Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca2+ signals.

The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca[Formula: see text] signaling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and live-cell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca[Formula: see text] releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca[Formula: see text] release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca[Formula: see text] delivery system.

Characterizing the targets of transcription regulators by aggregating ChIP-seq and perturbation expression data sets.

Mapping the gene targets of chromatin-associated transcription regulators (TRs) is a major goal of genomics research. ChIP-seq of TRs and experiments that perturb a TR and measure the differential abundance of gene transcripts are a primary means by which direct relationships are tested on a genomic scale. It has been reported that there is a poor overlap in the evidence across gene regulation strategies, emphasizing the need for integrating results from multiple experiments. Although research consortia interested in gene regulation have produced a valuable trove of high-quality data, there is an even greater volume of TR-specific data throughout the literature. In this study, we show a workflow for the identification, uniform processing, and aggregation of ChIP-seq and TR perturbation experiments for the ultimate purpose of ranking human and mouse TR-target interactions. Focusing on an initial set of eight regulators (ASCL1, HES1, MECP2, MEF2C, NEUROD1, PAX6, RUNX1, and TCF4), we identified 497 experiments suitable for analysis. We used this corpus to examine data concordance, to identify systematic patterns of the two data types, and to identify putative orthologous interactions between human and mouse. We build upon commonly used strategies to forward a procedure for aggregating and combining these two genomic methodologies, assessing these rankings against independent literature-curated evidence. Beyond a framework extensible to other TRs, our work also provides empirically ranked TR-target listings, as well as transparent experiment-level gene summaries for community use.

Human immunodeficiency virus infection challenges: Current therapeutic limitations and strategies for improved management through long-acting injectable formulation.

HIV infection has been a severe global health burden, with millions living with the virus and continuing new infections each year. Antiretroviral therapy can effectively suppress HIV replication but requires strict lifelong adherence to daily oral medication regimens, which presents a significant challenge. Long-acting formulations of antiretroviral drugs administered infrequently have emerged as a promising strategy to improve treatment outcomes and adherence to HIV therapy and prevention. Long-acting injectable (LAI) formulations are designed to gradually release drugs over extended periods of weeks or months following a single injection. Critical advantages of LAIs over conventional oral dosage forms include less frequent dosing requirements, enhanced patient privacy, reduced stigma associated with daily pill regimens, and optimised pharmacokinetic/pharmacodynamic profiles. Several LAI antiretroviral products have recently gained regulatory approval, such as the integrase strand transfer inhibitor cabotegravir for HIV preexposure prophylaxis and the Cabotegravir/Rilpivirine combination for HIV treatment. A leading approach for developing long-acting antiretroviral depots involves encapsulating drug compounds in polymeric microspheres composed of biocompatible, biodegradable materials like poly (lactic-co-glycolic acid). These injectable depot formulations enable high drug loading with customisable extended-release kinetics controlled by the polymeric matrix. Compared to daily oral therapies, LAI antiretroviral formulations leveraging biodegradable polymeric microspheres offer notable benefits, including prolonged therapeutic effects, reduced dosing frequency for improved adherence, and the potential to kerb the initial HIV transmission event. The present manuscript aims to review the pathogenesis of the virus and its progression and propose therapeutic targets and long-acting drug delivery strategies that hold substantial promise for enhancing outcomes in HIV treatment and prevention.

Population Pharmacokinetics and Limited Sampling Strategy of Mycophenolate Mofetil for Indian Patients with Lupus Nephritis.

BACKGROUND: Mycophenolic acid is widely used to treat lupus nephritis (LN). However, it exhibits complex pharmacokinetics with large interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model and a 3-sample limited sampling strategy (LSS) to optimize therapeutic drug monitoring in Indian patients with LN. METHODS: Five blood samples from each LN patient treated with mycophenolic acid were collected at steady-state predose and 1, 2, 4, and 6 hours postdose. Demographic parameters were tested as covariates to explain interindividual variability. PopPK analysis was performed using Monolix and the stochastic approximation expectation-maximization algorithm. An LSS was derived from 500 simulated pharmacokinetic (PK) profiles using maximum a posteriori Bayesian estimation to estimate individual PK parameters and area under the curve (AUC). The LSS-calculated AUC was compared with the AUC calculated using the trapezoidal rule and all the simulated samples. RESULTS: A total of 51 patients were included in this study. Based on the 245 mycophenolic acid concentrations, a 1-compartmental model with double absorption using gamma distributions best fitted the data. None of the covariates improved the model significantly. The model was internally validated using diagnostic plots, prediction-corrected visual predictive checks, and bootstrapping. The best LSS included samples at 1, 2, and 4 hours postdose and exhibited good performances in an external dataset (root mean squared error, 21.9%; mean bias, -4.20%). CONCLUSIONS: The popPK model developed in this study adequately estimated the PK of mycophenolic acid in adult Indian patients with LN. This simple LSS can optimize TDM based on the AUC in routine practice.

Rheumatoid arthritis synovial fluid shows enrichment of T-cells producing GMCSF which are polyfunctional for TNFα and IFNγ.

OBJECTIVES: GMCSF+T-cells may be involved in pathogenesis of rheumatoid arthritis (RA), and polyfunctionality may be a marker of pathogenicity. Although, higher frequencies of CD4+GMCSF+ T-cells have been reported, there are no data on CD8+GMCSF+ T-cells or polyfunctionality.Our objective was to enumerate frequencies of CD8+GMCSF+ T cells in RA blood and synovial fluid (SF), and assess their polyfunctionality, memory phenotype and cytotoxic ability. METHODS: This study included RA patients (blood samples,in some with paired synovial fluid (SF)), healthy controls (HC) (blood) and SpA patients (SF). In some RA patients' blood was sampled twice, before and 16-24 weeks after methotrexate (MTX) treatment. After mononuclear cell isolation from blood and SF, ex-vivo stimulation using PMA/Ionomycin was done, and cells were stained (surface and intracellular after permeabilisation/fixation). Subsequently, frequencies of GMCSF+CD8+ and CD4+ T-cells, polyfunctionality (TNFα, IFNγ, IL-17), phenotype (memory) and perforin/granzyme expression were assessed by flowcytometry. RESULTS: There was no significant difference in frequencies of GMCSF+CD8+ (3.7, 4.1%, p=0.540) or GMCSF+CD4+ T-cells (4.5, 5.2%, p=0.450) inblood of RA and HC. However, there was significant enrichment of both CD8+GMCSF+ (5.8, 3.9%, p=0.0045) and CD4+GMCSF+ (8.5, 4.5%, p=0.0008) T-cells inSF compared to blood in RA patients. Polyfunctional triple cytokine positive TNFα+IFNγ+GMCSF+CD8+T-cells (81, 36%, p=0.049) and CD4+T-cells (48, 32%, p=0.010) was also higher in SF compared to blood in RA. CD8+ T cells showed higher frequency of effector-memory phenotype and granzyme-B expression in RA-SF. On longitudinal follow-up, blood CD4+GMCSF+ T-cells significantly declined (4.6, 2.9%, p=0.0014) post-MTX. CONCLUSIONS: We report a novel finding of enrichment of CD8+GMCSF+ in addition to CD4+GMCSF+ T-cells in RA-SF. These cells showed higher polyfunctionality for TNFα and IFNγ, and effector memory phenotype suggesting their involvement in RA pathogenesis.

Recent Developments in 1,2,3-Triazole based α-Glucosidase Inhibitors: Design Strategies, Structure-activity Relationship and Mechanistic Insights.

Diabetes mellitus is a chronic and most prevalent metabolic disorder affecting 422 million the people worldwide and causing life-threatening associated conditions including disorders of kidney, heart, and nervous system as well as leg amputation and retinopathy. Steadily rising cases from the last few decades suggest the failure of currently available drugs in containment of this disease. α-Glucosidase is a potential target for effectively tackling this disease and attracting significant interest from medicinal chemists around the globe. Besides having a set of side effects, currently available α-glucosidase inhibitors (carbohydrate mimics) offer better tolerability, safety, and synergistic pharmacological outcomes with other antidiabetic drugs therefore medicinal chemists have working extensively over last three decades for developing alternative α-glucosidase inhibitors. The 1,2,3-Triazole nucleus is energetically used by various research groups around the globe for the development of α-glucosidase inhibitors posing it as an optimum scaffold in the field of antidiabetic drug development. This review is a systematic analysis of α-glucosidase inhibitors developed by employing 1,2,3-triazole scaffold with special focus on design strategies, structure-activity relationships, and mechanism of inhibitory effect. This article will act as lantern for medicinal chemists in developing of potent, safer, and effective α-glucosidase inhibitors with desired properties and improved therapeutic efficacy.

Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.

Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.

Efficacy and safety of pan-genotypic sofosbuvir and velpatasvir in patients with hepatitis C and HIV coinfection on dolutegravir-based antiretroviral therapy.

Hepatitis C virus (HCV) infection is more prevalent in people living with HIV-AIDS (PLHA) and portends a poorer prognosis. Pharmacokinetic studies suggest the absence of significant interaction between velpatasvir and dolutegravir which has been recently recommended as part of preferred first-line antiretroviral therapy (ART) regimens by WHO. However, clinical data on the use of velpatasvir-based regimen in PLHA taking dolutegavir is lacking. Hence, we aimed to assess the efficacy and safety of sofosbuvir and velpatasvir (SOF + VEL) in HCV and HIV coinfected patients on dolutegravir-based ART. Forty-five consecutive PLHA with HCV coinfection on dolutegravir-based ART were prospectively enrolled. All patients were treated SOF + VEL for 12 weeks. Complete haemogram, liver and renal function tests were assessed at baseline, 4 weeks and at end of treatment. Sustained virological response (SVR) was assessed at 12 weeks after end of treatment. The majority were males (95.5%) with a mean age of 32.8 ± 12.3 years. Cirrhosis was present in 6 (13.3%) patients. All patients completed 12 weeks of therapy with SOF + VEL, but SVR could not be assessed in two patients. Forty-two (97.7%) of the remaining 43 patients attained SVR-12. SVR-12 rate was 97.7% and 93.3% by per protocol and intention to treat analysis, respectively. No grade III/IV adverse events were reported, and there was no worsening of blood counts, liver or renal function test parameters. The pan-genotypic regimen of SOF + VEL is safe and effective in PLHA with HCV coinfection who are on dolutegravir-based ART.

Sex differences in cognitive function among people with HIV-1 clade C infection in Northern India.

Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.

High frequency of memory stem cells with a distinct gene signature in HIV patients with treatment interruption.

Reservoirs of HIV remain a major obstacle to the complete eradication of virus despite regular anti-retroviral therapy (ART). Memory stem cells (Tscm), one of the major reservoirs, are relatively less studied owing to their presence in lower numbers and inaccessible anatomical locations. We have evaluated the molecular characteristics of Tscms in patients with ART interruption (n = 15) versus patients on uninterrupted ART (n = 12) using flow cytometry. RNA sequencing was done in the sorted Tscms to study the differential gene expression. Patients with ART interruption had significantly lower baseline CD4+T-cell counts and high viral loads as compared to patients on ART. The former group had significantly higher frequency of CD4+ and CD8+Tscms with a higher expression of PD-1 on CD8+Tscms. The transcriptome profile of Tscm was significantly different among the patient groups. The main pathways were cellular and metabolic pathways, cellular development pathways, cell differentiation and negative regulation of cellular migratory pathways. An increased yet dysfunctional CD8+ memory stem cells describe HIV-1-infected patients with break-in ART and a distinct transcriptional signature of CD4+ Tscm as compared to those of patients on ART. A more detailed understanding of the biology and dynamics of Tscm in future studies is warranted. Strategies to improve the functionality of the CD8+ Tscm will help these patients to tackle the outburst of viral replication that occurs after the cessation of therapy.

Mechanistic insight and structure activity relationship of isatin-based derivatives in development of anti-breast cancer agents.

Breast cancer is most common in women and most difficult to manage that causes highest mortality and morbidity among all diseases and posing significant threat to mankind as well as burden on healthcare system. In 2020, 2.3 million women were diagnosed with breast cancer and it was responsible for 685,000 deaths globally, suggesting the severity of this disease. Apart from that, relapsing of cases and resistance among available anticancer drugs along with associated side effects making the situation even worse. Therefore, it is a global emergency to develop potent and safer antibreast cancer agents. Isatin is most versatile and flying one nucleus which is an integral competent and various anticancer agent in clinical practice and widely used by various research groups around the globe for development of novel, potent, and safer antibreast cancer agents. This review will shed light on the structural insights and antiproliferative potential of various isatin-based derivatives developed for targeting breast cancer in last three decades that will help researchers in design and development of novel, potent, and safer isatin-based antibreast cancer agents.

Psychiatric comorbidities in patients suffering from systemic lupus erythematosus admitted to a tertiary care hospital in Northern India.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with multiorgan involvement presenting with a myriad of symptoms, including neuropsychiatric symptoms. Although many studies have evaluated screening questionnaires based psychiatric morbidity, very few studies have used contemporary diagnostic criteria. OBJECTIVE: This study aimed to evaluate the prevalence of psychiatric disorders in patients with SLE admitted to a tertiary care hospital. METHODS: A total of 79 patients diagnosed with SLE for at least for 1 year, who were not in delirium were assessed by a qualified psychiatrist for psychiatric morbidity as per the International Classification of Diseases, 10th Revision (ICD-10) criteria. Additionally, these patients were assessed on Patient Health Questionnaire-9 (PHQ-9) item version, Patient Health Questionnaire-15 (PHQ-15) item version, Generalized Anxiety Disorder-7 item scale and Montreal Cognitive Assessment (MoCA). RESULTS: 51% (n = 40) of the participants were diagnosed with a psychiatric diagnosis, with depressive disorders being the most common, seen in 36.7% (n = 29) of the participants. Additionally, 10% (n = 8) participants were diagnosed with adjustment disorder and 2.5% (n = 2) were diagnosed with anxiety (not otherwise specified). Only one patient was diagnosed with organic psychosis. On PHQ-9, 39.8% (n = 33) were diagnosed with depression. 44.3% (n = 35) expressed death wishes and/or suicidal ideations. On PHQ-15, 17.7% (n = 14) of the participants scored for severe somatic distress (score >15). On GAD-7, 55.7% (n = 44) screened positive for anxiety symptoms, but only 7.6% (n = ) had a score of 15 or more to indicate severe anxiety. Nearly half (n = 43; 52%) of the participants also had cognitive impairment as assessed on MoCA, with 13.3% (n = 11) of the participants having scores indicating severe dementia. CONCLUSIONS: Patients with SLE have a high prevalence of psychiatric comorbidities and should be routinely screened for psychiatric morbidity. They should be appropriately treated, to improve the overall treatment outcomes.

Overlap syndrome of anti-aquaporin-4 positive neuromyelitis optica spectrum disorder and systemic lupus erythematosus: A systematic review of individual patient data.

BACKGROUND: Neurological involvement can occur in systemic lupus erythematosus (SLE) due to co-existing neuromyelitis optica spectrum disorder (NMOSD). The symptoms can mimic those of neuropsychiatric manifestations of SLE. Pathogenic anti-aquaporin-4 (AQP4) antibodies, commonly found in NMOSD, are responsible for the neuroinflammatory response and secondary demyelinating lesions. These anti-AQP4 antibodies can be the drivers of neuroinflammatory process in SLE patients, which is distinct from the immunopathogenesis seen in traditional neuropsychiatric SLE. The clinical course is often a relapsing one and is managed differently. In this review, we describe and outline the clinical course and outcomes of AQP4+ NMOSD/SLE overlap cases. METHODS: To investigate the co-existence of SLE with AQP4+NMOSD, we conducted a systematic review of individual patient data from case reports and case series reported in major databases. The study extracted clinic-demographic features, imaging and laboratory profiles, treatment approaches, and outcomes of these patients. Inclusion criteria for the review required patients to have positivity for AQP4 or NMO in the blood and/or cerebrospinal fluid (CSF) and exhibit at least one manifestation of both NMOSD and SLE. RESULTS: In this overlap between SLE and AQP4+NMOSD, a high female preponderance was observed, with 42 out of 46 patients (91.3%) being female. Nearly half of the NMOSD cases (47.8%) had onset after lupus, with a median of 5 years between the two diagnoses. Hematological manifestations were seen in the majority of patients (63%), as well as longitudinally extensive transverse myelitis (87%), and brainstem involvement on imaging (29.6%). Cerebrospinal fluid analysis showed a dominantly lymphocytic pleocytosis, with oligoclonal bands being reported scarcely. Although cyclophosphamide was the most common steroid sparing agent used for maintenance, robust evidence for both efficacy and safety in AQP4+NMOSD is available for mycophenolate mofetil, azathioprine, and rituximab. The majority of reported cases showed a relapsing course, while one patient had a monophasic course. CONCLUSION: AQP4+NMOSD in SLE patients is a relapsing and neurologically disabling disorder that can mimic neuropsychiatric manifestations, frequently occurs after the onset of lupus or may predate, responds to immunosuppressants, and necessitates indefinite treatment.

MTBDRplus and MTBDRsl for simultaneous diagnosis of gastrointestinal tuberculosis and detection of first-line and second-line drug resistance.

BACKGROUND AND AIM: Emergence of drug resistance, especially to second-line drugs, hampers tuberculosis elimination efforts. The present study aimed to evaluate MTBDRplus and MTBDRsl assays for detecting first-line and second-line drug resistance, respectively, in gastrointestinal tuberculosis (GITB). METHODS: Thirty ileocecal biopsy specimens, processed in the Department of Microbiology between 2012 and 2022, that showed growth of Mycobacterium tuberculosis on culture were included in the study. DNA, extracted from culture, was subjected to MTBDRplus and MTBDRsl (Hain Lifescience GmbH, Nehren, Germany), following manufacturer's instructions. Their performance was compared against phenotypic drug susceptibility testing (pDST) and gene sequencing. RESULTS: Out of the 30 specimens, 4 (13.33%) were mono-isoniazid resistant, 4 (13.33%) were multidrug resistant (MDR), 2 (6.67%) were pre-extensively drug resistant (pre-XDR), and 2 (6.67%) were mono-fluoroquinolone resistant. The results were 100% concordant with pDST and gene sequencing. CONCLUSIONS: In the wake of growing drug resistance in all forms of extrapulmonary tuberculosis, including GITB, MTBDRplus and MTBDRsl are reliable tools for screening of resistance to both first-line and second-line drugs.

Enhancing proton mobility and thermal stability in phosphate glasses with WO3: the mixed glass former effect in proton conducting glasses.

This study aimed to investigate the impact of WO3 on the thermal stability of glass, as measured by the glass transition temperature (Tg), as well as the activation energy (Ea) of proton conduction and proton mobility (µH). These parameters were analyzed based on variations in the glass network structure and the nature of the P-O and O-H bonds in 35HO1/2-xWO3-8NbO5/2-5LaO3/2-(52 - x) PO5/2 (x = 2, 4, 6, and 8) glasses. As previously predicted by a linear regression model, replacing PO5/2 with WO3 resulted in an increase in Tg and µH at Tg. The observed enhancement rates were +9.1 °C per mol% of WO3 for Tg and 0.09 per mol% of WO3 for log(µH at Tg [cm2 V-1 s-1]), which aligned with the predicted values of +6.5 °C and 0.08, respectively, validating the linear regression model. The increased Tg was attributed to the formation of heteroatomic P-O-W linkages that tightly cross-linked the phosphate chains. The decrease in Ea and increase in µH at Tg with increasing WO3 content were attributed to the reduction of the energy barrier for inter-phosphate chain proton migration owing to the increasing proton migration paths through P-O-W linkages. This µH enhancement is distinct from previously reported ones due to the reduction of the energy barrier for proton dissociation from OH groups. This phenomenon can be attributed to the mixed glass former effect in proton conducting glass.

Overlap syndrome of anti-aquaporin 4 positive neuromyelitis optica spectrum disorder and primary Sjögren's syndrome: a systematic review of individual patient data.

Central nervous system (CNS) involvement can occur in primary Sjögren's syndrome (pSS) due to co-existing neuromyelitis optica spectrum disorder (NMOSD) which has a highly relapsing course requiring indefinite immunosuppression, and if not diagnosed early, damage accrual occurs over time leading to permanent disability and morbidity. In this review, we describe and outline the clinical course and outcomes of anti-aquaporin 4 (AQP4) antibody seropositive NMOSD with pSS overlap cases. To investigate the co-existence of AQP4 + NMOSD with pSS, we conducted a review of individual patient data from case reports and case series found in major databases. The study extracted clinico-demographic features, imaging and laboratory profiles, treatment approaches, and outcomes of these patients. Inclusion criteria for the review required patients to have positivity for anti-AQP4 or NMO-IgG autoantibodies in the blood and/or cerebrospinal fluid (CSF) and exhibit at least one manifestation of both pSS and NMOSD. In this overlap between AQP4 + NMOSD and pSS, 44 patients were included of whom 41 (93.2%) were females. The mean age of pSS onset was 44.8 ± 18.4 years and NMOSD onset was 43.2 ± 19.8 years. In 20 (45.5%) patients, NMOSD preceded pSS onset, 13 (29.5%) NMOSD occurred after pSS onset, and 11 (25%) patients had a simultaneous presentation. 31 (70.5%) patients experienced acute transverse myelitis, 21 (47.7%) optic neuritis, 14 (31.8%) cerebral syndrome, 10 (22.7%) acute brainstem syndrome, 5 (11.4%) area postrema syndrome, and 2 (4.5%) diencephalic clinical syndromes. For the treatment of acute phase, 40 (90.9%) patients received intravenous methylprednisolone, 15 (34.1%) received plasma exchange, and 10 (22.7%) received intravenous immunoglobulin; and for the induction/maintenance therapy, 16 (36.4%) patients received cyclophosphamide, 6 (13.6%) received rituximab, 16 (36.4%) received azathioprine, and 10 (22.7%) received mycophenolate mofetil. Disease course was monophasic in 2 (4.5%) and relapsing in 27 (61.4%) patients. At median (IQR) follow-up duration of 2.4 (6) years, 39 (88.6%) patients showed improvement, 3 (6.8%) showed stabilization and 2 (4.5%) showed worsening of their NMOSD manifestations. In this overlap syndrome of AQP4 + NMOSD and pSS, patients have a neurologically disabling disorder that can mimic neurological manifestations of pSS, frequently occurs prior to the onset of pSS, has a relapsing course, responds well to immunosuppressants, and necessitates indefinite treatment. Collaborative multicentre studies are needed to clarify the natural history and outcomes of this rare overlap syndrome.

Severity and determinants of psychosocial comorbidities in granulomatosis with polyangiitis and their impact on quality of life.

Depression, anxiety, sleep disturbances, and fatigue are inadequately addressed comorbidities in granulomatosis with polyangiitis (GPA). We determined the prevalence, severity, determinants, and the impact of these comorbidities on quality-of-life (QoL) in GPA. This observational study included adult GPA patients; patients with RA and lupus were included as comparators. Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorder 7-item scale for anxiety, Epworth Sleepiness Scale for sleep disturbances, and Fatigue Severity Scale for fatigue were administered prospectively to estimate prevalence and severity. QoL and disability were estimated using PROMIS-HAQ, HAQ-health and HAQ-pain. Correlations among these parameters were assessed. Stepwise regression analyses were performed to identify determinants of depression, anxiety, excessive sleepiness, and fatigue. One hundred eighty-one patients-62 GPA [mean age 43 (13) years], 57 RA and 62 SLE- were included. The prevalence of depression (47%), excessive sleepiness (21%), and fatigue (39%) in GPA were comparable to RA and lupus; anxiety was less prevalent (29% versus 46% and 53%, p = 0.02). Severity was mostly mild-moderate. Younger age [OR = 0.93 (0.89-0.98)], higher BMI [OR = 1.2 (1.0-1.4)], and greater disease damage [OR = 2.0 (1.3-3.3)] independently predicted presence of depression. Higher BMI [OR = 1.3 (1.1-1.5)] and concomitant FMS [OR = 80.9 (5.1-1289.2)] were independently associated with excessive sleepiness. No association with disease activity, duration, or gender was seen. GPA patients with depression, anxiety, excessive sleepiness, and fatigue had worse PROMIS-HAQ, HAQ-pain, and HAQ-health. In conclusion, depression, anxiety, sleep disturbances, and fatigue are common in GPA. Although their severity is mostly mild-moderate, they impair QoL significantly. Potentially modifiable determinants that can form targets for future interventions have been identified.

Comparison between methotrexate and apremilast in Psoriatic Arthritis-a single blind randomized controlled trial (APREMEPsA study).

To compare the efficacy of methotrexate and apremilast in psoriatic arthritis (PsA). This Single blinded (physician), parallel group, randomized controlled trial was conducted at a single centre between October 2019 and December 2020. Adult PsA patients (age > 18 years), fulfilling CASPAR criteria, not on methotrexate/apremilast in last 3 months and never receiving bDMARDs or, JAK inhibitors, having active articular disease (one or more swollen joint or, having one or more tender entheseal point) were recruited. Primary outcome measure was rate of major cDAPSA response at week 24 and secondary outcome measures were ACR 20 response, change in PASI score, Maastricht enthesitis score, Leeds dactylitis index, and health assessment questionnaire-disability index (HAQ-DI) and number of adverse events at week 24 between methotrexate and apremilast groups. A total of 31 patients were recruited (15 in the apremilast arm and 16 in the methotrexate arm) amongst whom 26 patients completed 24 weeks follow up (13 patients in the apremilast arm and 13 patients in the methotrexate arm). Median cDAPSA score at baseline was 23 (9) in the apremilast group and 20 (21) in the methotrexate group. No difference in major cDAPSA response at week 24 was observed between apremilast and methotrexate arm (20% vs. 37.5%; p = 0.433). In the secondary outcome measures, there was no significant differences between both the groups. Both the drugs were safe without any serious adverse events. There was no significant difference between methotrexate and apremilast in terms of efficacy as measured by cDAPSA and ACR20 responses.

Long-term persistence of oral methotrexate and associated factors in rheumatoid arthritis: a retrospective cohort study.

There is little data on long-term persistence/continuation of methotrexate among Indian Rheumatoid arthritis patients. We assembled a retrospective single-center cohort consisting of RA patients (fulfilling 1987 ACR criteria) started on methotrexate as part of three academic studies (including two RCTs) from 2011 to 2016. Oral methotrexate was started at 7.5 or 15 mg per week with a target dose of 25 mg per week. Between August and December 2020, all patients were contacted (telephonically) and data were obtained from clinic files to evaluate self-reported continuation/persistence of methotrexate and reasons for discontinuation. Survival analysis using Kaplan-Meier and cox-regression were used to assess methotrexate continuation rates and factors associated with its discontinuation. This study included 317 patients with rheumatoid arthritis, with mean age and disease duration (at enrollment) of 43 years and 2 years; And positive rheumatoid factor and anti-CCP in 69 and 75%. At follow-up, 16 patients (5%) had died, whereas 103 (32.5%) had discontinued methotrexate. On Kaplan-Meier survival analysis, the mean survival (continuation) time for methotrexate was 7.3 years (95% CI 7-7.6 years). The actuarial continuation/persistence of methotrexate at 3, 5 and 9 years was 92, 81 and 51%, respectively. Among those who discontinued methotrexate, common reasons were remission of disease, symptomatic adverse effects (intolerance), perceived lack of efficacy and socioeconomic reasons. On multivariable cox-regression, symptomatic adverse effects during the first 12-24 weeks (Hazard ratio, 95% CI 1.8 (1.2-2.8)) and anti-CCP positivity (Hazard ratio, 95% CI 0.6 (0.3-1.0)) were significantly associated with hazard of discontinuation. Persistence or continuation of methotrexate was found to be good and comparable to reports in other centers world-wide. Apart from remission, the most important cause of methotrexate discontinuation was symptomatic adverse effects (intolerance).

Artificial intelligence-based preventive, personalized and precision medicine for cardiovascular disease/stroke risk assessment in rheumatoid arthritis patients: a narrative review.

The challenges associated with diagnosing and treating cardiovascular disease (CVD)/Stroke in Rheumatoid arthritis (RA) arise from the delayed onset of symptoms. Existing clinical risk scores are inadequate in predicting cardiac events, and conventional risk factors alone do not accurately classify many individuals at risk. Several CVD biomarkers consider the multiple pathways involved in the development of atherosclerosis, which is the primary cause of CVD/Stroke in RA. To enhance the accuracy of CVD/Stroke risk assessment in the RA framework, a proposed approach involves combining genomic-based biomarkers (GBBM) derived from plasma and/or serum samples with innovative non-invasive radiomic-based biomarkers (RBBM), such as measurements of synovial fluid, plaque area, and plaque burden. This review presents two hypotheses: (i) RBBM and GBBM biomarkers exhibit a significant correlation and can precisely detect the severity of CVD/Stroke in RA patients. (ii) Artificial Intelligence (AI)-based preventive, precision, and personalized (aiP3) CVD/Stroke risk AtheroEdge™ model (AtheroPoint™, CA, USA) that utilizes deep learning (DL) to accurately classify the risk of CVD/stroke in RA framework. The authors conducted a comprehensive search using the PRISMA technique, identifying 153 studies that assessed the features/biomarkers of RBBM and GBBM for CVD/Stroke. The study demonstrates how DL models can be integrated into the AtheroEdge™-aiP3 framework to determine the risk of CVD/Stroke in RA patients. The findings of this review suggest that the combination of RBBM with GBBM introduces a new dimension to the assessment of CVD/Stroke risk in the RA framework. Synovial fluid levels that are higher than normal lead to an increase in the plaque burden. Additionally, the review provides recommendations for novel, unbiased, and pruned DL algorithms that can predict CVD/Stroke risk within a RA framework that is preventive, precise, and personalized.