri-color mechanochromic luminescence behavior, while the meta and para isomers, due to their centrosymmetric packing and diminished crystal void volume, remain inert to mechanical pressure. Expanding the horizon of possibilities, the non-centrosymmetric nature of ortho -isomer further renders it an excellent SHG material, with a χ (2) value of 0.19 pm V -1 at 1220 nm and a laser-induced damage threshold (LIDT) value of 13.27 GW cm -2 . Overall, a comprehensive investigation into the regio-isomers has been carried out, encompassing their TADF, SHG, and mechanochromic luminescent properties., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Living with a chronic illness such as rheumatoid arthritis (RA) requires medications and therapies, as well as long-term follow-up with multidisciplinary clinical teams. Patient involvement in the shared decision-making process on medication regimens is an important element in promoting medication adherence. Literature review and needs assessment showed the viability of technology-based interventions to equip patients with knowledge about chronic illness and competencies to improve their adherence to medications. Thus, a web-based intervention was developed to empower patients living with RA to adhere to their disease-modifying antirheumatic drugs (DMARDs) medication regimen., Objective: This study aims to discuss the intervention mapping process in the design of a web-based intervention that supports patient empowerment to medication adherence and to evaluate its feasibility among patients living with RA., Methods: The theory-based Patient Empowerment to Medication Adherence Programme (PE2MAP) for patients with RA was built upon the Zimmerman Psychological Empowerment framework, a web-based program launched through the Udemy website. PE2MAP was developed using a 6-step intervention mapping process: (1) needs assessment, (2) program objectives, (3) conceptual framework to guide the intervention, (4) program plan, (5) adoption, and (6) evaluation involving multidisciplinary health care professionals (HCPs) and a multimedia team. PE2MAP is designed as a 4-week web-based intervention program with a complementary RA handbook. A feasibility randomized controlled trial was completed on 30 participants from the intervention group who are actively taking DMARD medication for RA to test the acceptability and feasibility of the PE2MAP., Results: The mean age and disease duration of the 30 participants were 52.63 and 8.50 years, respectively. The feasibility data showed 87% (n=26) completed the 4-week web-based PE2MAP intervention, 57% (n=17) completed all 100% of the contents, and 27% (n=8) completed 96% to 74% of the contents, indicating the overall feasibility of the intervention. As a whole, 96% (n=24) of the participants found the information on managing the side effects of medications, keeping fit, managing flare-ups, and monitoring joint swelling/pain/stiffness as the most useful contents of the intervention. In addition, 88% (n=23) and 92% (n=24) agreed that the intervention improved their adherence to medications and management of their side effects, including confidence in communicating with their health care team, respectively. The dos and do nots of traditional Chinese medicine were found by 96% (n=25) to be useful. Goal setting was rated as the least useful skill by 6 (23.1%) of the participants., Conclusions: The web-based PE2MAP intervention was found to be acceptable, feasible, and effective as a web-based tool to empower patients with RA to manage and adhere to their DMARD medications. Further well-designed randomized controlled trials are warranted to explore the effectiveness of this intervention in the management of patients with RA., (©Siriwan Lim, Ponrathi Athilingam, Manjari Lahiri, Peter Pak Moon Cheung, Hong-Gu He, Violeta Lopez. Originally published in JMIR Formative Research (https://formative.jmir.org), 06.11.2023.)

Interferometric methods form the basis of highly sensitive measurement techniques from astronomy to bioimaging. Interferometry typically requires high stability between the measured and reference beams. The presence of rapid phase fluctuations washes out interference fringes, making phase profile recovery impossible. This challenge can be addressed by shortening the measurement time. However, such an approach reduces photon-counting rates, precluding applications in low-intensity imaging. We introduce a phase imaging technique which is immune to time-dependent phase fluctuations. Our technique, relying on intensity correlation instead of direct intensity measurements, allows one to obtain high interference visibility for arbitrarily long acquisition times. We prove the optimality of our method using the Cramér-Rao bound in the extreme case when no more than two photons are detected within the time window of phase stability. Our technique will broaden prospects in phase measurements, including emerging applications such as in infrared and x-ray imaging and quantum and matter-wave interferometry.

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a detoxifying enzyme overexpressed in tumors, plays a key role in protecting cancer cells against oxidative stress and thus has been considered an attractive candidate for activating prodrug(s). Herein, we report the first use of NQO1 for the selective activation of 'protransporter' systems in cancer cells leading to the induction of apoptosis. Salicylamides, easily synthesizable small molecules, have been effectively used for efficient H + /Cl - symport across lipid membranes. The ion transport activity of salicylamides was efficiently abated by caging the OH group with NQO1 activatable quinones via either ether or ester linkage. The release of active transporters, following the reduction of quinone caged 'protransporters' by NQO1, was verified. Both the transporters and protransporters exhibited significant toxicity towards the MCF-7 breast cancer line, mediated via the induction of oxidative stress, mitochondrial membrane depolarization, and lysosomal deacidification. Induction of cell death via intrinsic apoptotic pathway was verified by monitoring PARP1 cleavage., (© 2023 Wiley-VCH GmbH.)

Objective: To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA)., Methods: A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI)., Results: Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA., Conclusion: About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA., (© 2023. The Author(s).)

Introduction: This review aims to provide evidence-based recommendations for an enhanced primary series (third dose) coronavirus disease 2019 (COVID-19) vaccination in people with rheumatic diseases (PRDs) in the local and regional context., Methods: Literature reviews were performed regarding the necessity, efficacy, safety and strategies for enhanced primary series COVID-19 vaccination in PRDs. Recommendations were developed based on evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Evidence was synthesised by eight working group members, and the consensus was achieved by a Delphi method with nine members of an expert task force panel., Results: Two graded recommendations and one ungraded position statement were developed. PRDs have impaired immunogenicity from the COVID-19 vaccine and are at an increased risk of postvaccine breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poor clinical outcomes, compared to the general population. We strongly recommend that PRDs on immunomodulatory drugs be offered a third dose of the messenger RNA (mRNA) vaccine as part of an enhanced primary series, after the standard two-dose regimen. We conditionally recommend that the third dose of mRNA vaccine against SARS-CoV-2 be given at least 4 weeks after the second dose or as soon as possible thereafter. There is insufficient data to inform whether the third mRNA vaccine should be homologous or heterologous in PRDs., Conclusion: These recommendations that were developed through evidence synthesis and formal consensus process provide guidance for an enhanced primary series COVID-19 vaccination in PRDs., Competing Interests: None

Artificial biomimetic chloride anionophores have shown promising applications as anticancer scaffolds. Importantly, stimuli-responsive chloride transporters that can be selectively activated inside the cancer cells to avoid undesired toxicity to normal, healthy cells are very rare. Particularly, light-responsive systems promise better applicability for photodynamic therapy because of their spatiotemporal controllability, low toxicity, and high tunability. Here, in this work, we report o -nitrobenzyl-linked, benzimidazole-based singly and doubly protected photocaged protransporters 2a, 2b, 3a, and 3b, respectively, and benzimidazole-2-amine-based active transporters 1a-1d. Among the active compounds, trifluoromethyl -based anionophore 1a showed efficient ion transport activity (EC 50 = 1.2 ± 0.2 μM). Detailed mechanistic studies revealed Cl - /NO 3 - antiport as the main ion transport process. Interestingly, double protection with photocages was found to be necessary to achieve the complete "OFF-state" that could be activated by external light. The procarriers were eventually activated inside the MCF-7 cancer cells to induce phototoxic cell death., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: We aimed to describe the extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including their frequency, onset with respect to respiratory symptoms, pathogenesis and association with disease severity., Methods: We searched the MEDLINE and Embase databases for SARS-CoV-2-related studies. Meta-analysis, observational studies, case series and case reports published in English or Chinese between 1 January 2020 and 1 May 2020 were included. Reports with only paediatric or obstetric cases were excluded., Results: 169 articles were included. Early manifestations (preceding respiratory symptoms until Day 6 of onset) included olfactory and gustatory disturbance (self-reported in up to 68% and 85% of cases, respectively), gastrointestinal symptoms (up to 65.9%) and rash (up to 20.4%). From Day 7 onwards, hypercytokinaemia, paralleled multi-organ complications including acute cardiac injury (pooled incidence of 17.7% in 1,412 patients, mostly with severe disease and 17.4% mortality), kidney and liver injury (up to 17% and 33%, respectively) and thrombocytopenia (up to 30%). Hypercoagulability resulted in venous thromboembolic events in up to 31% of all patients. Uncommon disease presentation and complications comprised Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis and spontaneous pneumomediastinum., Conclusion: Although the systemic manifestations of SARS-CoV-2 infection are variegated, they are deeply interwoven by shared mechanisms. Two phases of extrapulmonary disease were identified: (a) an early phase with possible gastrointestinal, ocular and cutaneous involvement; and (b) a late phase characterised by multiorgan dysfunction and clinical deterioration. A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome in SARS-CoV-2 is needed., Competing Interests: None

Background: Apoptosis or programmed cell death plays a vital role in maintaining homeostasis and, therefore, is a tightly regulated process. Deregulation of apoptosis signalling can favour carcinogenesis. Apoptosis inhibitor 5 (Api5), an inhibitor of apoptosis, is upregulated in cancers. Interestingly, Api5 is shown to regulate both apoptosis and cell proliferation. To address the precise functional significance of Api5 in carcinogenesis here we investigate the role of Api5 in breast carcinogenesis., Methods: Initially, we carried out in silico analyses using TCGA and GENT2 datasets to understand expression pattern of API5 in breast cancer patients followed by investigating the protein expression in Indian breast cancer patient samples. To investigate the functional importance of Api5 in breast carcinogenesis, we utilised MCF10A 3D breast acinar cultures and spheroid cultures of malignant breast cells with altered Api5 expression. Various phenotypic and molecular changes induced by altered Api5 expression were studied using these 3D culture models. Furthermore, in vivo tumorigenicity studies were used to confirm the importance of Api5 in breast carcinogenesis., Results: In-silico analysis revealed elevated levels of Api5 transcript in breast cancer patients which correlated with poor prognosis. Overexpression of Api5 in non-tumorigenic breast acinar cultures resulted in increased proliferation and cells exhibited a partial EMT-like phenotype with higher migratory potential and disruption in cell polarity. Furthermore, during acini development, the influence of Api5 is mediated via the combined action of FGF2 activated PDK1-Akt/cMYC signalling and Ras-ERK pathways. Conversely, Api5 knock-down downregulated FGF2 signalling leading to reduced proliferation and diminished in vivo tumorigenic potential of the breast cancer cells., Conclusion: Taken together, our study identifies Api5 as a central player involved in regulating multiple events during breast carcinogenesis including proliferation, and apoptosis through deregulation of FGF2 signalling pathway., (© 2023. The Author(s).)

Measuring entanglement is an essential step in a wide range of applied and foundational quantum experiments. When a two-particle quantum state is not pure, standard methods to measure the entanglement require detection of both particles. We realize a conceptually new method for verifying and measuring entanglement in a class of two-part (bipartite) mixed states. Contrary to the approaches known to date, in our experiment we verify and measure entanglement in mixed quantum bipartite states by detecting only one subsystem, the other remains undetected. Only one copy of the mixed or pure state is used but that state is in a superposition of having been created in two identical sources. We show that information shared in entangled systems can be accessed through single-particle interference patterns. Our experiment enables entanglement characterization even when one of the subsystems cannot be detected, for example, when suitable detectors are not available.

Aims: To describe inflammatory arthritis (IA) patients initiating biologic disease-modifying anti-rheumatic drugs (bDMARDs) who use complementary and alternative medicine (CAM), and determine the impact of CAM on predicting modified Health Assessment Questionnaire (mHAQ) at 6 months., Methods: This was a prospective inception cohort study of patients ≥21 years old initiating a bDMARD for IA after July 2016. Data were obtained via questionnaires and abstraction from medical records. Baseline characteristics between ever-CAM and CAM non-users were compared. CAM as a predictor of mHAQ ≥1 at 6 months after bDMARD initiation was analyzed using multivariate logistic regression, adjusting for other baseline characteristics., Results: We recruited 299 patients (36.2% male, mean age 49.0 years). There were 45.8% who had rheumatoid arthritis, 54.2% had a spondyloarthropathy, median disease duration of 1.1 years and median mHAQ of 0.4. Compared to CAM non-users, ever-CAM users had a lower mean body mass index, were less likely to speak English, and more likely to smoke and drink alcohol. There was no association of CAM use with high mHAQ and no interaction with smoking. Smoking (odds ratio [OR] 938.9; 95% CI 3.20-275 884.1), baseline mHAQ (OR 252.2; 95% CI 5.34-11 899.2) and Charlson's Comorbidity Index score ≥4 (OR 237.4; 95% CI 1.22-46 184.4) independently predicted high mHAQ at 6 months., Conclusions: CAM use was not associated with high mHAQ at 6 months. Smoking was an independent predictor of residual functional disability at 6 months, even after adjusting for age, comorbidity and baseline mHAQ. Greater emphasis on smoking cessation may improve long-term functional outcomes in IA patients on bDMARDs., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias., Methods: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis., Findings: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]., Interpretation: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Establishing a potent scheme against α-synuclein aggregation involved in Parkinson's disease has been evaluated as a promising route to identify compounds that either inhibit or promote the aggregation process of α-synuclein. In the last two decades, this perspective has guided a dramatic increase in the efforts, focused on developing potent drugs either for retardation or promotion of the self-assembly process of α-synuclein. To address this issue, using a chemical kinetics platform, we developed a strategy that enabled a progressively detailed analysis of the molecular events leading to protein aggregation at the microscopic level in the presence of a recently synthesized 2-hydroxyisophthalamide class of small organic molecules based on their binding affinity. Furthermore, qualitatively, we have developed a strategy of disintegration of α-synuclein fibrils in the presence of these organic molecules. Finally, we have shown that these organic molecules effectively suppress the toxicity of α-synuclein oligomers in neuron cells.

Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia in the United States, and its prevalence is expected to increase along with associated morbidity and economic burden. Prior research has demonstrated differing prevalence patterns of AF between racial and ethnic groups, with lower rates identified in Black patients. However, to date there have been no studies on AF prevalence in people of Middle Eastern descent within the United States. This retrospective cross-sectional study aimed to characterize prevalence patterns of AF in Middle Eastern patients in Southeast Michigan relative to White and Black patients. The final cohort included 919,454 patients with a median (IQR) age of 53 (33) years (515,902 [56 %] female). The overall prevalence of AF was approximately 5 %. We observed a lower prevalence of AF in Middle Eastern (2.8 %) and Black patients (3.4 %) than in White patients (6.5 %). Middle Eastern patients with AF were younger with a lower prevalence of cardiovascular risk factors than White patients. Multivariable analysis showed that Middle Eastern (OR 0.75; 95 % CI 0.71-0.80; P < 0.001) and Black racial identity (OR 0.48; 95 % CI 9.47-0.49; P < 0.001) were associated with a lower odds of AF, even after adjustment for traditional risk factors., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Several models have been developed to study cancer, such as rodent models and established cell lines. Valuable insights into carcinogenesis have been provided by studies using these models. Cell lines have provided an understanding of the deregulation of molecular signaling associated with breast tumorigenesis, while rodent models are widely used to study cellular and molecular characteristics of breast cancer in vivo. The establishment of 3D cultures of breast epithelial and cancerous cells aids in bridging the gap between in vivo and in vitro models by mimicking the in vivo conditions in vitro. This model can be used to understand the deregulation of complex molecular signaling events and the cellular characteristics during breast carcinogenesis. Here, a 3D culture system is modified to study a phospholipid mediator-induced (Platelet Activating Factor, PAF) transformation. Immunomodulators and other secreted molecules play a major role in tumor initiation and progression in the breast. In the present study, 3D acinar cultures of breast epithelial cells are exposed to PAF exhibited transformation characteristics such as loss of polarity and altered cellular characteristics. This 3D culture system will assist in shedding light on genetic and/or epigenetic perturbations induced by various small molecule entities in the tumor microenvironment. Additionally, this system will also provide a platform for the identification of novel as well as known genes that may be involved in the process of transformation.

To characterise gout patients at high risk of hospitalisation and to develop a web-based prognostic model to predict the likelihood of gout-related hospital admissions. This was a retrospective single-centre study of 1417 patients presenting to the emergency department (ED) with a gout flare between 2015 and 2017 with a 1-year look-back period. The dataset was randomly divided, with 80% forming the derivation and the remaining forming the validation cohort. A multivariable logistic regression model was used to determine the likelihood of hospitalisation from a gout flare in the derivation cohort. The coefficients for the variables with statistically significant adjusted odds ratios were used for the development of a web-based hospitalisation risk estimator. The performance of this risk estimator model was assessed via the area under the receiver operating characteristic curve (AUROC), calibration plot, and brier score. Patients who were hospitalised with gout tended to be older, less likely male, more likely to have had a previous hospital stay with an inpatient primary diagnosis of gout, or a previous ED visit for gout, less likely to have been prescribed standby acute gout therapy, and had a significant burden of comorbidities. In the multivariable-adjusted analyses, previous hospitalisation for gout was associated with the highest odds of gout-related admission. Early identification of patients with a high likelihood of gout-related hospitalisation using our web-based validated risk estimator model may assist to target resources to the highest risk individuals, reducing the frequency of gout-related admissions and improving the overall health-related quality of life in the long term. KEY POINTS : • We reported the characteristics of gout patients visiting a tertiary hospital in Singapore. • We developed a web-based prognostic model with non-invasive variables to predict the likelihood of gout-relatedhospital admissions., (© 2021. The Author(s).)

Background and Purpose: Health-Related Quality of Life (HR-QOL) is an important patient-reported domain in patients with rheumatoid arthritis (RA). The uptake of multidisciplinary team (MDT) care in RA is generally low, due to initial high demand for resources. We hypothesised that whilst pharmacological treatments are effective in controlling disease activity, a multipronged intervention in an MDT may have a positive impact on HR-QOL., Methods: This was a single-centre randomized parallel group, single-blind controlled trial of MDT vs. usual care in an established RA clinic. Data were collected through face-to-face questionnaires, medical records review, and joint counts by a blinded assessor at 0, 3 and 6 months. Adult RA patients were randomly assigned in a single visit to a 6-member MDT (rheumatologist, nurse, social worker, physiotherapist, occupational therapist, and podiatrist) or usual care. MDT providers prescribed medications and counselled patients on managing flares, medication adherence, coping, joint protection, exercise, footwear. The primary outcome was minimal clinically important difference (MCID) in HR-QOL (increase in European QOL-5-Dimension-3-Level, EQ-5D-3L by 0.1) at six months., Results: 140 patients (86.3% female, 53.4% Chinese, median (IQR) age 56.6 (46.7, 62.4) years); 70 were randomized to each arm. Median (IQR) disease duration was 5.5 (2.4, 11.0) years and disease activity in 28 joints (DAS28) was 2.87 (2.08, 3.66). 123 patients completed the study. Twenty-six (40.6%) MDT vs. 23 (34.3%) usual care patients achieved an MCID in EQ-5D-3L, OR 1.3 (0.6, 2.7). In multivariable logistic regression, baseline EQ-5D-3L was the only predictor of achieving MCID. There was more disease modifying anti-rheumatic drug escalation in MDT (34.4% vs. 19.4%). Patients with high disease activity were more likely to achieve MCID in the MDT arm., Conclusions: A single visit by stable patients with low disease activity to an MDT failed to achieve MCID in the EQ-5D-3L; however, did achieve small but significant improvements in the EQ-5D-3L, DAS28, pain, coping and self-efficacy. To be sustainable, MDT care should be targeted at patients with high disease activity or those with a new diagnosis of RA., Trial Registration: The study is registered on ClinicalTrials.gov, identifier: NCT03099668., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Multifunctional organic luminogens exhibiting simultaneous aggregation induced emission (AIE), room-temperature phosphorescence (RTP), and mechanochromism have recently attracted considerable attention owing to their potential applications in optoelectronics and bioimaging. However, a comprehensive correlation among these three distinguished properties is yet to be unveiled, which will help to decipher defined methodologies to design future generation multifunctional organic materials. Herein, we have demonstrated a route to obtain a multifunctional organic luminogen, starting from an ACQphore (TPANDI) by simple structural engineering. We have shown that a slight reduction in length of the planar acceptor moieties can effectively inhibit the undesirable π-π stacking interaction between molecules in the condensed state and thereby cause an ACQ to AIE type transformation from TPANDI to TPANMI and TPAPMI. Both TPANMI and TPAPMI exhibit RTP properties (even in ambient condition) because of the presence of a reasonably low singlet-triplet energy gap (Δ E ST ). In our study, these two luminogens were found to be mechano-inactive. Interestingly, an insertion of cyano-ethylene group and benzene linker in between the triphenylamine and phthalimide moieties introduced another luminogen TPACNPMI, which can simultaneously exhibit AIE, RTP, and mechanochromic properties.

Quantum imaging with undetected photons (QIUP) is a unique method of image acquisition where the photons illuminating the object are not detected. This method relies on quantum interference and spatial correlations between the twin photons to form an image. Here we present a detailed study of the resolution limits of position correlation enabled QIUP. We establish a quantitative relation between the spatial resolution and the twin-photon position correlation. Furthermore, we also quantitatively establish the roles that the wavelength of the undetected illumination field and the wavelength of the detected field play in the resolution. Like ghost imaging and unlike conventional imaging, the resolution limit imposed by the spatial correlation between the twin photons in QIUP cannot be further improved by conventional optical techniques.

Background and Purpose: With the increasing emphasis on personal and professional development in pharmacy curricula, programs often need to enhance or modify existing resources to meet standards. A major initiative of developing a consistent and standardized student advising process involving both clinical and non-clinical faculty as advisors to promote development of pharmacy students was an avenue taken at our institution., Educational Activity and Setting: Faculty were identified as ideal individuals to assist in mentoring and assessing students' personal and professional development given the long-term relationships they develop with students throughout both the didactic and experiential curriculum. Development and implementation of a longitudinal faculty advising program incorporating elements of student self-assessment, reflection, and faculty-based objective assessment is described., Findings: We found both students and faculty benefited from this advising program in different ways, with students feeling more supported and faculty feeling more engaged and informed about the pharmacy curricula and student career-pathways., Summary: A faculty advising program, as described in this article, can be utilized for both student success and faculty development in the pharmacy education setting., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Clinical remission is an attainable goal for Rheumatoid Arthritis (RA). However, data on RA remission rates from multinational studies in the Asia-Pacific region are limited. We conducted a cross-sectional multicentric study to evaluate the clinical remission status and the related factors in RA patients in the Asia-Pacific region., Methods: RA patients receiving standard care were enrolled consecutively from 17 sites in 11 countries from APLAR RA SIG group. Data were collected on-site by rheumatologists with a standardized case-report form. Remission was analyzed by different definitions including disease activity score using 28 joints (DAS28) based on ESR and CRP, clinical disease activity index (CDAI), simplified disease activity index (SDAI), Boolean remission definition, and clinical deep remission (CliDR). Logistic regression was used to determine related factors of remission., Findings: A total of 2010 RA patients was included in the study, the overall remission rates were 62•3% (DAS28-CRP), 35•5% (DAS28-ESR), 30•8% (CDAI), 26•5% (SDAI), 24•7% (Boolean), and 17•1% (CliDR), respectively, and varied from countries to countries in the Asia-Pacific region. Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) prescription rate was low (17•9%). Compared to patients in non-remission, patients in remission had higher rates of b/tsDMARDs usage and lower rates of GC usage. The favorable related factors were male sex, younger age, fewer comorbidities, fewer extra-articular manifestations (EAM), and use of b/tsDMARDs, while treatment with GC was negatively related to remission., Interpretation: Remission rates were low and varied in the Asia-Pacific region. Treatment with b/tsDMARDs and less GC usage were related to higher remission rate. There is an unmet need for RA remission in the Asia-Pacific region., Competing Interests: ML reports speaker fees from Abbvie and Johnson & Johnson, conference sponsorship from Johnson & Johnson, Pfizer, and Sanofi, and has provided advisory services for Gilead, Eli Lilly. KF has received grants or contracts from Chugai, Bristol Myers, Abbvie, Otsuka Pharmaceutical, Eli Lilly, Pfizer, Tsumura, Asahi Kasei, Mitsubishi Tanabe, Esai, Japan Blood Products Organization, Novartis, Sanofi, and Astellas, reports payments or honoraria from Astellas, Abbvie, Amgen, Ayumi, MSD, Esai, Ono, Gilead, Kowa, Sanofi, Japan Blood Products Organization, Novartis, Pfizer, Bristol Myers, Mylan EPD, Janssen, Asahi Kasei, Daiichi Sankyo, Chugai, Mitsubishi Tanabe, Eli Lilly, and Boehringer Ingelheim and has participated in the Data Safety Monitoring Board or Advisory Board for Asahi Kasei, Astellas, Abbvie, Amgen, Ono, Gilead, Chugai, Eli Lilly, Bristol Myers, and Mylan EPD. PC reports honoraria from Novartis and Johnson and Johnson, is a member of the advisory board for Johnson & Johnson, and reports samples of Amgevita, Baricitinib, and Ixekizumab. All other authors declare no competing interests., (© 2021 The Authors. Published by Elsevier Ltd.)

Api5, is a known anti-apoptotic and nuclear protein that is responsible for inhibiting cell death in serum-starved conditions. The only known post-translational modification of Api5 is acetylation at lysine 251 (K251). K251 acetylation of Api5 is responsible for maintaining its stability while the de-acetylated form of Api5 is unstable. This study aimed to find out the enzymes regulating acetylation and deacetylation of Api5 and the effect of acetylation on its function. Our studies suggest that acetylation of Api5 at lysine 251 is mediated by p300 histone acetyltransferase while de-acetylation is carried out by HDAC1. Inhibition of acetylation by p300 leads to a reduction in Api5 levels while inhibition of deacetylation by HDAC1 results in increased levels of Api5. This dynamic switch between acetylation and deacetylation regulates the localisation of Api5 in the cell. This study also demonstrates that the regulation of acetylation and deacetylation of Api5 is an essential factor for the progression of the cell cycle., (© 2021. The Author(s).)

Quantum imaging with undetected photons (QIUP) is a unique imaging technique that does not require the detection of the light used for illuminating the object. This technique requires a correlated pair of photons. In the existing implementations of QIUP, the imaging is enabled by the momentum correlation between the twin photons. We investigate the complementary scenario in which the imaging is instead enabled by the position correlation between the two photons. We present a general theory and show that the properties of the images obtained in these two cases are significantly distinct.

The endoplasmic reticulum (ER) is one of the crucial sub-cellular organelles controlling myriads of functions including protein biosynthesis, folding, misfolding and unfolding. As a result, dysregulation of these pathways in the ER is implicated in cancer development and progression. Subsequently, targeting the ER in cancer cells emerged as an interesting unorthodox strategy in next-generation anticancer therapy. However, development of small molecules to selectively target the ER for cancer therapy remained elusive and unexplored. To address this, herein, we have developed a novel small molecule library of sulfonylhydrazide-hydrazones through a short and concise chemical synthetic strategy. We identified a fluorescent small molecule that localized into the endoplasmic reticulum (ER) of HeLa cells, induced ER stress followed by triggering autophagy which was subsequently inhibited by chloroquine (autophagy inhibitor) to initiate apoptosis. This small molecule showed remarkable cancer cell killing efficacy in different cancer cells as mono and combination therapy with chloroquine, thus opening a new direction to illuminate ER-biology towards the development of novel anticancer therapeutics., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: People with rheumatic diseases (PRD) remain vulnerable in the era of the COVID-19 pandemic. We formulated recommendations to meet the urgent need for a consensus for vaccination against SARS-CoV-2 in PRD., Methods: Systematic literature reviews were performed to evaluate: (a) outcomes in PRD with COVID-19; (b) efficacy, immunogenicity and safety of COVID-19 vaccination; and (c) published guidelines/recommendations for non-live, non-COVID-19 vaccinations in PRD. Recommendations were formulated based on the evidence and expert opinion according to the Grading of Recommendations Assessment, Development and Evaluation methodology., Results: The consensus comprises 2 overarching principles and 7 recommendations. Vaccination against SARS-CoV-2 in PRD should be aligned with prevailing national policy and should be individualized through shared decision between the healthcare provider and patient. We strongly recommend that eligible PRD and household contacts be vaccinated against SARS-CoV-2. We conditionally recommended that the COVID-19 vaccine be administered during quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued alongside vaccination. We conditionally recommend that the COVID-19 vaccine be administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the next dose of rituximab. Post-vaccination antibody titers against SARS-CoV-2 need not be measured. Any of the approved COVID-19 vaccines may be used, with no particular preference., Conclusion: These recommendations provide guidance for COVID-19 vaccination in PRD. Most recommendations in this consensus are conditional, reflecting a lack of evidence or low-level evidence., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Lipid species are known to have various biological functions owing to their structural differences, and each of them possesses a specific role to play depending upon their location and distribution in the cell. Some of these lipids interact with proteins on the cell membrane and acts as second messengers. The level of lipid mediators is generally maintained in the cell by feedback mechanisms; however, their improper degradation or enhanced production leads to their accumulation in the tumor microenvironment and disturbs the homeostasis of the cell. Platelet activating factor (PAF) is a known phospholipid mediator secreted upon immunological challenges by platelets, neutrophils, basophils, and macrophages. PAF, as a potent inflammatory molecule, is well studied, and its role in various cancers and cardiovascular diseases has also been investigated. Interestingly, increased levels of PAF have been found in the blood plasma of smokers, and breast cancer cells have shown the accumulation of PAF in presence of cigarette smoke extract. This accumulation was found to increase tumor cell motility that in turn could promote metastasis. Beyond this, however, the effect of PAF on tumorigenesis has not yet been well explored. Here, we show that the continuous exposure of 3D breast acinar cultures to PAF resulted in the activation of various oncogenic signaling pathways leading to transformation. We also found that the presence of PAF in the micro-environment increased the expression of PAF receptor (PAF-R), which corroborated with the higher expression of PAF-R detected in some epithelial cancers, as per literature. Thus, this study impresses on the fact that the presence of PAF alters the cellular microenvironment and eventually triggers irreversible effects that can cumulatively lead to transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chakravarty, Anandi, Ashiq, Abhijith, Umesh and Lahiri.)

Objective. To evaluate a tool designed to assess Doctor of Pharmacy (PharmD) students' personal and professional development prior to beginning advanced pharmacy practice experiences (APPEs). Methods. A five-item instrument, entitled the Faculty Advisor's Assessment of the Advisee (FAAA) tool, was developed to assess and monitor pharmacy students' progress over the three-year didactic curriculum. Question anchors were created to describe characteristics exhibited by the student that matched categories of not engaged, beginning, emerging, or engaged. Possible FAAA composite scores ranged from 7 to 20. Using the FAAA tool, faculty advisors assessed their advisees' values, engagement, self-awareness, professionalism, and leadership in 2017, 2018, and 2019. Individual and aggregate cohort reports were run and data for each of the three years were matched with students. To determine if the FAAA showed progression in assessed dimensions in the students during the first, second, and third professional (P1, P2, and P3) years, a Friedman test was performed. Cronbach alpha was used to assess the reliability of the instrument. Results. The data of 93 students were matched for the P1 through the P3 years. Median (IQR) for the FAAA composite score levels for the P1, P2, and P3 were 13 (12-16), 17 (15-19) and 18 (16-20), respectively. Significant differences existed at all timepoints compared, including from the P1 to P2, P2 to P3, and P1 to P3 years. The reliability of the FAAA scale was strong across all three years (winter 2017, α=0.87; winter 2018, α=0.89; and winter 2019, α=0.87). All items appeared worthy of retention as removal did not significantly increase their reliability. Conclusion. A five-item tool which assesses pharmacy students' personal and professional development during the first three years of a PharmD program could be used by faculty advisors to assess student's progress across the didactic curriculum., (© 2021 American Association of Colleges of Pharmacy.)

Introduction: The objective of this project was to evaluate the effect of adjusting the solution reporting phase of problem-based learning (PBL) while keeping core components of the pedagogy constant., Methods: A PBL course for third year pharmacy students changed delivery of the problem solution from a written format to a verbal defense. Comparisons were made between the written format and verbal defense groups. The primary outcome was the change in the motivation domain of the Motivated Strategies for Learning Questionnaire (MSLQ). Secondary outcomes included evaluation of the learning strategies domain of the MSLQ, changes in MSLQ scores within each group, exam scores, and themes identified using focus groups., Results: There was no difference in the change of motivation and learning domains between the groups. However, scores in both groups increased significantly from the beginning to the end of the semester for both motivation and learning. There was no difference in exam scores and facilitator confidence between groups. Themes from focus groups who used the written format were appreciation of PBL outcomes, discomfort with the pedagogy, and disconnect of assessments. Themes from the verbal format group were realism, increased confidence, and comments with course logistics., Conclusions: No difference in motivation and learning was observed between the groups, although both groups improved over the course of the semester. Changes to PBL approach within the confines of the pedagogy may not impact motivation and learning., Competing Interests: Declaration of competing interest None, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate attitudes and behaviors of patients with rheumatic diseases during the coronavirus disease 2019 (COVID-19) pandemic., Methods: An online survey delivered by text message to 4695 patients on follow-up at a tertiary rheumatology center. Latent class analysis was performed on the survey variables., Results: There were 2239 (47.7%) who responded to the survey and 3 clusters were identified. Cluster 3 (C3) was defined by patients who were most worried about COVID-19, more likely to wear face masks, and more likely to alter or stop their medications. Patients in C3 were more likely to be female, Malay, and unemployed., Conclusion: We identified 3 clusters with different healthcare beliefs and distinct sociodemographics.

The formation of a supramolecular synthetic M + /Cl - channel in the membrane phospholipid bilayer has been reported upon activation of a methyl pivalate-linked N 1 ,N 3 -dialkyl-2-hydroxyisophthalamide by esterases. The channel formation induces apoptosis in cancer cells via the intrinsic pathway. Interestingly, the supramolecular channel was also shown to disrupt autophagy in cancer cells by causing alkalization of lysosomes - a feature that has been confirmed at the cellular and protein level., (© 2020 Wiley‐VCH GmbH.)

Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance. In this study, we describe a novel 2,4-nitrobenzenesulfonyl (DNS) protected 2-hydroxyisophthalamide system that exploits GSH for its activation into free 2-hydroxyisophthalamide forming supramolecular M + /Cl - channels. Better permeation of the DNS protected compound into MCF-7 cells compared to the free 2-hydroxyisophthalamide and GSH-activatable ion transport resulted in higher cytotoxicity, which was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway. The GSH-activatable transport-mediated cell death was further validated in rat insulinoma cells (INS-1E); wherein the intracellular GSH levels showed a direct correlation to the resulting cytotoxicity. Lastly, the active compound was found to restrict the growth and proliferation of 3D spheroids of MCF-7 cells with efficiency similar to that of the anticancer drug doxorubicin., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: The field of axial spondyloarthritis (axSpA) has undergone significant changes recently in particular with disease classification, assessment of disease activity and increased treatment options for biologics. In order to reflect these developments, we aimed to update the local consensus recommendations for subsidization of biologics., Methods: A modified Delphi approach was used. Six published guidelines from major rheumatology societies and healthcare authorities on axSpA were reviewed. Findings were synthesized and used in formulating updated recommendation statements. Recommendations were rated by 10 practicing rheumatologists in Singapore. Consensus was reached if there was more than 70% agreement or disagreement., Results: Ten statements achieved consensus. Patients may be considered for subsidization of biologic therapy if they fulfill the Assessment of Spondyloarthritis International Society or modified New York criteria, with persistently active disease (defined either by Ankylosing Spondylitis Disease Activity Score ≥ 2.1 or Bath Spondylitis Disease Activity Index ≥ 4), despite 4 weeks of full-dose non-steroidal anti-inflammatory drugs and regular exercise. Either tumor necrosis factor inhibitors or interleukin 17 inhibitors may be used as first-line therapy, and should be continued if adequate response is achieved at 6 months., Conclusion: Recommendation statements were formulated through a formal consensus process by local experts with a view to assist relevant authorities in funding considerations and for use in clinical practice., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Approximately 30% of patients with rheumatoid arthritis (RA) respond inadequately to conventional-synthetic disease-modifying anti-rheumatic drugs (csDMARDs). However, widespread use of biologic DMARDs (bDMARDs) and targeted-synthetic (tsDMARDs) is limited by cost. We formulated updated recommendations for eligibility criteria for government-assisted funding of bDMARDs/tsDMARDs for RA patients in Singapore., Materials and Methods: Published guidelines regarding use of bDMARD and tsDMARDs were reviewed. We excluded those without a systematic literature review, formal consensus process or evidence grading. Separately, unpublished national reimbursement guidelines were included., Results: Eleven recommendations regarding choice of disease activity measure, initiation, order of selection and continuation of bDMARD/tsDMARDs were formulated. A bDMARD/tsDMARD is indicated if a patient has: (a) at least moderately active RA with a Disease Activity Score in 28 joints/erythrocyte sedimentation rate (DAS28-ESR) score of ≥3.2; (b) failed ≥2 csDMARD strategies, 1 of which must be a combination; (c) received an adequate dose regimen of ≥3 months for each strategy. For the first-line bDMARD/tsDMARD, either tumor necrosis factor inhibitors (TNFi), non-TNFi (abatacept, tocilizumab, rituximab), or tsDMARDs, may be considered. If a first-line TNFi fails, options include another TNFi, non-TNFi biologic or tsDMARDs. If a first-line non-TNFi biologic or tsDMARD fails, options include TNFi or another non-TNF biologic or tsDMARD. For continued bDMARD/tsDMARD subsidization, a patient must have a documented DAS28-ESR every 3 months and at least a moderate European League Against Rheumatism response by 6 months., Conclusion: These recommendations are useful for guiding funding decisions, making bDMARD/tsDMARDs usage accessible and equitable in RA patients who fail csDMARDs., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Aim: There have been major advances in biologic treatment options for psoriatic arthritis (PsA) since the publication of the 2015 consensus recommendations by the Chapter of Rheumatologists, College of Physicians, Academy of Medicine, Singapore, for government-assisted funding, thus warranting a revision of this guideline., Methods: Recent trials and nine published guidelines on the use of biologic therapy for PsA were reviewed. Based on the synthesized evidence, a task force panel (TFP), consisting of 10 practicing rheumatologists in Singapore, rated the statements pertaining to the use of biologic therapy, using a modified Delphi approach. Consensus was obtained if >70% agreed on a statement., Results: The TFP agreed on 10 recommendations pertaining to the initiation, choice and continuation of biologic therapy. A biologic is indicated in patients with PsA: (a) with at least three swollen and tender joints, digits or entheses; and (b) who have failed at least two conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) strategies for a minimum of 3 months each. Any approved drug class including tumor necrosis factor inhibitors, interleukin-17 inhibitors (IL-17i), IL-12/23i or targeted synthetic DMARDs may be considered as first-line treatment, and continued only if a response is achieved by 6 months., Conclusion: These recommendations developed through a formal consensus method may be useful to guide funding considerations for appropriate and equitable use of biologic therapy for eligible patients with PsA., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Synthetic transmembrane ion transport systems are emerging as new tools for anticancer therapy. Here, a series of 2-hydroxy- N 1 -diarylisophthalamide-based fluorescent ion channel-forming compounds are reported. Ion transport studies across large unilamellar vesicles confirmed that the compound with two 3,5-bis(trifluoromethyl)phenyl arms is the most efficient transporter among the series and it facilitates M N 3 -diarylisophthalamide-based fluorescent ion channel-forming compounds are reported. Ion transport studies across large unilamellar vesicles confirmed that the compound with two 3,5-bis(trifluoromethyl)phenyl arms is the most efficient transporter among the series and it facilitates M + /Cl - symport. The compound formed supramolecular ion channels with a single-channel conductance of 100 ± 2 pS, a diameter of 5.06 ± 0.16 Å and a permeability ratio, P Cl - / P K + , of 8.29 ± 1. The molecular dynamics simulations of the proposed M2.11 channel ( i.e. 11 coaxial layers of a dimeric rosette) with K + and Cl - in the preequilibrated POPC lipid bilayer with water molecules illustrated various aspects of channel formation and ion permeation. Cell viability assay with the designed compounds indicated that cell death is being induced by the individual compounds which follow the order of their ion transport activity and chloride and cations play roles in cell death. The inherent fluorescence of the most active transporter was helpful to monitor its permeation in cells by confocal microscopy. The apoptosis-inducing activity upon perturbation of intracellular ionic homeostasis was established by monitoring mitochondrial membrane depolarization, generation of reactive oxygen species, cytochrome c release, activation of the caspase 9 pathway, and finally the uptake of the propidium iodide dye in the treated MCF7 cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: This study aims to describe the association between sociodemographic factors and trajectories of disease, disability and health-related quality of life (HRQoL) in early rheumatoid arthritis (ERA)., Methods: Data were collected prospectively over 3 years in the Singapore Early Arthritis Cohort study. Trajectories were modeled using multi-trajectory group-based trajectory modeling (GBTM) and determinants of trajectory membership were identified using multinomial logistic regression., Results: Two hundred and thirteen patients were included: 58.2% Chinese, 16.4% Malay, 21.6% Indian, mean (SD) age 51.3 (12.6) years and symptom duration 21.8 (15.3) weeks. In the multi-trajectory analysis, three groups of disease trajectories and corresponding disability and HRQoL trajectories were identified: group 1 (moderate disease rapid response, 49.9%), group 2 (high disease rapid response, 31.1%) and group 3 (high disease slow response, 19.1%). Malay patients had higher relative risk ratio (RRR) of being in trajectory groups 2 and 3 compared to group 1 (RRR = 2.30, 95% CI 1.05-3.98 and RRR = 4.02, 95% CI 1.45-6.43, respectively) while patients with tertiary education had lower relative risk (RRR = 0.56, 95% CI 0.45-0.89 and RRR = 0.33, (95% CI 0.14-0.83, respectively). In the analysis of individual outcomes, ethnicity, education level and body mass index were determinants of the heterogeneous disease activity trajectories. Gender and education level were determinants of the disability trajectories. Only gender was a determinant of the HRQoL trajectories. Further, 96.2% of the patients were treated with conventional synthetic disease-modifying antirheumatic drugs., Conclusion: Disparities in sociodemographic factors should be taken into consideration in formulating treatment strategies in ERA., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Interval laboratory investigations are necessary for monitoring chronic diseases. However, testing too frequently may not be beneficial clinically and can be considered low-value care. We examined the frequency of glycosylated haemoglobin, lipids, iron panels (serum iron, ferritin, transferrin, iron binding) thyroid function (free T4 and thyroid stimulating hormone) and 25-OH vitamin D tests in a 1290-bed tertiary hospital in Singapore. All tests done over a 20-month period (January 2016 to August 2017) were retrieved from the laboratory database. Of the 275 565 tests done for 115 971 patients, 5.2% were repeat tests done at intervals shorter than the minimum retesting interval, as defined by the Royal College of Pathologist and Irish Guidelines on the Use of the Laboratory. Using the Centers for Medicare and Medicaid Services Clinical Laboratory Fee Schedule, we estimated a cost burden of US$222 096 per year. Strategies to reduce unnecessary repetitive testing can result in significant cost savings., (© 2019 Royal Australasian College of Physicians.)

Objectives: Data on flares in Asian patients with systemic lupus erythematosus (SLE) are scarce. Here, we aim to identify the baseline predictors of flares in a cohort of Southeast Asian patients with SLE., Methods: Consecutive adult patients with prevalent SLE according to the 1997 ACR or 2012 SLICC criteria were enrolled and followed three-monthly. Clinical and laboratory data were collected at every visit using a standardised protocol. Flares were defined using the SELENA-SLEDAI Flare Index (SFI). Baseline predictors of flare in patients with stable disease (SLE Disease Activity Index-2K (SLEDAI-2K) of ≤ 4) were determined using Cox proportional hazards., Results: Of the 210 patients recruited, 148 (70.5%) were Chinese. The median (IQR) SLEDAI-2K at entry was 2 (0-4) and the median (IQR) disease duration was 10 (4.4-16.4) years. At baseline, 152 (72.4%) patients had stable disease. After a median (IQR) follow-up of 31.5 (24.1-36.3) months, 109 (51.9%) flared. Stable patients who flared tended to be in the lowest tertile of age (HR 3.08, 95% CI 1.72-5.48, p < 0.01), had thrombocytopenia (HR 5.01, 95% CI 1.32-18.99, p = 0.02), hypocomplementemia (HR 3.35, 95% CI 1.54-7.30, p < 0.01) and had the highest baseline prednisolone doses (HR 2.39, 95% CI 1.28-4.46, p = 0.01). Conversely, patients in the lowest tertile of disease duration tended not to flare (HR 0.41, 95% CI 0.21-0.80, p = 0.01)., Conclusion: Flares are common in Asian SLE patients with initial stable disease. Close monitoring is needed for patients who are younger, with longer disease duration, thrombocytopenia, hypocomplementemia, or who required a higher baseline prednisolone dose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fork stabilization at DNA impediments is key to maintaining replication fork integrity and preventing chromosome breaks. Mrc1 and Tof1 are two known stabilizers that travel with the replication fork. In addition to a structural role, Mrc1 has a DNA damage checkpoint function. Using a yeast model system, we analyzed the role of Mrc1 and Tof1 at expanded CAG repeats of medium and long lengths, which are known to stall replication forks and cause trinucleotide expansion diseases such as Huntington's disease and myotonic dystrophy. We demonstrate that the fork stabilizer but not the checkpoint activation function of Mrc1 is key for preventing DNA breakage and death of cells containing expanded CAG tracts. In contrast, both Mrc1 functions are important in preventing repeat length instability. Mrc1 has a general fork protector role that is evident at forks traversing both repetitive and non-repetitive DNA, though it becomes crucial at long CAG repeat lengths. In contrast, the role of Tof1 in preventing fork breakage is specific to long CAG tracts of 85 or more repeats. Our results indicate that long CAG repeats have a particular need for Tof1 and highlight the importance of fork stabilizers in maintaining fork integrity during replication of structure-forming repeats.

Introduction: Data on inappropriate and appropriate ICD therapy, and efficacy of ICD programing strategies by race are limited., Methods: In MADIT-RIT, we evaluated the risk of ICD therapy by race, and the efficacy of high rate cut-off ventricular tachycardia (VT) zone ≥200 beats per minute (bpm) (Arm B), or 60 seconds delay in VT zone 170-199 bpm (Arm C), compared to 2.5 seconds delay at 170 bpm (Arm A) among black and white patients., Results: MADIT-RIT enrolled 272 (20%) black and 1119 (80%) white patients. The risk of inappropriate therapy was similar among blacks and whites, HR 1.25, 95% CI (0.82-1.93), P  =  0.30. High rate cut-off or delayed VT therapy was associated with significant reductions in inappropriate therapy among whites, Arm B versus Arm A, HR 0.15, 95% CI (0.08-0.29), P < 0.0001, Arm C versus Arm A, HR 0.19, 95% CI (0.11-0.33), P < 0.001, and black individuals Arm B versus Arm A, HR 0.24, 95% CI (0.01-0.56), P  =  0.0001, Arm C versus Arm A, HR 0.30, 95% CI (0.13-0.68), P  =  0.004, P interaction > 0.10). However, delayed VT therapy was associated with a trend toward greater reduction in appropriate therapy in black individuals, HR 0.08, 95% CI (0.03-0.27), P < 0.0001 relative to white individuals, HR 0.27, 95% CI (0.16-0.43), P < 0.0001, P interaction  =  0.077., Conclusion: In MADIT-RIT, high rate and delayed detection ICD programming provided similar benefit with reductions in both inappropriate therapy and unnecessary appropriate therapy among black and white individuals. CLINICALTRIALS., Gov Identifier: NCT00947310., (© 2018 Wiley Periodicals, Inc.)

Breast cancer is the most devastating disease among females globally. Conventional chemotherapeutic regimen relies on the use of highly cytotoxic drugs as monotherapy and combination therapy leading to severe side effects to the patients as collateral damage. Moreover, combining hydrophobic and hydrophilic drugs create erratic biodistribution and suboptimal medicinal outcome. Hence, packaging multiple drugs of diverse mechanisms of action and biodistribution for safe delivery into tumor tissues with optimal dosages is indispensable for next-generation breast cancer therapy. To address these, in this report, we describe a unique cisplatin-triggered self-assembly of linear polymer into 3D-spherical sub 200 nm particles. These nanoparticles comprise a hydrophobic (paclitaxel) and hydrophilic drug (cisplatin) simultaneously in a single particle. Molecular dynamics simulation revealed hydrophilic-hydrophilic interaction and interchain H-bonding as underlying mechanisms of self-assembly. Confocal microscopy studies evidently demonstrated that these novel nanoparticles can home into lysosomes in breast cancer cells, fragment subcellular nuclei, and prevent cell division, leading to improved breast cancer cell death compared to free drug combination. Moreover, 3D-breast tumor spheroids were reduced remarkably by the treatment of these nanoparticles within 24 h. These dual-drug-loaded self-assembled polymeric nanoparticles have prospective to be translated into a clinical strategy for breast cancer patients., Competing Interests: The authors declare no competing financial interest.

DNA alkylating agents form the first line of cancer chemotherapy. They not only kill cells but also behave as potential carcinogens. MNU, a DNA methylating agent, is well known to induce mammary tumours in rodents. However, the mechanism of tumorigenesis is not well understood. Our study reports a novel role played by DNA-dependent protein kinase (DNA-PK) in methylation damage-induced transformation using three-dimensional breast acinar cultures. Here, we report that exposure of breast epithelial cells to MNU inhibited polarisation at the basolateral domain, increased dispersal of the Golgi at the apical domain and induced an epithelial-to-mesenchymal transition (EMT)-like phenotype as well as invasion. This altered Golgi phenotype correlated with impaired intracellular trafficking. Inhibition of DNA-PK resulted in almost complete reversal of the altered Golgi phenotype and partial rescue of the polarity defect and EMT-like phenotype. The results confirm that methylation damage-induced activation of DNA-PK is a major mechanism in mediating cellular transformation.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Aim: In Singapore, patients with psoriatic arthritis (PsA) constitute a significant disease burden. There is good evidence for the efficacy of anti-tumor necrosis factor (anti-TNF) in PsA; however cost remains a limiting factor. Non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) hence remain the first-line treatment option in PsA in spite of limited evidence. The Singapore Chapter of Rheumatologists aims to develop national guidelines for clinical eligibility for government-assisted funding of biologic disease modifying anti- rheumatic drugs (bDMARDs) for PsA patients in Singapore., Methods: Evidence synthesis was performed by reviewing seven published guidelines on use of biologics for PsA. Using the modified Research and Development/University of California at Los Angeles Appropriateness Method (RAM), rheumatologists rated indications for therapies for different clinical scenarios. Points reflecting the output from the formal group consensus were used to formulate the practice recommendations., Results: Ten recommendations were formulated relating to initiation, continuation and options of bDMARD therapy. The panellists agreed that a bDMARD is indicated if a patient has active PsA with at least five swollen and tender joints, digits or entheses and has failed two nbDMARD strategies at optimal doses for at least 3 months each. Any anti-TNF may be used and therapy may be continued if an adequate PsARC response is achieved by 3 months after commencement., Conclusion: The recommendations developed by a formal group consensus method may be useful for clinical practice and guiding funding decisions by relevant authorities in making bDMARD usage accessible and equitable to eligible patients in Singapore., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Introduction: The beneficial effects of biologic disease-modifying anti-rheumatic drugs (bDMARDs), such as tumour necrosis factor inhibitors (anti-TNF) in active ankylosing spondylitis (AS) are well established. The significant costs on patients in the absence of financial subsidization can limit their use. The objective was to describe a consensus development process on recommendations for government-assisted funding of biologic therapy for AS patients in Singapore., Methods: Evidence synthesis followed by a modified RAND/UCLA Appropriateness Method (RAM) was used. Eleven rheumatologists rated indications for therapies for different proposed clinical scenarios. Points reflecting the output from the formal group consensus were used to formulate 10 practice recommendations., Results: It was agreed that a bDMARD (anti-TNF) is indicated if a patient has active AS with a Bath Ankylosing Spondylitis Activity Index (BASDAI) ≥ 4 and spinal pain of ≥ 4 cm on visual analogue scale (VAS) on two occasions at least 12 weeks apart, despite being on a minimum of two sequential non-steroidal anti-inflammatory drugs at maximal tolerated dose for at least 4 weeks, in addition to adherence to an appropriate physiotherapy program for at least 3 months. To qualify for continued biologic therapy, a patient must have documentation of response every 3 months and at least 50% improvement in BASDAI and reduction of spinal pain VAS ≥ 2 cm., Conclusion: A validated and feasible consensus process can enable pragmatic standardized recommendations to be developed for bDMARD subsidization for AS patients in a local Asian context., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)