Meta-analysis of the serum/plasma proteome identifies significant associations between COVID-19 with Alzheimer's/Parkinson's diseases.

In recent years, we have seen the widespread devastations and serious health complications manifested by COVID-19 globally. Although we have effectively controlled the pandemic, uncertainties persist regarding its potential long-term effects, including prolonged neurological issues. To gain comprehensive insights, we conducted a meta-analysis of mass spectrometry-based proteomics data retrieved from different studies with a total of 538 COVID-19 patients and 523 healthy controls. The meta-analysis revealed that top-enriched pathways were associated with neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD). Further analysis confirmed a direct correlation in the expression patterns of 24 proteins involved in Alzheimer's and 23 proteins in Parkinson's disease with COVID-19. Protein-protein interaction network and cluster analysis identified SNCA as a hub protein, a known biomarker for Parkinson's disease, in both AD and PD. To the best of our knowledge, this is the first meta-analysis study providing proteomic profiling evidence linking COVID-19 to neurological complications.

Computational identification of potential bioactive compounds from Triphala against alcoholic liver injury by targeting alcohol dehydrogenase.

Alcoholic liver injury resulting from excessive alcohol consumption is a significant social concern. Alcohol dehydrogenase (ADH) plays a critical role in the conversion of alcohol to acetaldehyde, leading to tissue damage. The management of alcoholic liver injury encompasses nutritional support and, in severe cases liver transplantation, but potential adverse effects exist, and effective medications are currently unavailable. Natural products with their potential benefits and historical use in traditional medicine emerge as promising alternatives. Triphala, a traditional polyherbal formula demonstrates beneficial effects in addressing diverse health concerns, with a notable impact on treating alcoholic liver damage through enhanced liver metabolism. The present study aims to identify potential active phytocompounds in Triphala targeting ADH to prevent alcoholic liver injury. Screening 119 phytocompounds from the Triphala formulation revealed 62 of them showing binding affinity to the active site of the ADH1B protein. Promising lipid-like molecule from Terminalia bellirica, (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid showed high binding efficiency to a competitive ADH inhibitor, 4-Methylpyrazole. Pharmacokinetic analysis further confirmed the drug-likeness and non-hepatotoxicity of the top-ranked compound. Molecular dynamics simulation and MM-PBSA studies revealed the stability of the docked complexes with minimal fluctuation and consistency of the hydrogen bonds throughout the simulation. Together, computational investigations suggest that (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid from the Triphala formulation holds promise as an ADH inhibitor, suggesting an alternative therapy for alcoholic liver injury.

Targeting AFP-RARß complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARß interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARß complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARß complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.

Hydrogeochemical characteristics of surface and groundwater: suitability for human consumption and irrigated agriculture purposes in Suruliyar sub basin, South India.

The Suruliyar sub basin in Tamil Nadu, India, was monitored for the assessment of water and soil quality. Surface water, groundwater, and soil samples were collected during the pre-monsoon (June 2016) and post-monsoon (December 2016) seasons within the sub basin area and analyzed for various physical, chemical, and biological properties, namely, pH, electrical conductivity, total dissolved solids (TDS), calcium, magnesium, sodium, nitrate, sulfate, fluoride, chloride, biological oxygen demand, chemical oxygen demand, and total and fecal coliform. All the values were compared with Indian and global standards, and the values for each parameter were within the permissible limits. However, some samples were edging toward the upward limit. Fecal coliforms (14 to 36 counts per 100 ml) were present in the river water, thus indicating anthropogenic contamination. Correlation analysis confirmed that TDS was significantly positively correlated with most of the cations and anions. Groundwater was assessed using several indices, such as the Piper diagram, United States Salinity Laboratory diagram, sodium adsorption ratio, and sodium percentage. Results showed that all the groundwater samples could be used for irrigation purposes; however, the chloride contents exceeded the permissible limit. Soil analysis results showed that all nutrients were within the permissible limits. Drought assessment showed the existence of both dry and wet years occurring most frequently, which might have a strong influence on the quality of water and soil parameters. This study suggests that the monitoring of surface, groundwater, and soil parameters is essential to maintain the sub basin area for ensuring sustainable development in the future.

Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis.

AIMS: The mechanisms underlying the selective degeneration of motor neurones in amyotrophic lateral sclerosis (ALS) are poorly understood. The aim of this study was to implement spatially resolved RNA sequencing in human post mortem cortical tissue from an ALS patient harbouring the C9orf72 hexanucleotide repeat expansion to identify dysregulated transcripts that may account for differential vulnerabilities of distinct (i) cell types and (ii) brain regions in the pathogenesis of ALS. METHODS: Using spatial transcriptomics (ST) we analysed the transcriptome of post mortem brain tissue, with spatial resolution down to 100 µm. Validation of these findings was then performed using BaseScope, an adapted, in situ hybridization technique with single-transcript single-cell-resolution, providing extensive regional and cell-type specific confirmation of these dysregulated transcripts. The validation cohort was then extended to include multiple post mortem brain regions and spinal cord tissue from an extended cohort of C9orf72, sporadic ALS (sALS) and SOD1 ALS cases. RESULTS: We identified sixteen dysregulated transcripts of proteins that have roles within six disease-related pathways. Furthermore, these complementary molecular pathology techniques converged to identify two spatially dysregulated transcripts, GRM3 and USP47, that are commonly dysregulated across sALS, SOD1 and C9orf72 cases alike. CONCLUSIONS: This study presents the first description of ST in human post mortem cortical tissue from an ALS patient harbouring the C9orf72 hexanucleotide repeat expansion. These data taken together highlight the importance of preserving spatial resolution, facilitating the identification of genes whose dysregulation may in part underlie regional susceptibilities to ALS, crucially highlighting potential therapeutic and diagnostic targets.

Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis.

AIMS: Clusterin is a topologically dynamic chaperone protein with the ability to participate in both intra- and extacellular proteostasis. Clusterin has been shown to be upregulated in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and has been shown to protect against TDP-43 protein misfolding in animal and cell models. Previous studies have demonstrated an association between the pathological burden of TDP-43 misfolding and cognitive deficits in ALS, demonstrating high specificity, but correspondingly low sensitivity owing to a subset of individuals with no evidence of cognitive deficits despite a high burden of TDP-43 pathology, called mismatch cases. METHODS: Hypothesizing that differences in the ability to cope with protein misfolding in these cases may be due to differences in expression of protective mechanisms such as clusterin expression, we assessed the spatial expression of clusterin and another chaperone protein, HspB8, in post mortem brain tissue of mismatch cases. We employed a modified in situ hybridization technique called BaseScope, with single cell, single transcript resolution. RESULTS: Mismatch cases demonstrated differential spatial expression of clusterin, with a predominantly neuronal pattern, compared to cases with cognitive manifestations of their TDP-43 pathology who demonstrated a predominantly glial distribution of expression. CONCLUSIONS: Our data suggest that, in individuals with TDP-43 pathology, predominantly neuronal expression of clusterin in extra-motor brain regions may indicate a cell protective mechanism delaying clinical manifestations such as cognitive dysfunction.

Femtomolar Detection of Spermidine Using Au Decorated SiO2 Nanohybrid on Plasmon-Coupled Extended Cavity Nanointerface: A Smartphone-Based Fluorescence Dequenching Approach.

Coupling of photons with molecular emitters in different nanocavities have resulted in transformative plasmonic applications. The rapidly expanding field of surface plasmon-coupled emission (SPCE) has synergistically employed subwavelength optical properties of localized surface plasmon resonance (LSPR) supported by nanoparticles (NPs) and propagating surface plasmon polaritons assisted by metal thin films for diagnostic and point-of-care analysis. Gold nanoparticles (AuNPs) significantly quench the molecular emission from fluorescent molecules (at close distances <5 nm). More often, complex strategies are employed for providing a spacer layer around the AuNPs to avoid direct contact with fluorescent molecules, thereby preventing quenching. In this study we demonstrate a rapid and facile strategy with the use of Au-decorated SiO2 NPs (AuSil), a metal (Au)-dielectric (SiO2) hybrid material for dequenching the otherwise quenched fluorescence emission from radiating dipoles and to realize 88-fold enhancement using the SPCE platform. Different loading of AuNPs were studied to tailor fluorescence emission enhancements in spacer, cavity, and extended (ext.) cavity nanointerfaces. We also present femtomolar detection of spermidine using this nanohybrid in a highly desirable ext. cavity interface. This interface serves as an efficient coupling configuration with dual benefits of spacer and cavity architectures that has been widely explored hitherto. The multifold hot-spots rendered by the AuSil nanohybrids assist in augmented electromagnetic (EM)-field intensity that can be captured using a smartphone-based SPCE platform presenting excellent reliability and reproducibility in spermidine detection.

'Pai Syndrome' with anterior alveolar polyp: A variant of a rare clinical entity.

'Pai syndrome' (PS) is a rare congenital syndrome. Presented here, a new-born baby-girl who exhibited the characteristic features of having a midline nasal (septal) polyp, an anterior alveolar process polyp, and a pericallosal lipoma associated with corpus callosum dysgenesis of the brain. Both polyps were lined with stratified-squamous epithelium. The overall features were largely consistent with those described by Pai et al., in 1987. A midline cleft-lip (with or without cleft-alveolus) is one of the most common features of the syndrome which was however absent in this case. Instead, an anterior alveolar polyp is present, which is relatively rare.

Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii.

AIMS: This study aimed to evaluate the antibiofilm potential of phytol and cefotaxime combinations (PCCs) against Acinetobacter baumannii and to elucidate the molecular mechanism of their antibiofilm potential through the transcriptomic approach. METHODS AND RESULTS: Phytol and cefotaxime combination(s) (PCC(s) [160 µg ml-1  + 8 µg ml-1 for microbial type culture collection (MTCC) strain and 160 µg ml-1  + 0.5 µg ml-1 for clinical isolate] effectively inhibited the A. baumannii biofilm formation. Additionally, light, confocal laser scanning and scanning electron microscopic analyses validated the antibiofilm potential of PCCs. Furthermore, PCCs treated A. baumannii cells showed a decreased level of hydrophobicity index compared to their respective controls. Fourier-transform infrared (FT-IR) spectra of exopolysaccharide matrix extracted from PCCs-treated A. baumannii cells showed a visible decrease in absorbance of polysaccharides, nucleic acids and protein regions compared to the spectra of untreated controls. In the blood sensitivity assay, the PCCs-treated A. baumannii plates showed reduced a number of bacterial colonies compared to their control plates. Reduced level of catalase production was also observed in the PCCs treatment compared to their controls. Transcriptomic analysis revealed the downregulation of bfmR, bap, csuA/B, ompA, pgaA, pgaC and katE biofilm virulence genes in both the A. baumannii strains on treatment with PCCs. CONCLUSION: The obtained results of this study indicate that PCCs have potent antibiofilm activity and downregulate the biofilm-related virulence genes expression in A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, this is the pioneering study, which shows the antibiofilm effect of PCCs against A. baumannii along with their molecular mechanism. The antibiofilm effect of PCCs could be a successful strategy for eradicating infections related to A. baumannii biofilms in nosocomial settings.

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants.

Early subclinical inflammation in kidney transplants is associated with later graft fibrosis and dysfunction. Regulatory T cells (Tregs) can reverse established inflammation in animal models. We conducted a pilot safety and feasibility trial of autologous Treg cell therapy in three kidney transplant recipients with subclinical inflammation noted on 6-month surveillance biopsies. Tregs were purified from peripheral blood and polyclonally expanded ex vivo using medium containing deuterated glucose to label the cells. All patients received a single infusion of ~320 × 106 (319, 321, and 363.8 × 106 ) expanded Tregs. Persistence of the infused Tregs was tracked. Graft inflammation was monitored with follow-up biopsies and urinary biomarkers. Nearly 1 × 109 (0.932, 0.956, 1.565 × 109 ) Tregs were successfully manufactured for each patient. There were no infusion reactions or serious therapy-related adverse events. The infused cells demonstrated patterns of persistence and stability similar to those observed in non-immunosuppressed subjects receiving the same dose of Tregs. Isolation and expansion of Tregs is feasible in kidney transplant patients on immunosuppression. Infusion of these cells was safe and well tolerated. Future trials will test the efficacy of polyclonal and donor alloantigen-reactive Tregs for the treatment of inflammation in kidney transplants.

Complications of Ultrasound-Guided Renal Transplant Biopsies.

Renal transplant biopsies to diagnose transplant pathology are routinely performed using ultrasound guidance. Few large studies have assessed the rate and risk factors of major biopsy complications. This study is a single-center 5-year retrospective cohort analysis of 2514 biopsies. Major complications occurred in 47 of 2514 patients (1.9%) and included hospitalization, transfusion of blood products, operative exploration and interventional radiology procedures. The complication rate among "cause" biopsies was significantly higher than in "protocol" biopsies (2.7% vs. 0.33%, p < 0.001). Complications presented on postbiopsy days 0-14, with the majority diagnosed on the same day as the biopsy and manifested by hematocrit drop, although the presence of such delayed presentation of complications occurring >24 h after the biopsy on days 2-14 is previously unreported. Specific patient characteristics associated with increased risk of a complication were increased age and blood urea nitrogen, decreased platelet count, history of prior renal transplant, deceased donor transplant type and use of anticoagulant medications but not aspirin.

Can we ease the financial burden of colonoscopy? Using real-time endoscopic assessment of polyp histology to predict surveillance intervals.

BACKGROUND: Polyps identified at colonoscopy are predominantly diminutive (<5 mm) with a small risk (>1%) of high-grade dysplasia or carcinoma; however, the cost of histological assessment is substantial. AIM: The aim of this study was to determine whether prediction of colonoscopy surveillance intervals based on real-time endoscopic assessment of polyp histology is accurate and cost effective. METHODS: A prospective cohort study was conducted across a tertiary care and private community hospital. Ninety-four patients underwent colonoscopy and polypectomy of diminutive (≤5 mm) polyps from October 2012 to July 2013, yielding a total of 159 polyps. Polyps were examined and classified according to the Sano-Emura classification system. The endoscopic assessment (optical diagnosis) of polyp histology was used to predict appropriate colonoscopy surveillance intervals. The main outcome measure was the accuracy of optical diagnosis of diminutive colonic polyps against the gold standard of histological assessment. RESULTS: Optical diagnosis was correct in 105/108 (97.2%) adenomas. This yielded a sensitivity, specificity and positive and negative predictive values (with 95%CI) of 97.2% (92.1-99.4%), 78.4% (64.7-88.7%), 90.5% (83.7-95.2%) and 93% (80.9-98.5%) respectively. Ninety-two (98%) patients were correctly triaged to their repeat surveillance colonoscopy. Based on these findings, a cut and discard approach would have resulted in a saving of $319.77 per patient. CONCLUSION: Endoscopists within a tertiary care setting can accurately predict diminutive polyp histology and confer an appropriate surveillance interval with an associated financial benefit to the healthcare system. However, limitations to its application in the community setting exist, which may improve with further training and high-definition colonoscopes.

Risk factors for mortality in Down syndrome.

BACKGROUND: Down syndrome is a genetic condition that contributes to a significantly shorter life expectancy compared with the general population. We investigated the most common comorbidities in a population of acute hospital patients with Down syndrome and further explored what the most common risk factors for mortality are within this population. METHOD: From our database of one million patients admitted to National Health Service (NHS) Trusts in northern England, we identified 558 people who had Down syndrome. We compared this group with an age- and gender-matched control group of 5580 people. RESULTS: The most prevalent comorbid diseases within the Down's population were hypothyroidism (22.9%) and epilepsy (20.3%). However, the conditions that had the highest relative risks (RRs) in the Down's population were septal defects and dementia. Respiratory failure, dementia and pneumonia were the most significantly related comorbidities to mortality in the Down syndrome population. In the control population, respiratory failure, dementia and renal failure were the most significant disease contributors. When these contributors were analysed using multivariate analysis, heart failure, respiratory failure, pneumonia and epilepsy were the identified risk factors for in-hospital mortality in the Down syndrome population. Respiratory failure was the sole risk factor for mortality in the Down syndrome population [RR = 9.791 (1.6-59.9) P ≤ 0.05], when compared with the risk factors for mortality in the control population. CONCLUSIONS: There is significant medical morbidity in Down syndrome. This morbidity contributes to the lower life expectancy. Respiratory failure is a risk factor for mortality in Down syndrome. We need to thoroughly investigate people with Down syndrome to ensure any treatable illnesses are well managed.

Detection of carbapenem resistance genes and cephalosporin, and quinolone resistance genes along with oqxAB gene in Escherichia coli in hospital wastewater: a matter of concern.

AIMS: This study was performed to detect the presence of Escherichia coli resistant to cephalosporins, carbapenems and quinolones in hospital wastewater. METHODS AND RESULTS: Wastewaters from a rural (H1) and an urban (H2) hospital were tested for E. coli resistant to cephalosporins, carbapenem and quinolones. Genes coding for chromosomal and plasmid-mediated resistance and phylogenetic grouping was detected by multiplex polymerase chain reaction (PCR) and for genetic relatedness by rep-PCR. Of 190 (H1 = 94; H2 = 96) E. coli examined, 44% were resistant to both cephalosporins and quinolones and 3% to imipenem. ESBLs were detected phenotypically in 96% of the isolates, the gene blaCTX-M coding for 87% and blaTEM for 63%. Quinolone resistance was due to mutations in gyrA and parC genes in 97% and plasmid-coded aac-(6')-Ib-cr in 89% of isolates. Only in one carbapenem-resistant E. coli, NDM-1 was detected. Nearly 67% of the isolates belonged to phylogenetic group B2. There was no genetic relatedness among the isolates. CONCLUSIONS: Hospital wastewater contains genetically diverse multidrug-resistant E. coli. SIGNIFICANCE AND IMPACT OF THE STUDY: This study stresses the need for efficient water treatment plants in healthcare settings as a public health measure to minimize spread of multidrug-resistant bacteria into the environment.

Patterns of condom use by men who have sex with men before and after the Avahan intervention in Andhra Pradesh state of India.

BACKGROUND: Two rounds of integrated biological and behavioural assessment (IBBA) surveys were done among men who have sex with men (MSM) in Andhra Pradesh during 2006 and 2009. Avahan, the India AIDS initiative, funded by the Bill and Melinda Gates Foundation implemented HIV prevention interventions among MSM starting around the time of the first round of IBBA. METHODS: Data on socio-demographic, sex behaviour characteristics and HIV status of MSM from the two IBBA rounds were used. Changes in the rates of consistent condom use over the past one month by MSM with various types of partners between the two rounds were assessed. Multivariate analysis was performed to assess associations between various factors and inconsistent condom use for sex with regular partners as well as HIV in MSM. RESULTS: A significant increase in consistent condom use by MSM was noted from 2006 to 2009 for paid male partners (19.5% to 93.8%), occasional male partners (13.2% to 86.2%), and paid female partners (25.9% to 94.2%). Consistent condom use with regular sex partners also increased but remained lower with regular male partner (75.8%) and very low with regular female partners (15.7%). MSM who used condoms inconsistently with their regular male partner were also more likely to use condoms inconsistently with their regular female partner. Multivariate analysis showed MSM who used condoms inconsistently with regular male partner had higher odds of HIV (odds ratio 1.8; 95% CI 1.2-2.7). MSM who received condoms from Avahan had the lowest odds (odds ratio 0.3; 95% CI 0.1-0.5) of inconsistent condom use with regular male partners. CONCLUSIONS: Condom use by MSM increased markedly after implementation of Avahan, though a causal association cannot be assessed with the available data. The relatively lower condom use with regular partners of MSM suggests that additional programme effort is needed to address this aspect specifically.

Experimental observation of the ν1+3ν3 combination bands of 16O14N18O and 18O14N18O in the near infrared spectral region.

The first observation of the ν1+3ν3 combination band of the nitrogen dioxide isotopologue 16O14N18O is presented. The band was measured using Fourier-Transform Incoherent Broad-Band Cavity Enhanced Absorption Spectroscopy (FT-IBBCEAS) in the region between 5870 cm-1 and 5940 cm-1. To confirm the assignment, the band was simulated using a standard asymmetric top Watson Hamiltonian using extrapolated rotational and centrifugal distortion constants. Furthermore, the first experimental observation of the ν1+3ν3 band of the 18O14N18O isotopologue is also reported. The positions of ro-vibrational lines of the ν1+3ν3 band of the naturally most abundant isotopologue 16O14N16O were used for wavenumber calibration of line positions.

Targeting the Pseudomonas aeruginosa quorum sensing system to inhibit virulence factors and eradicate biofilm formation using AHL-analogue phytochemicals.

Quorum sensing plays a major role in the expression of virulence and development of biofilm in the human pathogen Pseudomonas aeruginosa. Natural compounds are well-known for their antibacterial characteristics by blocking various metabolic pathways. The goal of this study is to find natural compounds that mimic AHL (Acyl homoserine lactone) and suppress virulence in P. aeruginosa, which is triggered by quorum sensing-dependent pathways as an alternative drug development strategy. To support this rationale, functional network analysis and in silico investigations were carried out to find natural AHL analogues, followed by molecular docking studies. Out of the 16 top-hit AHL analogues derived from phytochemicals, seven ligands were found to bind to the quorum sensing activator proteins. Cassialactone, an AHL analogue, exhibited the highest binding affinity for RhlI, RhlR, and PqsE of P. aeruginosa, with a docking score of -9.4, -8.9, and -8.7 kcal/mol, respectively. 2(5H)-Furanone, a well-known inhibitor, was also docked to compare the docking score and intermolecular interactions between the ligand and the target protein. Furthermore, molecular dynamics simulations and binding free energy calculations were performed to determine the stability of the docked complexes. Additionally, the ADME properties of the analogues were also analyzed to evaluate the pharmacological parameters. Functional network analysis further showed that the interconnectedness of proteins such as RhlI, RhlR, LasI, and PqsE with the virulence and biofilm phenotype of the pathogen could offer potential as a therapeutic target.Communicated by Ramaswamy H. Sarma.

Modelling long-term outcomes for patients with systemic lupus erythematosus.

BACKGROUND: New treatments for systemic lupus erythematosus (SLE) aim to improve tolerability and disease activity control over standard of care (SoC) treatment. SoC typically includes daily glucocorticoid (GC) which carries a risk of organ damage over time. This study sought to develop natural history models to identify predictors of long-term outcomes with current SoC SLE treatment. METHODS: Generalized linear and parametric accelerated failure time survival models (GLM) and parametric accelerated failure time (AFT) survival models were designed to identify predictors of disease activity, flare rate, GC use, organ damage, and mortality beyond the first year of treatment in patients with SLE. Models were run using a longitudinal retrospective analysis of prospectively collected Toronto Lupus Cohort (TLC) study data, collected between 1997 and 2020. Covariates of clinical and statistical significance were selected by bivariate- then multi-variate regression to find the model of best fit. FINDINGS: Of the 1255 subjects included, 89 % were female 89 % and 65 % Caucasian. Mean follow-up was 10·5 years. At first visit, 51 % of patients had moderate-to-severe disease activity (SLEDAI-2 K score ≥ 6). Mean organ damage scores gradually increased over the years following diagnosis. Median survival of the cohort was ∼35 years from study entry. In the GLM models, SLEDAI-2 K yearly average, and average GC dose were key for predicting change in SLEDAI-2 K, GC use/ dose, and flare (any/rate). Together, adjusted mean SLEDAI-2 K and GC dose were shown to be predictors of mortality and damage in at least 9 of 12 organ systems considered. INTERPRETATION: These comprehensive, longitudinal, predictive models show that disease activity and GC use are significant predictors of organ damage and mortality in a patient population with predominantly moderate to severe SLE. This deepens understanding of SLE natural history and underscores the need for new treatment approaches that reduce disease activity and GC use with an aim to improve long-term SLE outcomes. FUNDING: This study was funded by AstraZeneca.