tbuckley/cabot-search huggingface dataset:
AB0803 TOTAL GLUCOSIDES OF PAEONY INHIBITING NLRP3 INFLAMMASOME ACTIVATION OF SUBMANDIBULAR GLAND CELLS IN MICE WITH SJÖGREN’S SYNDROME
Authors: T. Jiang, G. Yao
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Sjögren's syndrome (SS) is a chronic systemic autoimmune disease. So far, there is no specific treatment for this disease. Some therapeutic drugs have shown certain effects. However, they also increase the risk of infection and malignant tumors in patients. Therefore, exploring novel medicine with good therapeutic effects and few side effects is urgently needed. Total glucosides of paeony (TGP) is the main active ingredient of white peony. Clinical studies have shown that TGP had certain curative effects in the treatment of rheumatoid arthritis, systemic lupus erythematosus and SS. However, the mechanisms of the beneficial effects of TGP on SS remain to be elucidated. <h3>Objectives:</h3> We aim to explore the relationship between the therapeutic effects of TGP in the treatment of SS and NLRP3 inflammasome activation in submandibular gland (SG) cells. <h3>Methods:</h3> Female non-obese diabetic (NOD) mice were selected as the model of SS. TGP was administered intragastrically every day for 4 weeks in NOD mice. The SS-like symptoms and pathological changes of the SG of mice were analyzed. The activation of NLRP3 inflammasome in SG was detected. The SG cells with activation of NLRP3 inflammasome were treated with or without TGP. Then, NLRP3 inflammasome activation was assessed. <h3>Results:</h3> Compared with control mice, NOD mice showed SS-like symptoms and lymphocyte infiltration in SG, and the expression of NLRP3 inflammasome in SG was significantly increased. The SS-like symptoms were alleviated, and lymphocyte infiltration in SG was reduced, and the level of NLRP3 inflammasome in SG mice was decreased after TGP treatment (Figure 1). TGP also significantly inhibit the activation of NLRP3 inflammasome of SG cells in vitro (Figure 2). <h3>Conclusion:</h3> In summary, our findings indicated that SG cells showed excessive NLRP3 inflammasome activation, other than an injured target in SS. We demonstrated that TGP alleviated the symptoms of experimental Sjögren's syndrome. Our data highlight that the beneficial effects of TGP on SS is related to limit overactivation of NLRP3 inflammasome of SG. These findings not only reveal the new mechanism of TGP in the treatment of SS, but also provide new evidence for the further application of TGP in the treatment of SS. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB1321 EFFECTIVENESS OF JANUS KINASE INHIBITORS IN REFRACTORY TAKAYASU ARTERITIS. CASE REPORTS AND LITERATURE REVIEW
Authors: F. López-Gutiérrez, J. Loricera, J. Narváez, V. Emperiale, R. Blanco
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Takayasu arteritis (TA) can be refractory to immunosuppressive treatment with glucocorticoids and conventional and biologic disease-modifying drugs (cDMARDs and bDMARDs). JAK/STAT signalling pathway is involved in TA, and JAK inhibitors (JAKi) may be useful in its treatment. <h3>Objectives:</h3> To assess the effectiveness of JAKi in TA refractory to cDMARDs and/or bDMARDs. <h3>Methods:</h3> National multicentric study of clinical practice and literature review of TA treated with JAKi. For literature review, search was conducted in PubMed, Embase and the Cochrane library from inception to 30 Nov 2023. <h3>Results:</h3> We present 3 patients (2 women) with TA refractory to FAMEc and/or FAMEb, who received treatment with JAKi. Mean±SD age at JAKi initiation was 47.3±15.0 years. Previous treatment received was: methotrexate (n=3), azathioprine (n=1), mycophenolate mofetil (n=1), cyclophosphamide (n=1), infliximab (n=3), tocilizumab (n=3), etanercept (n=1), rituximab (n=1), and ustekinumab (n=1). A 30 yo woman started baricitinib (BARI) (4 mg/24h) with partial clinical improvement. Another patient started upadacitinib (UPA) (15 mg/24h) with clinical remission, while the remaining patient was a 57 yo man who received tofacitinib (TOFA) (5 mg/12h) with clinical remission. In the literature review we found 55 patients (44 women and 11 men) with TA treated with JAKi: TOFA (n=52), BARI (n=2), and ruxolitinib (n=1). Most patients improved with JAKi (Table 1). <h3>Conclusion:</h3> JAKi appear to be a relatively effective and safe treatment, even in TA refractory to cDMARDs and/or bDMARDs. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Fernando López-Gutiérrez Janssen, Abbvie, Roche, Novartis, MSD, UCB Pharma, Celgene, Lilly, Pfizer, Galápagos, Javier Loricera García Roche, Galápagos, Novartis, UCB Pharma, MSD, Celgene, Astra Zeneca, and Grünenthal, Janssen, Abbvie, Roche, Novartis, MSD, UCB Pharma, Celgene, Lilly, Pfizer, Galápagos, Javier Narváez: None declared, Valentina Emperiale: None declared, Ricardo Blanco AbbVie, Pfizer, Roche, Bristol-Myers, Lilly, Galapagos, Novartis, Janssen, GSK, UCB, and MSD, AbbVie, Pfizer, Roche, Lilly, Janssen.
AB0678 SOMATOSENSORY TEMPORAL DISCRIMINATION THRESHOLD IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: B. Tan, H. Kilinc, Z. Gunendi, S. Tan, F. N. Göğüş
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Somatosensory temporal discrimination (STD) is the ability to perceive two separate stimuli applied to the body with a short time interval. STD ability requires the functionality of central nervous system structures. Therefore, it is thought that STD evaluation provides information about the central processing of sensory stimuli. STD ability has not been previously evaluated in patients with RA. <h3>Objectives:</h3> To evaluate central processing of sensory stimuli with STD test in patients with Rheumatoid arthritis (RA). <h3>Methods:</h3> We enrolled 20 patients (14 women and 6 men; mean age± SD 54.9±7.72 years) and 20 healthy subjects (14 women and 6 men; mean age± SD: 53.75±7.61 years). Before STD evaluation, disease duration, patient global assessment (PGA) and evaluator global assessment (EGA), swollen joint count (SJC), tender joint count (TJC), C-reactive protein, erythrocyte sedimentation rate (ESR) in Disease activity score 28(DAS28), modified health assessment questionnaire disability index (mHAQ), Leeds assessment of neuropathic symptoms and sign (LANSS), pain catastrophizing scale (PCS), the central sensitization inventory (CSI) and the hospital anxiety and depression scale (HADS) were used to evaluate in patient with RA. Fibromyalgia symptom scale was used to exclude the presence of fibromyalgia. The Somatosensory temporal discrimination threshold (STDt) was assessed by a clinician blinded to the clinical diagnosis. <h3>Results:</h3> The mean age, BMI and education years were similar between two groups. Compared to the control group, the RA group had significantly higher STDT value (116.62±30.54, 48.62±15.89; p&lt; 0.01). DAS28, ESR, CRP, SJC, TJC, EGA, PGA, mHAQ, CSI, LANSS, PCA, HADS, age and the disease duration of the RA group were not significantly correlated STDt (p&gt; 0.05). <h3>Conclusion:</h3> Somatosensory temporal discrimination ability in patients with RA is disrupted compared to healthy subjects. We suggest that the prolongation of STDt in RA may be linked to impaired intracortical temporal inhibition in the primary sensory cortex. STDt does not seem to be affected by patients' psychological factors, inflammation and disease activity level of the patients. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB0629 UPADACITINIB EFFECTIVENESS AND SAFETY IN DIFFICULT TO TREAT RHEUMATOID ARTHRITIS – A MULTICENTER POST-MARKETING EXPERIENCE
Authors: C. Ancuta, C. Bran, C. Pomirleanu, G. Strugariu, L. Petrariu, E. Ancuta, R. Chirieac
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> In a market still dominated by biologics (bDMARDs), JAK inhibitors have rapidly become an attractive therapeutic choice, with undeniably efficacy and safety validated in various clinical scenarios. <h3>Objectives:</h3> We underwent a prospective longitudinal multicenter study on real-world clinical use of Upadacitinib (UPA) in Rheumatoid Arthritis (RA) aiming (i) to explore the prescription pattern of JAK inhibitors in a Romanian population; (ii) to evaluate disease activity with UPA as monotherapy and in combination with synthetic disease modifying anti-rheumatic drugs (csDMARDs) and (iii) to identify potential predictors associated with response to treatment. <h3>Methods:</h3> RA patients receiving UPA according to local regulations were monitored every 6 months for drug efficacy and safety focusing on standard clinical as well as ultrasound (US) assessments. <h3>Results:</h3> fifty-three patients (46 women) out of 508 RA actively receiving biologics and targeted synthetic (b/ts) DMARDs in our register of rheumatic diseases were included; at baseline, 40 cases have had a history of at least one b/ts DMARDs, 31 being classified as difficult to treat RA. We reported a statistical significant improvement for the majority of patients at 6 months as demonstrated by Disease Activity Score (DAS28-ESR) and Simplified Clinical Disease Activity Index (SDAI) (p&lt;0.05), maintained through at least 12 months; moreover, half were in remission at 6 months; US findings (synovitis with or without power Doppler positivity) also showed significant improvement (p &lt;0.05). Increased ESR or CRP at baseline were the main predictors of treatment response for both DAS28-ESR and SDAI (p&lt;0.05) as demonstrated by regression analysis, as well as ACPA serology and the number of previous b/tsDMARDs. Cycling in the JAK inhibitors class has no negative impact of treatment response. However, 7 cases discontinued UPA as lack or suboptimal efficacy. No cardiovascular adverse events, such as deep venous thrombosis, pulmonary embolism, were reported, while only one herpes zoster virus infection. <h3>Conclusion:</h3> Conclusion: our data endorse upadacitinib efficacy and safety in real-life settings, emphasizing its value in difficult to treat RA cases. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> CODRINA ANCUTA Novartis, Abbvie, Pfizer, UCB, Eli Lilly, Codruta Bran Novartis, Abbvie, Pfizer, UCB, Eli Lilly, Ewopharma, Alfasigma, Cristina Pomirleanu Novartis, Abbvie, Pfizer, UCB, Eli Lilly, Georgiana Strugariu Novartis, Abbvie, Pfizer, UCB, Eli Lilly, Luiza Petrariu Novartis, Abbvie, Pfizer, UCB, Eli Lilly, Eugen Ancuta UCB, Rodica Chirieac Novartis, Abbvie, Pfizer, UCB, Eli Lilly.
AB0734 PEPTIDYLARGININE DEIMINASE 4 (PAD4) INHIBITOR 4,6-BIS(2,2,2-TRIFLUOROETHOXY)-1,3,5-TRIAZIN-2-AMINE II AMELIORATES COLLAGEN-INDUCED ARTHRITIS IN MICE
Authors: Z. Y. Huang, W. N. Huang, C. C. Lin
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Peptidylarginine deiminase-4 (PAD4) is a calcium-dependent enzyme that catalyzes the conversion of arginine into citrulline in macromolecules within the body. Dysregulated PAD4 plays a crucial role in the occurrence and development of Rheumatoid arthritis (RA). Therefore, PAD4 is considered a promising target for diagnosing and treating RA. <h3>Objectives:</h3> In this study, we explored for the first time the therapeutic potential of the PAD4 inhibitor known as 4,6-bis(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-amine, referred to as TTA, in collagen-induced arthritis. <h3>Methods:</h3> We immunized DBA/1 mice with type II collagen, and the TTA treatment commenced on the 21st day after induction. Throughout the treatment period, we closely monitored alterations in body weight, assessed paw swelling through clinical scoring, and conducted histological examinations of the joints. On the 42nd day, we further examined changes in inflammatory cytokines in the serum and analyzed shifts in T-cell subpopulations within lymphatic tissues using ELISA and flow cytometry techniques. <h3>Results:</h3> The findings revealed that TTA treatment could alleviate arthritis symptoms, with improvements observed in joint manifestations and histological damage. Additionally, lung histological staining and experimental analysis of the pro-inflammatory cytokine TNF-α indicated signs of improvement. Furthermore, intracellular staining analysis of the immune system within the inguinal lymph nodes and spleen suggested a reduction in Th17 cells. <h3>Conclusion:</h3> In summary, TTA effectively mitigated collagen-induced arthritis in mice, indicating its potential as a future therapeutic option for the treatment of rheumatoid arthritis. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB0602 IMPACT OF RHEUMATOID ARTHRITIS IN TEMPOROMANDIBULAR JOINT: A CROSS-SECTIONAL STUDY ABOUT 128 PATIENT
Authors: M. Brahem, M. Khemiss, Y. Ben Slama, O. Jomaa, M. Ardhaoui, C. Knani, M. Jguiri, N. Bergaoui, M. Ben Khelifa, M. Younes
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disorder that is characterized by joint inflammation and multiple joint involvement such as the temporomandibular joint (TMJ), which is a vital organ which is closely associated with masticatory and swallowing functions. Its defect or damage can severely reduces the patients quality of life <h3>Objectives:</h3> The aim of the study was to predict a possible link between RA and temporomandibular joint disorders. <h3>Methods:</h3> This is a comparative cross-sectional study conducted at the dental and Rheumatology departments. We compared patients with RA and healthy ones. To achieve this objective, a clinical examination of TMJs was carried out in both groups. <h3>Results:</h3> A total of 128 patients were included in the study (95.3% women and 4.7% men) with a mean age of 51.1 ± 9.7 years. Among which 57 were diagnosed with RA and 71 were healthy. Within the group of patients with RA, highly active disease (DAS-28 ≥5.1) was found in 31 patients. Seventy-nine per cent of RA patients had Insufficient oral hygiene (compared to 56% in the control group). Among the sick patients, 26.3% had TMJ pain, 24.6% had joint sounds, 7% had a limitation of the mouth opening and 8.8% had a deviated mandibular trajectory. The control group exhibited results that were nearly comparable to the affected group (28.2% had TMJ pain, 29.6% had joint sounds, 12.7% had a limitation of the mouth opening and 14.1% had a deviated mandibular trajectory). Hence, there was not a significant difference between the two groups concerning temporomandibular joint disorders (p&gt; 0.3). <h3>Conclusion:</h3> TMJ is usually among the last joints to be involved in RA, but, TMJ disorders are not rare in affected patients. Specialized examination of the TMJ is important since its deficiency greatly impacts the patients quality of life. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
OP0266 QUANTITATIVE HRCT ASSESSMENT DURING NINTEDANIB TREATMENT IN SYSTEMIC SCLEROSIS INTERSTITIAL LUNG DISEASE AND IDIOPATHIC PULMONARY FIBROSIS
Authors: M. DI Battista, C. Romei, L. Tavanti, V. Uggenti, L. Colligiani, A. Della Rossa, M. Mosca
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Nintedanib (NIN) is an antifibrotic drug first approved for the treatment of idiopathic pulmonary fibrosis (IPF) and then for systemic sclerosis-associated interstitial lung disease (SSc-ILD) which has proved to slow the functional progression of both conditions. High-resolution computed tomography (HRCT) is the gold standard imaging technique for the assessment of pulmonary fibrosis related to SSc and IPF. More recently, HRCT has been implemented with a quantitative post-processing software (CALIPER), yielding promising results. <h3>Objectives:</h3> We aimed to assess the effect of NIN by HRCT quantitative changes in SSc-ILD and IPF patients. <h3>Methods:</h3> Two groups of SSc-ILD and IPF patients treated with NIN were enrolled along with two historical groups of fibrotic SSc-ILD and IPF subjects who did not receive any antifibrotic treatment (ratio 1:1:1:1). Only patients with a usual interstitial pneumonia HRCT pattern and with two evaluations at least one year apart were considered. All four groups were comparable for age, gender and mean follow-up period. HRCT scans were processed by the texture analysis software CALIPER, thus obtaining quantitative data about lung percentages of honeycombing (HC), ground glass (GG), reticulation (RET), pulmonary vascular-related structures (VRS) and normal parenchyma. <h3>Results:</h3> Forty-eight patients (12 per group, 50% female, mean age 68 years, mean follow-up 23 months) were evaluated. No CALIPER differences were detected at baseline between the groups. As shown in Table 1 and Figure 1, SSc-ILD and IPF patients treated with NIN did not show any significant change in CALIPER percentages except for VRS that was found to be increased at follow-up (p=0.02 and p=0.006, respectively). Conversely, fibrotic SSc-ILD and IPF patients who were not treated with any antifibrotic therapy, exhibited a significant worsening of almost all CALIPER parameters. <h3>Conclusion:</h3> Treatment with NIN was associated with a stabilization of almost all lung parameters assessed by quantitative HRCT both in fibrotic SSc-ILD and IPF, thus avoiding the natural progressive worsening observed in patients who did not receive antifibrotic treatment. The worsening of VRS also in patients treated with NIN requires further investigations but could be related to a vascular progression which in some way is not completely dependent on pulmonary fibrosis and therefore not manageable with NIN. Quantitative HRCT emerges as a useful tool for the longitudinal follow-up of patients with ILD during antifibrotic treatment. <h3>REFERENCES:</h3> <b>NIL.</b> <b>Table 1.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB0743 CEPHARANTHINE RESTORES FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS BY DIFFERENTIALLY REGULATING E2F1 AND NRF2 PATHWAYS
Authors: C. Lu, Y. Liu, Q. Zhang, S. Li, Y. Pan
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Fibroblast-like synoviocytes (FLS) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Cepharanthine (CEP), an alkaloid derived from Stephania cepharantha Hayata, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effects on RA FLS remain unclear. <h3>Objectives:</h3> To investigate the mechanisms of CEP in treating RA by targeting FLS. <h3>Methods:</h3> Proliferation of RA FLS was determined with CCK-8 while cell migration and invasion was assessed using a scratch wound assay and Transwell chambers, respectively. To determine transcriptional changes caused by CEP, bulk RNA sequencing (RNA-seq) was performed, followed by pathway enrichment and gene-set enrichment analysis. Cell cycle was assessed by flow cytometry. Metabolites in supernatants were measured by HPLC-MS, while cellular lipid reactive oxygen species (ROS) were tested by flow cytometry with BODIPY-C11 probing. Lipid peroxidation product 4-hydroxynonenal (4-HNE) in the conditioned media of FLS and in joints of collagen-induced arthritis were measured by ELISA and immunohistochemistry, respectively. E2F1 and NRF2 gene were knocked down with Lipofectamine and corresponding silencing RNAs. QPCR and Western blotting were applied to determine gene expression. <h3>Results:</h3> CEP inhibited the proliferation of RA FLS significantly in a dose-dependent manner and suppressed TNFα-induced migration and invasion. CEP caused significant changes to the gene expression in RA FLS and CEP-downregulated genes were related to cell cycle, glycolytic metabolism and citric acid cycle, etc. Consistently, CEP-treated RA FLS had a lower proportion of cells at S phase but a higher proportion of cells at G0/G1 phase. Expression levels of HIF-1α, PKM2, LDHA were downregulated, SIRT6 was upregulated by CEP, and levels of citric acid, lactate, and cis-aconitate in conditioned media were reduced by CEP. Transcription factor E2F1 was predicted to mediate the anti-proliferation, anti-migration, and metabolic modulation of CEP in RA FLS. In addition, NRF2 was the top transcription factor for CEP-upregulated genes. CEP could upregulate system Xc<sup>-</sup> (SLC7A11 and SLC3A2) by enhancing NRF2 expression. CEP decreased the production of lipid ROS and 4-HNE in RA FLS efficiently. Reduced 4-HNE level was also observed in the synovium from CEP-treated arthritis mice, along with alleviated synovial inflammation and joint destruction. <h3>Conclusion:</h3> Our results showed that CEP was able to restore inflammatory phenotypes of FLS, pointing to its use as an alternative agent for RA treatment. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB0748 IMPACT OF PRAC ANNOUNCEMENT ON JAKI PRESCRIBING AMONG HIGHER-RISK RHEUMATOID ARTHRITIS PATIENTS
Authors: S. Brown, M. I. Tanase, M. Hollis, R. Samuels, J. Godfrey
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> In January 2023, EMA's CHMP endorsed the Pharmacovigilance Risk Assessment Committee's (PRAC) measures for Janus kinase inhibitors (JAKi), addressing serious side effects in treating chronic inflammatory conditions, including Rheumatoid Arthritis (RA). The use of these medications is now restricted in specific high risk patients including, but not limited to, those aged 65 years or older, those with specific cardiovascular comorbidities, smokers, and those at higher risk of developing malignancies. Caution is advised among patients in these risk categories and JAKi doses should be reduced based on an individuals risk. <h3>Objectives:</h3> Real-world patient data was used to investigate the impact of the PRAC announcement on patients with Rheumatoid Arthritis and physicians' JAKi prescribing patterns. <h3>Methods:</h3> Informed consent was obtained from 228 Rheumatologists across the main 5 European markets: France, Germany, Italy, Spain, and United Kingdom (EU5). They provided 1593 anonymised patient record forms (PRF) for RA patients on an advanced therapy (AT) in the Research Partnership's Q4 2023 Therapy Watch Rheumatology study. The data is weighted based on physicians' proportions of dynamic (initiated or switched AT in the last 3 months) and stable patients, where each physician has an individual weight factor. <h3>Results:</h3> Of the 1593 patients, 50% had at least one PRAC risk factor. 14% of patients were aged ≥ 65 years old, whilst 35% had at least one CV risk factor. The prevalence of current smokers stood at ~11%, former smokers who quit &lt;5 years ago amounted to ~2%, those who quit 5-10 years ago accounted for ~5%, and those who quit &gt;10 years ago represented ~3%. Comparably, the proportion of patients with a high risk of cancer was 8%. The biggest difference in JAKi market share was among individuals with a CV risk, where JAKis market share reported a decline (15%) vs. Q1 2023. However, JAKi prescribing has remained stable among patients ≥ 65 years old. <h3>Conclusion:</h3> Of those patients who fall under the PRAC warning, the greatest proportion do so due to one or more CV risk factors. Patients over 65 years old represent a small Rheumatoid Arthritis patient population at risk when using JAKi. Our findings suggest the PRAC warning impacted JAKi prescribing over the past year; however, this may vary across EU5 markets and risk populations may be small in size. As of Q4 2023, the data suggests that JAKi use among higher risk patients has stabilised throughout the year. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>