Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

The association between abcb1 gene polymorphism and clopidogrel response variability in stroke ischemic: a cross sectional study.

BACKGROUND: Clopidogrel has been the primary choice of antiplatelet in ischemic stroke that inhibits adenosine diphosphate (ADP)-induced platelet aggregation. P-glycoprotein (P-gp) multidrug resistance-1 (MDR1) is a transmembrane efflux transporter in intestinal cells that plays a significant role in clopidogrel absorption, therefore may affect platelet aggregation. P-gp is encoded by the ABCB1 gene. This study aims to evaluate the effect of ABCB1 polymorphism on clopidogrel response variability in ischemic stroke patients and its genotype frequency. METHODS: A cross-sectional study was conducted in ischemic stroke patients who received clopidogrel between 2020 and 2023 in RSUI/RSCM. All subjects were assessed for ABCB1 polymorphisms C3435T and C1236T. Platelet aggregation were measured using VerifyNow PRU. Clopidogrel response variability was classified into unresponsive (> 208 PRU), responsive (95-208 PRU), and bleeding risk (< 95 PRU). RESULTS: 124 subjects enrolled in this study, with 12,9% of subjects classified as non-responsive/resistant, 49,5% as responsive, and 41,9% as bleeding risk. ABCB1 C1236T homozygote wildtype (CC) was associated with 3,76 times higher bleeding risk than other variants (p = 0,008; 95%CI 1,41 - 10,07). Genotype frequency of ABCB1 C3435T homozygote wildtype, heterozygote, and homozygote variants were 35,9%, 43,5% and 16,9%, respectively; while the genotype frequency of ABCB1 C1236T were 17,8%, 39,5%, and 42,7%, respectively. CONCLUSION: ABCB1 C1236T homozygote wildtype was associated with 3,76 times higher bleeding risk than other variants. The most common genotype frequency of ABCB1 C1236T was homozygote variant; while for ABCB1 C3435T was heterozygote.

Facilities, selection, outcome measurement, and limitations of therapeutic plasma exchange for neuroimmunological disorders: The South East Asian survey study.

INTRODUCTION: Therapeutic plasma exchange (TPE) for neuroimmunological disorders has played an important role in the Southeast Asian region. This study investigates the challenges of performing TPE within the region. METHOD: A questionnaire-based survey was conducted and launched to 15 South East Asian Therapeutic Plasma Exchange Consortium (SEATPEC) members from seven countries in January 2021. It included demographics, TPE techniques, indications, challenges, timing, outcome measurement, and access to laboratory testing in each local center. RESULTS: A total of 15 neurologists from 12 participating centers were included. They usually perform five sessions of TPE (100.0%), with 1 to 1.5 plasma volume (93.3%), and exchanges via the central catheter (100.0%). Acute relapses of neuromyelitis optica spectrum disorder and myasthenia gravis are the most common indications. They used a combination of normal saline and 5% albumin (60.0%) as replacement fluid. Most (66.7%) used TPE as an add-on treatment in steroid-refractory cases or as first-line treatment for severe attacks. They suggested assessing the TPE efficacy of TPE by the interval to the next attack, post-TPE relapse rates, and TPE-related complications. The major challenges within our region are expense, reimbursibility, and access to TPE. CONCLUSION: Although countrywise differences exist, all share similarities regarding methods, indications, timing, obstacles, and challenges of TPE for neuroimmunological conditions. Regional collaboration will be essential to identify strategies to reduce these barriers to access to TPE in the future.

Prognostic identifier of cerebrovascular complications in tuberculous meningitis: Meta-analysis.

INTRODUCTION: Cerebrovascular complications could occur in 15-57 % of patients with tuberculous meningitis (TBM). It is crucial to rapidly identify TBM patients who are at risk for stroke. This study aimed to find predictors of stroke in patients with TBM. METHODS: This systematic review and meta-analysis were done using literature searches through online databases up to April 30th, 2022. Three independent authors performed literature screening, data extraction, and critical appraisal of the studies. Eight studies involving 1535 samples were included. RESULTS: We analyzed data regarding demographic, comorbidity, clinical presentation, radiologic, and laboratory parameters. Overall, clinical presentation that showed outcome difference was found in patients with findings of vomiting (OR = 2.71, 95 % CI: 1.30-5.63), cranial nerve deficit (OR = 4.10, 95 % CI: 1.83-9.21), focal deficit (OR = 5.56, 95 % CI: 2.24-13.79), and altered consciousness (OR = 1.90, 95 % CI: 1.24-2.92). Some comorbidities showed significant differences such as diabetes mellitus (OR = 2.58, 95 % CI: 1.51-4.41), hypertension (OR = 5.73, 95 % CI: 3.36-9.77), ischemic heart disease (OR = 2.18, 95 % CI: 1.02-4.63), and smoking (OR = 2.65, 95 % CI: 1.22-5.77). Two radiological changes shown to have significantly higher proportions are hydrocephalus (OR = 2.50, 95 % CI: 1.74-3.58) and meningeal enhancements (OR = 3.99, 95 % CI: 1.73-9.20). CONCLUSION: Our analysis indicated that clinical presentations of vomiting, cranial nerve deficit, focal deficit, altered consciousness; comorbidity of diabetes mellitus, hypertension, smoking history, ischemic heart disease; and radiological findings of meningeal enhancement and hydrocephalus showed significant association with stroke incidence in tuberculous meningitis.

Which NK cell populations mark the high burden of CMV present in all HIV patients beginning ART in Indonesia?

BACKGROUND: Cytomegalovirus (CMV) has been linked with cardiovascular disease (CVD) in populations where some individuals are seronegative. However, effects of CMV are unclear in HIV patients who all have high levels of CMV antibodies. Other metrics of their CMV burden are needed. Amongst transplant recipients, CMV drives the expansion of NK cell populations expressing NKG2C and/or LIR1 and lacking FcRγ. METHODS: Indonesian HIV patients (n = 40) were tested before ART and after 6 months, with healthy local controls (n = 20). All patients had high CMV antibody titres. 52% started therapy with CMV DNA detectable by qPCR, providing a crude measure of CMV burden. Proportions of CD56Hi or CD56Lo NK cells expressing FcRγ, NKG2C or LIR1 were determined flow cytometrically. CVD was predicted using carotid intimal media thickness (cIMT). Values were correlated with levels of CMV antibodies on ART. RESULTS: Patients had low proportions of CD56Lo and more CD56Hi NK cells. However proportions of FcRγ- NK cells were lowest in patients with CMV DNA, and cIMT values related inversely with FcRγ- NK cells in these patients. Percentages of NKG2C+CD56Lo NK cells were similar in patients and controls, but rose in patients with CMV DNA. Proportions of NKG2C+ CD56Hi NK cells correlated with levels of CMV antibodies in CMV DNA-negative patients. CONCLUSIONS: We show that the very high burdens of CMV in this population confound systems developed to study effects of CMV in other populations. FcRγ- NK cells may be depleted by very high CMV burdens, but NKG2C and antibody levels may be informative in patients on ART.

Understanding the effects of CMV on γδ T-cell populations in HIV patients starting antiretroviral therapy.

Cytomegalovirus (CMV) affects γδ T-cell profiles in healthy individuals and transplant recipients, but the effects of HIV and CMV have not been distinguished in HIV patients. CMV-seropositive Indonesian HIV patients (n = 40) were studied before ART and after six months, alongside healthy controls (n = 20). 50% of patients started ART with detectable CMV DNA. Proportions of Vδ2- γδ T-cells were high in patients and declined on ART, whilst proportions of Vδ2+ γδ T-cells were uniformly low, and correlated inversely with levels of CMV DNA and CMV-reactive antibody. Residual Vδ2+ cells were enriched for markers of terminal differentiation, but this did not associate with CMV metrics. Patients with CMV DNA at baseline showed a direct correlation between CMV reactive-antibody and CD8+ γδ T-cells. Our data are consistent with a role for CMV in the depletion of Vδ2+ γδ T-cells in HIV patients beginning ART, with no consistent evidence of a role for CMV in γδ T-cell activation or differentiation.

Impact of Covid-19 on the therapeutic plasma exchange service within the South East Asian region: Consensus recommendations and global perspectives.

INTRODUCTION: Therapeutic plasma exchange (TPE) for neuroimmunological disorders has played an increasingly important role within the Southeast Asian (SEA) region. The South East Asian Therapeutic Plasma exchange Consortium (SEATPEC) was formed in 2018 to promote education and research on TPE within the region. The advent of the Covid-19 pandemic has produced challenges for the development and expansion of this service. METHODOLOGY: A qualitative and semi-quantitative questionnaire-based survey was conducted by SEATPEC member countries from January to June 2020 (Phase 1) and then from July 2020 to January 2021 in (Phase 2) to assess the impact of Covid-19 on regional TPE. OBJECTIVES: The study's main objectives were to explore the challenges experienced and adaptations/adjustments taken by SEATPEC countries in order to continue safe and efficient TPE during the Covid-19 pandemic. RESULTS: The pandemic was found to disrupt the delivery of TPE services in all SEATPEC countries. Contributing factors were multifactorial due to overstretched medical services, staff shortages, quarantines and redeployments, fear of acquiring Covid-19, movement restriction orders, and patient's psychological fear of attending hospitals/testing for Covid-19. All SEATPEC countries practiced careful stratification of cases for TPE (electives vs emergencies, Covid-19 vs non-Covid-19 cases). SEATPEC countries had to modify TPE treatment protocols to include careful preprocedure screening of patient's for Covid-19, use of personal protective equipment (PPE) and post-TPE sanitization of machines and TPE suites. CONCLUSION: Based on the responses of the survey, SEATPEC countries produced a consensus statement with five recommendations for safe and effective TPE within the region.

Determinants of cognitive health in Indonesian HIV patients beginning antiretroviral therapy.

Cognitive impairment has been described in people living with HIV and stable on antiretroviral therapy (ART), but has not been monitored in young adults beginning ART with a high burden of cytomegalovirus. We recruited 80 subjects beginning ART with < 200 CD4 T cells/µL in Jakarta, Indonesia. Cognitive function (Z-scores) began low but improved on ART, stabilizing after 6 months with improvements in all domains except memory function. The burden of cytomegalovirus persisting on ART (assessed via antibody levels) correlated inversely with Z-scores (notably memory function) at baseline. In linear mixed models, improvements in Z-scores were influenced by age, education, and CD4 T cell counts.

Factors Related to Knowledge, Perception, and Practices Towards COVID-19 Among Patients with Autoimmune Diseases: A Multicenter Online Survey.

BACKGROUND: autoimmune patients can be more susceptible to infection. Proper knowledge, perception, and practices towards COVID-19 are essential for these patients during pandemic. This study aimed to know their knowledge, perception, and practices regarding COVID-19. METHODS: cross sectional study using online survey was conducted from April to May 2020. Patients with autoimmune disease were asked about demographic characteristics, diagnosis, history of treatment, knowledge, perception, and practice regarding COVID-19. RESULTS: there were 685 respondents. Most of them were female and had systemic lupus erythematosus with median age of 37 years old. Almost all respondents had good knowledge regarding transmission of COVID-19 and did proper prevention practices. Adequacy of information and steroid or mycophenolate mofetil/mycophenolic acid (MMF/MPA) use were related to perception of the effect of pandemic to their own health. Visiting private clinic and receiving hydroxychloroquine/chloroquine sulfate or sulfasalazine were related to perception that autoimmune conditions would make them more prone to COVID-19. Work from home was related to perception that when contracting COVID-19, the symptoms would be more severe. Living in Sumatra region and getting hydroxychloroquine/chloroquine sulfate or MMF/MPA were related to perception that autoimmune medications could reduce risk of getting COVID-19. Adequate information, university education, private clinic visit, and hydroxychloroquine/chloroquine sulfate use were related to perception that COVID-19 pandemic would cause difficulties in getting medications. CONCLUSION: almost all respondents had good knowledge and practices regarding COVID-19. Adequacy of information, autoimmune treatment, work from home, educational background, area of living, and health care facilities contributed to perception regarding COVID-19 pandemic.

Corpus callosum index correlates with brain volumetry and disability in multiple sclerosis patients.

OBJECTIVE: To analyze the correlation between corpus callosum index (CCI), brain volumetry, and disability in multiple sclerosis (MS) patients. The brain volumetry consists of the corpus callosum, cortical gray matter, subcortical gray matter, and white matter volumes. METHODS: This was a retrospective cross-sectional study from October 2018 to February 2019 of 30 patients with MS aged 20 to 61 years old. Brain volumetry was performed using FreeSurfer software. The CCI were measured manually using conventional best mid-sagittal T1W brain MRI. The anterior, posterior, and medium segments were measured and divided to its greatest anteroposterior diameter. Higher CCI values indicated greater corpus callosum volumes. Clinical evaluation was comprised of MS subtype, age of onset, relapse frequency and Expanded Disability Status Scale (EDSS). RESULTS: Thirty MS patients with median of age 22 years were included. Relapsing-remitting (RRMS) subtype were 73.3%. Very significant correlations were shown between the CCI and corpus callosum volume (CCV) (r=0.79; p<0.0001) and cerebral white matter volume (r=0.81; p<0.0001). Significant correlations were shown between the CCI and cortical gray matter volume (r=0.64; p<0.0001) and subcortical gray matter volume (r=0.69; p<0.0001). The CCI was positively correlated with age of onset and inversely with EDSS. The CCV and CCI were smaller in secondary progressive MS (SPMS). CONCLUSION: The CCI is easy and fast to obtain in conventional MRI and significantly correlated with brain volumetry, age of onset and disability in MS patients.

Characterization of Natural Killer Cells in HIV Patients Beginning Therapy with a High Burden of Cytomegalovirus.

BACKGROUND: Active infections with cytomegalovirus (CMV) increase NK cell expression of the inhibitory receptor LIR-1 and the activating receptor NKG2C in transplant recipients. However, the effects of CMV on NK cells are different in HIV patients stable on antiretroviral therapy (ART) and have not been analyzed in young HIV patients beginning ART. METHODOLOGY: We followed a cohort of 78 Indonesian HIV patients beginning ART. CMV antibodies were measured in plasma before ART (baseline), and after 1, 3, 6, and 12 months. CMV DNA was sought in blood granulocytes at baseline by quantitative PCR assay and a deletion in the NKG2C gene was identified by PCR. NK cell profiles were monitored by flow cytometry in 19 patients stratified by the presence of CMV DNA. Healthy controls (n = 17) were assessed once. RESULTS: All 78 patients were CMV seropositive and 41 had detectable CMV DNA. CMV DNA+ patients had higher proportions of total NK cells and CD16+ NK cells at baseline, but similar expression of LIR-1 and NKp30 on NK cells on ART. However, levels of CMV antibody were inversely related to median LIR-1 expression on NK cells. A dramatic elevation in cells expressing NKG2C was restricted to CMV DNA+ patients heterozygous for the NKG2C deletion. Patients with High NKG2C expression had lower levels of CMV antibodies. CONCLUSION: A subpopulation of NK cells expressing NKG2C was induced by CMV replication in HIV patients heterozygous for a deletion in this gene. Individuals with an abundant NKG2C+ and LIR-1+ NK cells displayed lower levels of CMV reactive antibody.

Validation of the Indonesian version of multiple sclerosis quality of life-54 (MSQOL-54 INA) questionnaire.

BACKGROUND: Quality of life assessment of patients with multiple sclerosis (MS) is not routinely performed in Indonesia due to the unavailability of the validated Indonesian version of a specific instrument. The objective of this study was to transculturally adapt and validate the Indonesian version of the MSQOL-54 (MSQOL-54 INA) questionnaire. METHODS: The transcultural adaptation was conducted by performing a standardized forward-backward method. Psychometric analysis was performed by assessing the reliability (Cronbach α), internal validation (item internal consistency and item discriminant validity), and external validation by measuring the correlation with a clinical factor such as EDSS and other demographic factors. RESULTS: Reliability test with Cronbach α showed good internal consistency (> 0.7) at each component, except for health perception (0.665) and social function (0.433). Construct validity using computation of correlation coefficient showed internal consistency in accordance with the original MSQOL-54 standard dimension, except for energy and role limitation due to emotional problems components. External validation with EDSS showed negative correlation on almost all components, except for sexual function, but both composite scores were statistically significant. CONCLUSION: MSQOL-54 INA questionnaire has good internal reliability and is proven to be valid and well-accepted by Indonesian MS patients. Therefore, it can be used by Indonesian clinicians for more comprehensive MS management.

HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV.

Cytomegalovirus (CMV) is a ß-herpesvirus. Latent infections are common in all populations. However age-associated increases in levels of CMV-reactive antibody are testament to repeated reactivations and periods of viral replication. CMV has been associated with several diseases of aging, including vasculopathy and neurocognitive impairment. These conditions occur at a younger age in persons with particularly high burdens of CMV - transplant recipients and people living with HIV. Here we define the "clinical footprints" as immunopathologies triggered by CMV that develop over many years. A high burden of CMV also drives accumulation of multifunctional terminally-differentiated αß T-cells, a novel population of Vδ2- γδ T-cells, and a population of CD56lo NK cells lacking a key regulatory molecule. An understanding of these "immunological footprints" of CMV may reveal how they collectively promote the "clinical footprints" of the virus. This is explored here in transplant recipients, HIV patients and healthy aging.

Second regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the immunomodulatory role of plasma exchange in central and peripheral nervous system disorders, Kuala Lumpur, Malaysia, 9th December 2017.

In December 2017, 79 delegates attended the 2nd regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the immunomodulatory role of plasma exchange in central and peripheral nervous system disorders in Kuala Lumpur, Malaysia. This meeting featured 6 plenary lectures, interactive sessions dedicated for experience sharing, case presentations, and a practical session for paramedics. Clinical experts and researchers from 7 SEA countries and India shared experience and challenges in treating autoimmune neurological disorders. While the spectrum of diseases and neurology practice remained largely similar, there was great disparities in accessibility of therapeutic plasma exchange (TPE) within SEA countries and between urban or rural settings. Costs, human resources, and healthcare policies are common challenges in providing sustainable TPE services. Novel techniques and innovative ideas in performing TPE were explored. A working consortium comprising of key opinion leaders was proposed to improve standards of TPE and enhance future research.

Factors affecting affect cardiovascular health in Indonesian HIV patients beginning ART.

BACKGROUND: We present a small longitudinal study of how demographic factors and persistent burdens of HIV and cytomegalovirus (CMV) influence cardiovascular health in young adults beginning ART in an inner-city clinic in Jakarta, Indonesia. METHODS: ART-naïve HIV patients [n = 67; aged 31 (19 to 48) years] were enrolled in the JakCCANDO Project. Echocardiography and carotid Doppler ultrasonography were performed before ART (V0) and after 3, 6, and 12 months (V3-12). Antibodies reactive with CMV lysate or IE-1 protein were assessed at each timepoint and CMV DNA was identified at V0. RESULTS: Markers of adverse cardiovascular prognosis [left ventricular mass index, ejection fraction and carotid intimal media thickness (cIMT)] were similar to healthy controls, but increased at V12. Internal diameters of the carotid arteries and systolic blood pressure correlated with HIV disease severity at V0, but cardiac parameters and cIMT did not. E/A ratios (left ventricular diastolic function) were lower in patients with CMV DNA at V0, but this effect waned by V6. Levels of antibody reactive with CMV IE-1 correlated inversely with CD4 T cell counts at V0, and levels at V6-V12 correlated directly with the right cIMT. CONCLUSIONS: Overall the severity of HIV disease and the response to ART have only subtle effects on cardiovascular health in this young Asian population. CMV replication before ART may have a transient effect on cardiac health, whilst antibody reactive with CMV IE-1 may mark a high persistent CMV burden with cumulative effects on the carotid artery.

Multidisciplinary re-evaluation of neuropsychiatric events to confirm the neuropsychiatric lupus diagnosis at an Indonesian tertiary hospital.

OBJECTIVE: Neuropsychiatric SLE (NPSLE) has a broad spectrum and to date, there is no gold-standard biomarker. The diagnosis relies on clinical assessment, supporting examinations and exclusion of other possible aetiologies. One method that can be used to establish NPSLE is to conduct a re-evaluation by involving several fields of medical science. This study aims to reassess SLE cases with neuropsychiatric (NP) manifestations through multidisciplinary re-evaluation and determine the final diagnosis of NPSLE or non-NPSLE. METHODS: This retrospective cross-sectional study used medical record data from patients with SLE with NP manifestations. Inclusion criteria included patients diagnosed with SLE, who had clinical manifestations of NP and were >18 years old. Multidisciplinary re-evaluation was conducted and agreed upon the diagnosis of NPSLE or non-NPSLE. RESULTS: We included 94 subjects with a total of 132 NP events consisting of 69 NPSLE and 63 non-NPSLE. After re-evaluating NPSLE events, 33.3% were still concluded to be NPSLE. Meanwhile, from the non-NPSLE group, 22.2% were then declared as NPSLE. There were no significant differences in demographic characteristics between the NPSLE and non-NPSLE groups. The proportion of NP events in both groups was almost the same except for cerebrovascular disease manifestations which were more common in the NPSLE group. Higher Mexican SLE Disease Activity Index scores with (p<0.001) or without NP (p=0.02) were observed in the NPSLE group compared with the non-NPSLE group, as well as higher proportion of active disease (p=0.03), higher anti-double-stranded DNA titres (p<0.001) and lower values of C3 (p=0.018) and C4 (p=0.001). CONCLUSIONS: Multidisciplinary re-evaluation can be used as a method to confirm the diagnosis of NPSLE. There is a tendency for overdiagnosis of NPSLE when clinicians are faced with NP events in patients with SLE. Complete clinical and supporting data are needed to determine the final diagnosis of NPSLE.

Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement.

BACKGROUND: Despite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. METHODS: The survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. RESULTS: All fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. CONCLUSION: This study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Effectiveness of transcranial direct current stimulation (tDCS) as adjunctive treatment for chronic headache in adults with clinically stable systemic lupus erythematosus (SHADE): a randomised double-blind multiarm sham controlled clinical trial.

BACKGROUND: Chronic headache is a 'silent' neuropsychiatric systemic lupus erythematosus symptom with heterogeneous prevalence, potentially reaching 54.4%. It may reduce quality of life by increasing the likelihood of depression and sleep disturbance. While pharmacotherapy remains the first-line treatment, the current management is still challenging and needs other non-invasive modalities. An effective, tolerable and disease-specific treatment modality including transcranial direct current stimulation (tDCS) is considered to reduce the frequency of chronic headaches, including in SLE. Until recently, there was no standard protocol for tDCS in treating headaches. METHODS AND ANALYSIS: SHADE is a single-centre randomised double-blind multiarm sham-controlled trial for adults with clinically stable SLE, chronic headaches and without history of traumatic brain injury, brain infection, stroke or brain tumour. Random allocation is conducted to 88 subjects into 3 treatment groups (administration at primary motor, primary sensory and dorsolateral prefrontal cortex) and control group in 1:1:1:1 ratio. The primary endpoint is reduced number of headache days after adjunctive tDCS. The secondary endpoints are reduced headache intensity, increased quality of life, increased sleep quality, decreased depression and reduced analgesics use. The outcome is measured monthly until 3-month postintervention using headache diary, 36-Item Short Form Survey, Chronic Headache Quality of Life Questionnaire, Pittsburgh Sleep Quality Index and Mini International Neuropsychiatry Interview version 10 (MINI ICD 10). Intention-to-treat analysis will be performed to determine the best tDCS electrode placement. ETHICS AND DISSEMINATION: Ethical approval had been obtained from the local Institutional Review Board of Faculty of Medicine Universitas Indonesia. Results will be published through scientific relevant peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05613582.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).