Symptom Appraisal and Help-Seeking Among Patients With Autoimmune Rheumatic Diseases: A Qualitative Study.

OBJECTIVE: Long diagnostic delay remains an unsolved problem in many autoimmune rheumatic diseases (ARDs). One of the major contributing factors is poor symptom appraisal and the resulting delays in help-seeking by patients themselves. We therefore aimed to understand the symptom appraisal and help-seeking experience among patients with ARDs in a multiethnic urban Asian population and to explore its influencing factors. METHODS: Semistructured interviews with 33 patients with ARDs were audio recorded and transcribed verbatim. We coded the transcripts deductively using the reported 3 stages of symptom appraisal (detection, interpretation, and response) as the framework, and inductively for newly emerging themes and subthemes. RESULTS: All 3 stages of the symptom appraisal and help-seeking journey (ie, symptom detection [by self and by others], symptom interpretation [causes, consequences, and required actions] and symptom response [no action, self-management, seeking help from nonhealthcare professionals, and seeking help from healthcare professionals]) were observed among patients. Interactions among these 3 stages were also observed: symptom interpretation was found to influence subsequent symptom detection, and the outcome of symptom response was found to influence both subsequent symptom detection and symptom interpretation. Various personal and socioenvironmental factors (eg, knowledge and cultural beliefs about the symptom) that influenced symptom appraisal and help-seeking were identified from the interviews. CONCLUSION: The symptom appraisal and help-seeking journey of patients with ARDs is an iterative process of detection, interpretation, and response, and is influenced by various personal and socioenvironmental factors. Addressing modifiable factors could shorten the symptom appraisal and help-seeking interval and improve patient outcomes.

Social cognitive theory to improve symptom appraisal and help-seeking among patients with autoimmune rheumatic diseases: A qualitative study.

AIM: Social cognitive theory (SCT) has been successfully employed to improve symptom appraisal and help-seeking among patients with various conditions but is yet to be applied in the context of autoimmune rheumatic diseases (ARDs). This study aimed to explore the applicability of SCT in and possible approaches to improving symptom appraisal and help-seeking of patients with ARDs, one of the key barriers to earlier diagnosis. METHODS: Semi-structured interviews were conducted with 33 ARD patients with a prolonged pre-diagnosis interval (>3 months). We coded the transcripts deductively using SCT as the overarching framework and inductively for approaches identified from the interviews. RESULTS: All six main concepts of SCT (behavioral capacity, expectations, self-efficacy, observational learning, reinforcements, and reciprocal determinism) were observed in the three stages of symptom appraisal and help-seeking (detection, interpretation, and response) of patients with ARDs. While many participants reported that they were able and confident to detect their symptoms, they lacked the behavioral capacity and self-efficacy to interpret symptoms correctly, which resulted in delayed help-seeking and diagnosis. Possible approaches to address this suggested by participants (such as education of the general population) could improve behavioral capacity and self-efficacy in symptom interpretation and enhance expectations, observational learning, reinforcements, and reciprocal determinism in symptom response. CONCLUSION: Lack of behavioral capacity and self-efficacy was observed in symptom interpretation of patients with ARDs, which resulted in delayed help-seeking. Approaches could target the behavioral capacity and self-efficacy for symptom interpretation to facilitate early help-seeking and, in turn, earlier diagnosis among individuals with possible ARDs.

Approaches to improving symptom appraisal: a systematic literature review.

OBJECTIVES: Poor symptom appraisal (detection, interpretation and response to symptoms) plays a major role in prolonged prediagnosis interval in various health conditions. Theories and models have been proposed to study the symptom appraisal process but how they could be employed to improve symptom appraisal remains unclear. We therefore aimed to review approaches to improving symptom appraisal in the literature and to develop a theoretical framework that could guide the development of approaches to improving symptom appraisal among individuals in the general population. DESIGN: Systematic review. DATA SOURCES: Medline, Web of Science, PsycINFO, Embase, CINAHL and Scopus were searched from inception to 30 March 2021. ELIGIBILITY CRITERIA: We included original articles in English in which approaches to improve the detection, interpretation or response to symptoms for symptomatic individuals were described. We excluded articles in which approaches were developed to improve symptom appraisal among healthcare professionals. DATA EXTRACTION AND SYNTHESIS: A predefined data extraction form was used to extract the development, characteristics and evaluation of approaches to improving symptom appraisal. This formed the basis for the narrative synthesis. RESULTS: Of 19 046 publications identified from the literature search, 112 were selected for full-text review and 29 approaches comprising provision of knowledge of symptoms/signs and additional components (eg, symptom self-examination and comparison) for symptom appraisal were included in the synthesis. Less than half (41.4%) of these approaches were developed based on theories/models. Interestingly, despite the variety of theories/models adopted in developing these approaches, the components of these approaches were similar. CONCLUSION: Symptom appraisal is an essential process in a patient's journey that can be targeted to facilitate early diagnosis but is largely unstudied. Building on the literature, we proposed a theoretical framework and approaches to improving symptom appraisal. This could facilitate early identification of a variety of health conditions in the general population. TRIAL REGISTRATION NUMBER: CRD42021279500.

Interval between symptom onset and diagnosis among patients with autoimmune rheumatic diseases in a multi-ethnic Asian population.

AIM: The interval between symptom onset and diagnosis (pre-diagnosis interval) can at times be longer than is ideal in patients with autoimmune rheumatic diseases (ARDs). In this study, we aimed to characterize this interval and to identify its associated factors. METHOD: We characterized pre-diagnosis interval into 4 intervals: Interval #1 between symptom onset and first visit to healthcare professionals; Interval #2 between first visit to healthcare professionals and rheumatology referral; Interval #3 between rheumatology referral and first rheumatology assessment; and Interval #4 between first rheumatology assessment and diagnosis. Median regression models were used to identify factors associated with longer pre-diagnosis interval and Interval #1. RESULTS: Among 259 patients (median age = 52.0 [41.6-61.9] years, 71% female, rheumatoid arthritis [n = 75], axial spondyloarthritis [axSpA] [n = 40] and psoriatic arthritis [n = 35]), median pre-diagnosis interval was 11.5 (4.7-36.0) months. Interval #1 (median = 4.9 months) was significantly longer than Intervals #2-#4 (median = 0.3, 1.5, and 0.0 months, respectively). Patients with axSpA had significantly longer pre-diagnosis interval (median = 38.7 months) and Interval #1 (median = 26.6 months) than patients with the other ARDs. Median regression suggested that patients referred from specialty care had significantly longer pre-diagnosis interval (median difference = 7.7 months) and Interval #1 (median difference = 6.4 months) compared to those referred from primary care. CONCLUSION: A long pre-diagnosis interval was observed among patients with ARDs (especially axSpA), due largely to a long interval between symptom onset and the first visit to healthcare professionals. This highlights the importance of interventions targeting patients prior to their first visit to healthcare professionals in reducing pre-diagnosis interval.

Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model.

We investigated the role of neutrophilic cells (neutrophils) in inflammatory angiogenesis and explored the possible mechanisms involved. Corneal angiogenesis was induced in vivo with a 75% silver nitrate applicator. Depletion of neutrophils was accomplished by the intraperitoneal administration of RB6-8C5, a neutrophil-depleting antibody. Angiogenesis, neutrophil infiltration, and the localization of vascular endothelial growth factor (VEGF) were evaluated by biomicroscopic observations, histology, and immunohistochemistry in control and RB6-8C5 treatment groups. Protein levels of VEGF, macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor alpha in the cornea were determined by enzyme-linked immunosorbent assay. An in vitro model of neutrophil activation was also used to examine the ability of neutrophils to produce and release VEGF, MIP-1alpha, and MIP-2. At day 1 after injury, neutrophil infiltration in the cornea was highest, and VEGF was expressed in the infiltrating neutrophils. The enhanced protein levels of VEGF, MIP-1alpha, and MIP-2 correlated with the degree of neutrophil infiltration. Neutrophil depletion significantly inhibited corneal angiogenesis and reduced the protein levels of VEGF, MIP-1alpha, and MIP-2 in the cornea. Upon stimulation, isolated neutrophils released VEGF from preformed stores and MIP-1alpha and MIP-2 by de novo synthesis. Neutrophil depletion thus significantly impaired inflammatory angiogenesis, identifying neutrophils as an important player in inflammatory angiogenesis. Neutrophils may exercise their angiogenic function by releasing proangiogenic factors such as VEGF. Intervention measures targeting neutrophils may therefore help to deal with abnormal angiogenesis involved in chronic inflammatory diseases.

Characterisation of soluble murine CD137 and its association with systemic lupus.

CD137 is a member of the tumor necrosis factor receptor family, and is involved in the regulation of activation, proliferation, differentiation and apoptosis of T cells, B cells, monocytes, dendritic cells, natural killer cells and granulocytes. Here report that soluble forms of murine CD137 (sCD137) are generated by differential splicing and are released by activated T cells. Levels of sCD137 correlate with cell activation and the extent of cell death but not with cellular proliferation. While CD8+ T cells express significantly more cell surface CD137 than CD4+ T cells, both T cell subsets express similar levels of sCD137, resulting a twofold increased ratio of soluble to cell surface CD137 for CD4+ T cells. sCD137 exists as a trimer and a higher order multimer, can bind to CD137 ligand, and inhibits secretion of IL-10 and IL-12. sCD137 is present in sera of mice with autoimmune disease but is undetectable in sera of healthy mice.

Should non-expert clinician examiners be used in objective structured assessment of communication skills among final year medical undergraduates?

BACKGROUND: Adoption of the objective structured clinical examination may be hindered by shortages of clinicians within a specialty. Clinicians from other specialties should be considered as alternative, non-expert examiners. AIMS: We assessed the inter-rater agreement between expert and non-expert clinician examiners in an integrated objective structured clinical examination for final year medical undergraduates. METHODS: Pairs of expert and non-expert clinician examiners used a rating checklist to assess students in 8 oral communication stations, representing commonly encountered scenarios from medicine, paediatrics, and surgery. These included breaking bad news, managing an angry relative, taking consent for lumbar puncture; and advising a mother on asthma and febrile fits, and an adult on medication use, lifestyle changes and post-suture care of a wound. 439 students participated in the OSCE (206 in 2005, 233 in 2006). RESULTS: There was good to very good agreement (intraclass coefficient: 0.57-0.79) between expert and non-expert clinician examiners, with 5 out of 8 stations having intraclass coefficients > or =0.70. Variation between paired examiners within stations contributed the lowest variance to student scores. CONCLUSION: These findings support the use of clinicians from other specialties, as 'non-expert' examiners, to assess communication skills, using a standardized checklist, thereby reducing the demand on clinicians' time.

Interleukin-18 promoter gene polymorphisms in Chinese patients with systemic lupus erythematosus: association with CC genotype at position -607.

INTRODUCTION: Interleukin-18 (IL-18) is a Th1 cytokine, which is postulated to play a role in systemic lupus erythematosus (SLE). Two single nucleotide polymorphisms (SNPs) in the IL-18 promoter gene region were found to influence the quantitative expression of the IL-18 protein. The aim of this study was to determine whether IL-18 promoter gene polymorphisms are associated with SLE. MATERIALS AND METHODS: One hundred and thirteen Chinese SLE patients and 218 Chinese healthy individuals were recruited. Genomic DNA was extracted from peripheral venous blood. Sequence-specific primer PCR and restriction fragment length polymorphism (RFLP) analysis were used to genotype the DNA samples for SNP-137 and SNP- 607. The following genotypes were obtained: SNP(-607) AA, AC, CC and SNP(-137) GG, GC, CC. Plasma IL-18 concentrations of patients and control subjects were measured by enzyme-linked immunosorbent assay. RESULTS: the frequency of SNP-607/CC genotype was significantly higher in SLE patients (Pc < 0.05) while genotype SNP-607/AC was significantly decreased in SLE patients compared to the control group (Pc <0.05). Plasma IL-18 concentrations were significantly higher in SLE patients than in control subjects (P <0.05). Both patients and control subjects with CC and AC genotypes have significantly higher IL-18 concentrations than those with AA genotype. CONCLUSION: The IL-18 promoter gene polymorphism SNP-607 C allele is associated with SLE and may result in the enhanced production of IL-18 protein in SLE and normal individuals.

Singapore Chapter of Rheumatologists consensus statement on the eligibility for government subsidy of biologic disease modifying anti-rheumatic agents for the treatment of psoriatic arthritis.

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.

Consensus development on eligibility of government subsidisation of biologic disease modifying anti-rheumatic agents for treatment of ankylosing spondylitis: The Singapore experience.

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.

The Impact of Education Reform: An Asian Medical School's Experience.

This study assessed the effectiveness of education reforms on student-reported learning outcomes at the end of the 5-year medical school (M5) and 1-year internship (HO) in 2006, 2007 and 2008. A self-administered anonymous survey with 17 learning outcomes assessed, derived from Harden's Three-Circle Outcomes Model for outcomes-based education, was administered to 683 students at the end of medical school (M5) and internship (HO) from 2006, 2007 and 2008. We identified learning outcomes which changed significantly for internship (Cohorts A, B and C) and medical school (Cohorts B, C and D) between cohorts from 2006 to 2008, and compared learning outcomes between medical school and internship within cohorts (i.e. Cohort B which was M5 in 2006 and HO in 2007; Cohort C which was M5 in 2007 and HO in 2008). The proportion of students who agreed that medical school helped them achieve learning outcomes increased significantly from 2006 to 2008 for 15 out of 17 learning outcomes assessed. The proportion of students who agreed that internship helped them achieve learning outcomes increased significantly from 2006 to 2008 for 6 learning outcomes assessed. For Cohorts B and C, internship was more effective than medical school in achieving 8 learning outcomes. Cohort C reported that internship was more effective than medical school in 3 additional learning outcomes than Cohort B: patient management, humility and dedication. We conclude that a successful journey of education reform is an ongoing process that needs to comprehensively address multifaceted components such as faculty, administration and curriculum.

Lupus erythematosus cell phenomenon in synovial and peritoneal fluids in systemic lupus erythematosus: smoking guns, crime scenes and a twist.

The presence of the lupus erythematosus (LE) phenomenon has been generally conceptualized as an in vitro occurrence where numerous damaged cells are present and substantial nucleo-phagocytosis has occurred. In systemic lupus erythematosus (SLE), the positive LE cell phenomenon has been shown to indicate active disease with major organ involvement which potentially warrants prompt and heavy immunosuppressive therapy. We report a 36-year-old woman with a known history of SLE who presented with fever, left knee effusion, polyserositis, pancytopenia, low complement and high anti-dsDNA antibody levels whose immunosuppressive treatment was escalated in view of the clinically and serologically active SLE, accompanied by the presence of LE cells in her inflammatory yet sterile left knee synovial fluid. Within 3 days of immunosuppressant escalation, her ascites worsened. While microscopic examination of the ascitic fluid also revealed LE cells, culture of the ascitic fluid later grew Candida parapsilosis. The patient subsequently responded to the addition of anti-fungal therapy into her augmented immunosuppressive regime. Coexistence of the LE cell phenomenon and infection in SLE patients has hitherto not been described. This case illustrates that infection remains to be meticulously excluded despite the presence of the LE phenomenon in the context of clinically and serologically active SLE.

Are medical students' views of an ideal physician eroding? A study on perceived qualities of a "role model" doctor before and after housemanship and between two cohorts five years apart.

INTRODUCTION: This study aimed to examine the impact of housemanship and cohort effect on the perceptions of what constitutes a "role model physician" between 2 cohorts of medical students. MATERIALS & METHODS: Final year medical students of the Yong Loo Lin School of Medicine, National University of Singapore, from the classes of 2005 (pre- and post-housemanship) and class of 2009 (pre-housemanship) responded to an anonymous 25-statement questionnaire reflecting Fones et al's 25-item characterisation of a "role model" doctor. Qualitative data was also collected on student's perceived qualities of a role model doctor. RESULTS: For the 2005 cohort pre- and post-housemanship, only 3 of the 25 items had increased in importance post-housemanship. However, when comparing the 2005 and 2009 cohorts pre-housemanship, the latter cohort placed significantly greater importance on 12 of the 25 items. Willingness to teach was identified via qualitative analysis as a new important quality of a role model doctor for medical students. CONCLUSION: The importance placed on characteristics of "role model" physicians were relatively unchanged by housemanship within the same cohort but increased with time between 2 cohorts 5 years apart. This suggests that professional standards of an "ideal" doctor expected and aspired to by medical students may not be eroding as feared by the medical profession and society.

Do English and Chinese EQ-5D versions demonstrate measurement equivalence? An exploratory study.

BACKGROUND: Although multiple language versions of health-related quality of life instruments are often used interchangeably in clinical research, the measurement equivalence of these versions (especially using alphabet vs pictogram-based languages) has rarely been assessed. We therefore investigated the measurement equivalence of English and Chinese versions of the EQ-5D, a widely used utility-based outcome instrument. METHODS: In a cross-sectional study, either EQ-5D version was administered to consecutive outpatients with rheumatic diseases. Measurement equivalence of EQ-5D item responses and utility and visual analog scale (EQ-VAS) scores between these versions was assessed using multiple regression models (with and without adjusting for potential confounding variables), by comparing the 95% confidence interval (95%CI) of score differences between these versions with pre-defined equivalence margins. An equivalence margin defined a magnitude of score differences (10% and 5% of entire score ranges for item responses and utility/EQ-VAS scores, respectively) which was felt to be clinically unimportant. RESULTS: Sixty-six subjects completed the English and 48 subjects the Chinese EQ-5D. The 95%CI of the score differences between these versions overlapped with but did not fall completely within pre-defined equivalence margins for 4 EQ-5D items, utility and EQ-VAS scores. For example, the 95%CI of the adjusted score difference between these EQ-5D versions was -0.14 to +0.03 points for utility scores and -11.6 to +3.3 points for EQ-VAS scores (equivalence margins of -0.05 to +0.05 and -5.0 to +5.0 respectively). CONCLUSION: These data provide promising evidence for the measurement equivalence of English and Chinese EQ-5D versions.

SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.

During sepsis, activation of phagocytes leads to the overproduction of proinflammatory cytokines, causing systemic inflammation. Despite substantial information regarding the underlying molecular mechanisms that lead to sepsis, several elements in the pathway remain to be elucidated. We found that the enzyme sphingosine kinase 1 (SphK1) is up-regulated in stimulated human phagocytes and in peritoneal phagocytes of patients with severe sepsis. Blockade of SphK1 inhibited phagocyte production of endotoxin-induced proinflammatory cytokines. We observed protection against sepsis in mice treated with a specific SphK1 inhibitor that was enhanced by treatment with a broad-spectrum antibiotic. These results demonstrated a critical role for SphK1 in endotoxin signaling and sepsis-induced inflammatory responses and suggest that inhibition of SphK1 is a potential therapy for septic shock.

The challenges of "continuing medical education" in a pandemic era.

Closure of medical schools or the barring of "live patient" contact during an epidemic or pandemic is potentially disruptive to medical education. During the SARS epidemic, the use of web-based learning, role play, video vignettes and both live and mannequin-based simulated patients minimised disruptions to medical education. This article examines the pedagogical innovations that allow clinical teaching to continue without medical students examining actual patients, and proposes a contingency plan in the event of future outbreaks that may necessitate similar containment measures.

Harnessing the IT factor in medical education.

Escalating healthcare costs in Singapore have produced a significant movement of patients into ambulatory care, and the consequent dearth of clinical teaching materials. This deficiency has likewise prompted the creation of ambulatory teaching clinics and the use of standardised patients and simulators. In the last few decades, educators have utilised digital technology, for instance, digitally recorded heart and breath sounds, and digitised video vignettes, in medical education. We describe several pedagogical initiatives that we have undertaken at our university school of medicine.