iTRAQ-based mass spectrometry screen to identify serum biomarkers in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disorder with no reliable serum biomarkers currently available other than autoantibodies. METHODS: In the present study, isobaric tags for relative and absolute quantitation-based mass spectrometry was used to screen the sera of patients with SLE to uncover potential disease biomarkers. RESULTS: 85 common proteins were identified, with 16 being elevated (≥1.3) and 23 being decreased (≤0.7) in SLE. Of the 16 elevated proteins, serum alpha-1-microglobulin/bikunin precursor (AMBP), zinc alpha-2 glycoprotein (AZGP) and retinol-binding protein 4 (RBP4) were validated in independent cross-sectional cohorts (Cohort I, N=52; Cohort II, N=117) using an orthogonal platform, ELISA. Serum AMBP, AZGP and RBP4 were validated to be significantly elevated in both patients with inactive SLE and patients with active SLE compared with healthy controls (HCs) (p<0.05, fold change >2.5) in Cohort I. All three proteins exhibited good discriminatory power for distinguishing active SLE and inactive SLE (area under the curve=0.82-0.96), from HCs. Serum AMBP exhibited the largest fold change in active SLE (5.96) compared with HCs and correlated with renal disease activity. The elevation in serum AMBP was validated in a second cohort of patients with SLE of different ethnic origins, correlating with serum creatinine (r=0.60, p<0.001). CONCLUSION: Since serum AMBP is validated to be elevated in SLE and correlated with renal disease, the clinical utility of this novel biomarker warrants further analysis in longitudinal cohorts of patients with lupus and lupus nephritis.

Effect of Community Treatment Orders on Mental Health Service Usage, Emergency Visits, and Violence: a Systematic Review and Meta-Analysis.

INTRODUCTION: Community treatment orders (CTOs) enable patients to actively engage in mental health services while being supervised in the community outside the hospital setting. However, the efficacy of CTOs remains controversial in terms of mental health services usage or service contacts, emergency visits, and violence. METHODS: The databases PsychINFO, Embase, and Medline were searched on 11 March 2022 by 2 independent reviewers through the Covidence website (www.covidence.org). Randomised or non-randomised case-control studies and pre-post studies were included if they examine the effect of CTOs on service contacts, emergency visits, and violence in individuals with mental illnesses by comparing with control groups or pre-CTO conditions. Conflicts were resolved by consultation of the third independent reviewer. RESULTS: Sixteen studies provided sufficient data in the target outcome measures and were included in analysis. Variability in the risk of bias was high among studies. Meta-analyses were conducted separately for case-control studies and pre-post studies. For service contacts, a total of 11 studies with 66,192 patients reported changes in the number of service contacts under CTOs. In 6 case-control studies, a small non-significant increase in service contacts was observed in those under CTOs (Hedge's g = 0.241, z = 1.535, p = 0.13). In 5 pre-post studies, a large and significant increase in service contacts was noted after CTOs (Hedge's g = 0.830, z = 5.056, p < 0.001). For emergency visits, a total of 6 studies with 930 patients reported changes in the number of emergency visits under CTOs. In 2 case-control studies, a small non-significant increase in emergency visits was noted in those under CTOs (Hedge's g = -0.196, z = -1.567, p = 0.117). In 4 pre-post studies, a small significant decrease in emergency visits was noted after CTOs (Hedge's g = 0.553, z = 3.101, p = 0.002). For violence, a total of 2 pre-post studies reported a moderate significant reduction in violence after CTOs (Hedge's g = 0.482, z = 5.173, p < 0.001). CONCLUSION: Case-control studies showed inconclusive evidence, but pre-post studies showed significant effects of CTOs in promoting service contacts and reducing emergency visits and violence. Future studies on cost-effectiveness analysis and qualitative analysis for specific populations with various cultures and backgrounds are warranted.

Isolated hypotension after the induction of general anesthesia refractory to fluids and vasopressors: An indicator of anaphylaxis.

Differentiating between anaphylaxis and hypotension during general anaesthesia is difficult, especially when patients present with only hypotension and without any of the other classical features of anaphylaxis. We report the successful management of an anaphylactic reaction to rocuronium that presented as isolated hypotension in a 45-year-old Indonesian man presented with lacerations on the scalp and right pinna caused by an assault to the head after the induction of general anaesthesia, refractory to fluids and high doses of vasopressors. This case highlights that a possible indicator of anaphylaxis can be the presence of isolated hypotension during.

Clinical utility of tumour marker velocity of cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) in breast cancer surveillance.

BACKGROUND: Serum tumour markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) are not routinely recommended for detecting breast cancer recurrence and monitoring treatment. In this study, we aim to evaluate the diagnostic accuracy of absolute CA 15-3 and CEA levels and report on the clinical utility of tumour marker velocity in breast cancer surveillance. METHODS: 67 consecutive patients over a 15-year period (1998-2012) with available serial serum CA 15-3 and CEA measurements at recurrence were matched to a control group of patients. Tumour marker velocity was derived from the average change in consecutive tumour marker values over time, expressed in unit/year. Logistic regression analysis was performed to investigate the association between tumour characteristics, tumour marker velocity and disease recurrence. RESULTS: Using the Youden index values, the optimal cut-off values for absolute CA 15-3 and CEA corresponded to the normal assay reference range while tumour marker velocity values were derived to be 2.5U/mL/year and 1.2ng/mL/year respectively. CA 15-3 velocity > 2.5U/mL/year had the highest AUROC value of 0.85 than CEA velocity alone. When either tumour marker velocity exceeded threshold values, the sensitivity, specificity, negative predictive value and positive predictive value were 94.0%, 73.1%, 92.5%, and 77.8% respectively. In the multivariate logistic regression analysis, having both CA 15-3 and CEA velocity exceeding the cut-off values was shown to be a significant predictor for disease recurrence (p = 0.01). CONCLUSION: These findings highlighted the clinical utility of serial tumour markers measurements and its velocity in breast cancer surveillance.

Impact of imagery-enhanced interpretation training on offline and online interpretations in worry.

Worry and rumination are forms of repetitive negative thinking (RNT) that are maintained by negative interpretations and a predominance of abstract, verbal thinking. Hence, facilitating more positive interpretations and imagery-based thinking in combination may reduce RNT. Study 1 administered interpretation training with and without enhanced imagery, and an active control condition (designed not to change interpretations), in individuals with high levels of RNT (worry and/or rumination). Combining interpretation training with sustained imagery resulted in the highest levels of positive interpretation bias using an offline test of interpretation bias (when individuals have time to reflect). Study 2 investigated whether imagery-enhanced interpretation training influences online interpretations when ambiguous information is first encountered, indexed by reaction times and amplitude of the N400 event-related potential, as well as enhances offline positive interpretations in high worriers. It also examined whether imagery-enhanced interpretation training reduces negative thought intrusions associated with worry. Both online (reaction time) and offline interpretations were more positive following imagery-enhanced interpretation training, and negative thoughts were reduced, compared to the active control. However, no differences emerged on neurophysiological markers during the online task. Hence, brief interpretation training encompassing sustained imagery modifies online and offline interpretations, but further training may be required to impact upon neurophysiological measures.

Network meta-analysis of novel and conventional sentinel lymph node biopsy techniques in breast cancer.

Background: The aim of this network meta-analysis was to compare the performance of blue dye alone or in combination with radioisotope (technetium-99m, Tc) with three novel techniques for sentinel lymph node detection in breast cancer: indocyanine green fluorescence (ICG), superparamagnetic iron oxide (SPIO) nanoparticles and contrast-enhanced ultrasound imaging (CEUS). Methods: PubMed, Embase, the Cochrane Library, China Knowledge Research Integrated Database, ClinicalTrials.gov and OpenGrey databases were searched up to 31 November 2017, without language restriction. Studies that compared the detection performance of at least one of the novel methods (ICG, SPIO and CEUS) with that of traditional methods (blue dye and/or radioisotope) were included in network meta-analysis. Results: Thirty-five studies were included. Pooled risk ratios (RRs) for Tc (1·09, 95 per cent c.i. 1·04 to 1·15), ICG (1·12, 1·07 to 1·16) and SPIO (1·09, 1·01 to 1·18) showed statistically better performance in detecting sentinel lymph nodes than blue dye alone. ICG had the lowest false-negative rate, with a RR of 0·29 (0·16 to 0·54), followed by Tc (RR 0·44, 0·20 to 0·96) and SPIO (RR 0·45, 0·14 to 1·45), with blue dye alone as the reference group. Conclusion: SPIO or ICG alone are superior to blue dye alone and comparable to the standard dual-modality technique of blue dye with Tc.

Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus.

Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20-40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

Systemic lupus erythematosus: what should family physicians know in 2018?

Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune disease with considerable clinical and immunological heterogeneity. Family physicians should be familiar with the protean manifestations of SLE to aid early diagnosis and monitoring of disease progression. The role of family physicians in SLE includes education, counselling, psychological support, management of mild disease, and recognition of the need for referral to other specialists for more serious disease and complications. Surveillance of cardiovascular risk factors and osteoporosis and advice about vaccination and reproductive issues can be performed in the primary care setting under close collaboration with rheumatologists and other specialists. This review provides family physicians with the latest classification criteria for SLE, recommendations on SLE-related health issues, and pharmacological therapies for SLE.

Long-term immunogenicity of a quadrivalent human papillomavirus vaccine in systemic lupus erythematosus.

OBJECTIVES: To evaluate the 5-year immunogenicity of a quadrivalent human papillomavirus (HPV) vaccine (GARDASIL) in patients with systemic lupus erythematosus (SLE). METHODS: Female SLE patients and controls, aged 18-35 years, who received GARDASIL in 2011 and sero-converted 12 months post-vaccination were followed for persistence of immunogenicity. Antibody measurement to HPV serotypes 6, 11, 16, 18 was repeated at 5 years. The rate of sero-reversion was compared between patients and controls, and factors associated with sero-reversion of the anti-HPV antibodies were studied. RESULTS: 50 SLE patients and 50 controls were vaccinated with GARDASIL. Among subjects who sero-converted at 1 year and consented for this study, antibodies to HPV serotypes 6, 11, 16 and 18 at 5 years were persistent in 24/27 (89%), 26/31 (84%), 32/34 (94%) and 24/25 (96%) of the SLE patients; and 32/33 (97%), 32/33 (97%), 32/32 (100%) and 23/24 (96%) of the controls, respectively. Antibody titers to HPV-6 and 16 were significantly lower in patients than controls. Seven (21%) SLE patients had sero-reversion of ≥1 anti-HPV antibodies. Sero-reverted patients experienced significantly more SLE flares, particularly renal, and had received significantly higher cumulative doses of prednisolone, mycophenolate mofetil and tacrolimus than those with persistent immunogenicity. The cumulative doses of prednisolone correlated inversely and significantly with the anti-HPV 6, 11, and 16 titers at 5 years. CONCLUSIONS: Immunogenicity of the quadrivalent HPV vaccine was retained in a high proportion of SLE patients at 5 year. Patients with more SLE renal flares and had received more immunosuppression were more likely to have sero-reversion of the anti-HPV antibodies. CLINICAL TRIAL REGISTRATION NUMBER: US ClinicalTrials.gov (NCT00911521 & NCT02477254).

Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort.

Objectives The aim of this study was to study the relationship between immunosuppressive drug treatment and survival in patients with systemic lupus erythematosus (SLE). Methods Patients who fulfilled four or more American College of Rheumatology criteria for SLE were followed longitudinally. Clinical characteristics, use of immunosuppressive agents and mortality were reviewed. Cox regression was used to study the relationship between immunosuppressive treatment and survival, adjusted for age, sex, vascular risk factors, organ damage, the anti-phospholipid antibodies and a propensity score for the indication of individual immunosuppressive agent derived from separate regression models. Results A total of 803 SLE patients were studied (92% women; age of SLE onset 33.2±14 years; follow-up time 10.8±7.7 years). The frequencies of ever use of immunosuppressive agents were: high-dose prednisolone (≥0.6 mg/kg/day for ≥4 weeks) (85%), azathioprine (63%), cyclophosphamide (25%), mycophenolate mofetil (27%), the calcineurin inhibitors (23%) and hydroxychloroquine (69%). Ninety-seven patients (12%) died and 56 (7%) patients were lost to follow-up. The causes of death were infection (44%), cerebrovascular events (12%), cardiovascular events (10%) and malignancy (8.2%). Cox regression revealed that the ever use of high-dose prednisolone, mycophenolate mofetil, calcineurin inhibitors or cyclophosphamide was not significantly associated with improved survival. However, the ever use of hydroxychloroquine (hazard ratio 0.59 (0.37-0.93); P=0.02) and azathioprine (hazard ratio 0.46 (0.28-0.75); P=0.002) was significantly associated with reduced mortality (41% and 54%, respectively) after adjustment for the propensity score and other confounding factors. A similar beneficial effect of hydroxychloroquine and azathioprine on survival was also observed in patients with lupus nephritis. Conclusions In this longitudinal cohort of Chinese SLE patients, the ever use of hydroxychloroquine and azathioprine was significantly associated with a probability of better survival. Treatment with high-dose prednisolone, cyclophosphamide, mycophenolate mofetil or the calcineurin inhibitors was not associated with long-term survival benefit.

Disease-specific quality of life in patients with lupus nephritis.

Background Patient-reported outcomes in lupus nephritis (LN) are not well studied. Studies with disease-targeted PRO tool in LN do not exist. Herein, we describe quality of life (QOL: HRQOL & non-HRQOL) among LN patients using LupusPRO. Methods International, cross-sectional data from 1259 patients with systemic lupus erythematosus (SLE) and LupusPRO were compared, stratified by (a) presence of LN (ACR classification criteria (ACR-LN)) at any time and, (b) active LN (on SLEDAI) at study visit. Damage was assessed by SLICC/ACR-SDI. Multivariate regression analyses for QOL against ACR-LN (active LN) after adjusting for age, gender, ethnicity and country of recruitment were performed. Results Mean (SD) age was 41.7 (13.5) yrs, 93% were women. Five hundred and thirty-nine of 1259 SLE patients had ACR-LN. ACR-LN group was younger, were more often on immunosuppressive medications, had worse QOL on lupus medications and procreation than non-ACR-LN patients. HRQOL and non-HRQOL scores were similar in both groups. One hundred and twenty-nine of 539 ACR-LN patients had active LN. Active LN group was younger, had greater disease activity and had worse HRQOL and non-HRQOL compared to patients without active LN. Specific domains adversely affected were lupus symptoms, lupus medications, procreation, emotional health, body image and desires-goals domains. Patients with ACR-LN and active LN fared significantly worse in lupus medications and procreation HRQOL domains, even after adjusting for age, ethnicity, gender and country of recruitment. Conclusions Lupus nephritis patients have poor QOL. Patients with active LN have worse HRQOL and non-HRQOL. Most domains affected are not included in the generic QOL tools used in SLE. LN patients must receive discussion on lupus medications and procreation issues. Patients with active LN need comprehensive assessments and addressal of QOL, along with treatment for active LN.

Potential applications of nonthermal plasmas against biofilm-associated micro-organisms in vitro.

Biofilms as complex microbial communities attached to surfaces pose several challenges in different sectors, ranging from food and healthcare to desalination and power generation. The biofilm mode of growth allows microorganisms to survive in hostile environments and biofilm cells exhibit distinct physiology and behaviour in comparison with their planktonic counterparts. They are ubiquitous, resilient and difficult to eradicate due to their resistant phenotype. Several chemical-based cleaning and disinfection regimens are conventionally used against biofilm-dwelling micro-organisms in vitro. Although such approaches are generally considered to be effective, they may contribute to the dissemination of antimicrobial resistance and environmental pollution. Consequently, advanced green technologies for biofilm control are constantly emerging. Disinfection using nonthermal plasmas (NTPs) is one of the novel strategies having a great potential for control of biofilms of a broad spectrum of micro-organisms. This review discusses several aspects related to the inactivation of biofilm-associated bacteria and fungi by different types of NTPs under in vitro conditions. A brief introduction summarizes prevailing methods in biofilm inactivation, followed by introduction to gas discharge plasmas, active plasma species and their inactivating mechanism. Subsequently, significance and aspects of NTP inactivation of biofilm-associated bacteria, especially those of medical importance, including opportunistic pathogens, oral pathogenic bacteria, foodborne pathogens and implant bacteria, are discussed. The remainder of the review discusses majorly about the synergistic effect of NTPs and their activity against biofilm-associated fungi, especially Candida species.

Sexual violence cases in a hospital setting in Hong Kong: victims' demographic, event characteristics, and management.

INTRODUCTION: Rainlily, the first one-stop crisis centre in Hong Kong, was set up in 2000 to protect female victims of sexual violence. This study aimed to analyse the characteristics of sexual assault cases and victims who presented to two hospitals in Hong Kong. The data are invaluable for health care professionals and policymakers to improve service provision to these victims. METHODS: This retrospective analysis of hospital records was conducted in two acute hospitals under the Hospital Authority in Hong Kong. Sexual assault victims who attended the two hospitals between May 2010 and April 2013 were included. Characteristics of the cases and the victims, the use of alcohol and drugs, involvement of violence, and the outcome of the victims were studied. RESULTS: During the study period, 154 sexual assault victims attended either one of the two hospitals. Their age ranged from 13 to 64 years. The time from assault to presentation ranged from 1 hour to more than 5 months. Approximately 50% of the assailants were strangers. Approximately 50% of victims presented with symptoms; the most common were pelvic and genitourinary symptoms. Those with symptoms (except pregnancy) presented earlier than those without. The use of alcohol and drugs was involved in 36.4% and 11.7% of cases, respectively. Approximately 10% of the screened victims were positive for Chlamydia trachomatis. There were 11 pregnancies with gestational age ranged from 6 weeks to 5 months at presentation. Less than half of the victims completed follow-up care. CONCLUSIONS: Involvement of alcohol and drugs is not uncommon in sexual assault cases. Efforts should be made to promote public education, enhance coordination between medical and social services, and improve the accessibility and availability of clinical care. Earlier management and better compliance with follow-up can minimise the health consequences and impact on victims.

Towards new avenues in the management of lupus glomerulonephritis.

Renal involvement in systemic lupus erythematosus (SLE) carries substantial morbidity and mortality. Conventional immunosuppressive agents (cyclophosphamide and azathioprine) have suboptimal efficacy and substantial toxicity. Mycophenolate mofetil has emerged as an alternative agent for both induction and maintenance therapy in lupus nephritis because of its reduced gonadal toxicity, despite its failure to demonstrate superiority over cyclophosphamide in pivotal studies. The calcineurin inhibitor tacrolimus has equivalent efficacy to cyclophosphamide and mycophenolate mofetil for inducing remission of lupus nephritis. Although rituximab has shown promise in refractory lupus nephritis, combining rituximab with mycophenolate mofetil as initial therapy offers no additional benefit. Considerable interethnic variation is evident in the efficacy and tolerability of the various immunosuppressive regimens, which necessitates individualized treatment and comparison of the efficacy of new regimens across different ethnic groups. For example, low-dose combinations of tacrolimus and mycophenolate mofetil seem to be more effective than pulse cyclophosphamide as induction therapy in Chinese patients. The same regimen has also been used successfully to treat refractory proliferative and membranous lupus nephritis in patients of various ethnic groups. Finally, novel serum and urinary biomarkers are being validated for diagnosis, prognostic stratification and early recognition of flares in lupus nephritis.