Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry.

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

Low-dose glucocorticoids withdrawn in systemic lupus erythematosus: a desirable and attainable goal.

OBJECTIVES: To assess the risk of flare in systemic lupus erythematosus (SLE) patients after low-dose glucocorticoid (GC) discontinuation and to evaluate the risk factors of flare. METHODS: SLE patients who ever discontinued GCs were identified from the Peking University First Hospital SLE cohort. The disease flare profile after GC discontinuation was analysed. The flare rate was analysed using Kaplan-Meier analysis. Cox regression was used to determine the effects of variables on SLE flare. A prognostic nomogram using Cox proportional hazards regression modelling was developed. RESULTS: A total of 132 SLE patients were eligible for the final analysis. They were followed up for a median of 21.8 months (interquartile range 9.01-36.7). The cumulative probability of flare after GC discontinuation was 8.3% at 6 months, 16.8% at 1 years and 27.5% at 2 years. In multivariate Cox analysis, hypocomplementemia and serologically active clinically quiescent (SACQ) were independent risk factors of flare [hazard ratio (HR0 2.53 (95% CI 1.32, 4.88); HR 3.17 (95% CI 1.44, 6.97), respectively]. Age ≥40 years at GC withdrawal and hydroxychloroquine (HCQ) usage were independent protective factors of flare [HR 0.53 (95% CI 0.29, 0.99); HR 0.32 (95% CI 0.17, 0.62), respectively]. The protective effect of HCQ was dosage related. From the perspective of different tapering strategies embodied as the duration from prednisone 5 mg/day to complete discontinuation, a slower tapering strategy (12-24 months) significantly reduced the risk of flare compared with a faster tapering strategy (<3 months) [HR 0.30 (95% CI 0.11, 0.82), P = 0.019]. The prognostic nomogram including the aforementioned factors effectively predicted the 1 and 2 year probability of being flare-free. CONCLUSION: Low-dose GC is feasibly discontinued in real-life settings. SACQ and younger age are potential risk factors of SLE flare, while HCQ use and slow GC tapering to withdrawal can reduce relapse. The visualized model we developed may help to predict the risk of flare among SLE patients who discontinued GC.

Dynamical trajectory of glucocorticoids tapering and discontinuation in patients with rheumatoid arthritis commencing glucocorticoids with csDMARDs: a real-world data from 2009 to 2020.

OBJECTIVE: To unravel the dynamical trajectory and features of glucocorticoids (GC) tapering and discontinuation in patients with rheumatoid arthritis (RA) commencing GC with concomitant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: We used data from longitudinal real-world Treat-to-TARget in RA cohort. Patients with RA who started GC and contaminant csDMARDs therapy were included. The changes in GC dose and disease activity were evaluated. GC discontinuation rate was analysed using Kaplan-Meier analysis. The relapse profile within 6 months after GC discontinuation was also analysed. RESULTS: A total of 207 patients with RA were included. During a median follow-up of 38.6 months, 124 patients discontinued GC. The median prednisolone dose of 10 (5-10) mg/day at initiation was reduced by 50% in the first 6 months and then more slowly, to zero by 48 months eventually. The cumulative probabilities of GC discontinuation were 9.7%, 26.6%, 48.0% and 58.6% at month 6, years 1, 2 and 3, with calculated median time to GC cessation of 27 months. In 110 DMARD-naïve patients, the corresponding cumulative probabilities of GC discontinuation were, respectively, 12.7%, 30.0%, 50.9% and 60.6%, with calculated median time to GC cessation of 24 months. Of the 124 patients who discontinued GC, adding other csDMARDs or concomitant csDMARDs increment was documented in 28.2% of them. Approximately half of 124 patients were in clinical remission at GC discontinuation. Within 6 months after GC withdrawal, 79.1% (91/115) of patients maintained relapse free. CONCLUSIONS: In patients with RA commencing GC besides csDMARDs, GC is feasibly discontinued with favourable control of disease activity in real-life setting, mostly without short-term flare. But the withdrawal time is far from reaching the recommended time frame, indicating the gap between real-world practice and current guidelines.

Low-dose glucocorticoids should be withdrawn or continued in systemic lupus erythematosus? A systematic review and meta-analysis on risk of flare and damage accrual.

OBJECTIVE: To assess the risk of flare and damage accrual after discontinuation of low-dose glucocorticoids (GCs) in SLE. METHODS: We performed a comprehensive literature search of the PubMed, Embase, Cochrane Library and Scopus databases from inception to July 2020 for studies concerning relapses/damage accrual in SLE patients. Pooled incidence rates of flare and time to flare with their 95% CIs after GC withdrawal were calculated. The summary risk ratio (RR) and 95% CI of flare/organ damage accrual risk were computed using a random- or fixed-effects model. RESULTS: A total of 738 SLE patients with GC discontinuation in 17 publications were eligible for the final analysis. In the primary meta-analysis, the pooled incidence of flare was 24% (95% CI 21, 27) and 13% (95% CI 8, 18) for global and major flares, respectively. Pooled time to flare was 21.08 months (95% CI 9.32, 32.85). In the secondary meta-analysis, GC discontinuation showed an increased risk of flare compared with GC continuation [RR 1.38 (95% CI 1.01, 1.89)], but the risk of major flares was not increased [RR 1.77 (95% CI 0.40, 7.83)]. Moreover, GC withdrawal was associated with a borderline risk reduction in the SLICC/ACR damage index increase compared with GC continuation [RR 0.64 (95% CI 0.38, 1.09)]. CONCLUSION: GC discontinuation leads to a slightly increased risk of flare, however, no increase in major flare and a borderline reduction of risk in further damage in SLE patients. Baseline screening for candidate patients and long-term follow-up after GC withdrawal are needed to reliably evaluate the organ damage increase.

Maternal and neonatal outcomes in pregnant women with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

OBJECTIVE: Psoriasis and PsA are inflammatory diseases that affect women in their reproductive years. We aimed to investigate whether maternal psoriasis and PsA are associated with adverse pregnancy outcomes. METHODS: We searched multiple electronic databases from inception to 3 August 2020, and reference lists of selected articles. Observational studies reporting at least one pregnancy outcome in women with psoriasis or PsA with a comparator of general population or healthy subjects were included. Data were pooled by random-effects models and expressed as odds ratio (OR) and 95% CI. RESULTS: Overall, 16 studies were included in the meta-analysis. The pooled analyses showed pregnant women with psoriatic diseases have a significantly higher risk of adverse maternal outcomes compared with the general population [caesarean delivery: 1.33 (1.17, 1.52); preterm birth: 1.32 (1.15, 1.52); (pre)eclampsia: 1.28 (1.14, 1.43); gestational diabetes: 1.19 (1.10, 1.30); gestational hypertension: 1.30 (1.18, 1.44)]. However, no statistically increased risks of fetal complications were observed in women with psoriatic diseases [small for gestational age: 1.02 (0.93, 1.11); low birth weight: 1.15 (0.93, 1.42); congenital malformations: 1.03 (0.93, 1.14); Apgar score <7: 1.07 (0.81, 1.39); neonatal mortality: 1.13 (0.90, 1.43); stillbirth: 1.19 (0.95, 1.50)]. Subgroup analysis found similar results in women with either psoriasis or PsA regarding maternal outcomes, and the magnitude of risk estimates seems to be greater in PsA, though without statistical difference. CONCLUSIONS: Pregnant women with psoriasis and PsA have excess risk of adverse maternal events, but not adverse neonatal events. Close monitoring of the mothers' clinical status before and during pregnancy is decidedly required in daily practice.

Digitizing omics profiles by divergence from a baseline.

Data collected from omics technologies have revealed pervasive heterogeneity and stochasticity of molecular states within and between phenotypes. A prominent example of such heterogeneity occurs between genome-wide mRNA, microRNA, and methylation profiles from one individual tumor to another, even within a cancer subtype. However, current methods in bioinformatics, such as detecting differentially expressed genes or CpG sites, are population-based and therefore do not effectively model intersample diversity. Here we introduce a unified theory to quantify sample-level heterogeneity that is applicable to a single omics profile. Specifically, we simplify an omics profile to a digital representation based on the omics profiles from a set of samples from a reference or baseline population (e.g., normal tissues). The state of any subprofile (e.g., expression vector for a subset of genes) is said to be "divergent" if it lies outside the estimated support of the baseline distribution and is consequently interpreted as "dysregulated" relative to that baseline. We focus on two cases: single features (e.g., individual genes) and distinguished subsets (e.g., regulatory pathways). Notably, since the divergence analysis is at the individual sample level, dysregulation can be analyzed probabilistically; for example, one can estimate the probability that a gene or pathway is divergent in some population. Finally, the reduction in complexity facilitates a more "personalized" and biologically interpretable analysis of variation, as illustrated by experiments involving tissue characterization, disease detection and progression, and disease-pathway associations.

Frequencies and predictors of the Lupus Low Disease Activity State and remission in treatment-naïve patients with systemic lupus erythematosus.

OBJECTIVES: To evaluate the attainability of Lupus Low Disease Activity State (LLDAS) and definitions of remission in SLE (DORIS) in a treatment-naïve cohort of SLE. METHODS: LLDAS5 was defined as LLDAS with a prednisone dose ≤5 mg/day. There were four definitions in DORIS: clinical remission on treatment (RONT), complete RONT, clinical remission off treatment (ROFT) and complete ROFT. The treatment-naïve patients from Peking University First Hospital SLE cohort were enrolled. The time to each state and their annual cumulative probabilities were estimated. The frequencies of patients who achieved each component of LLDAS or DORIS during follow-up were determined. The predictors of time to each state were identified. RESULTS: A total of 218 patients were included, with a median follow-up of 4.48 years. Respectively, 190 (87.2%), 160 (73.4%), 148 (67.9%), 94 (43.1%), 23 (10.6%) and 18 (8.3%) patients achieved LLDAS, LLDAS5, clinical RONT, complete RONT, clinical ROFT and complete ROFT. The median time to LLDAS, LLDAS5, clinical RONT and complete RONT were 1.4, 2.3, 2.6 and 4.7 years, respectively. Positive anti-dsDNA, RP and anaemia were significantly associated with prolonged time to LLDAS, LLDAS5 or clinical RONT. CONCLUSION: Our data confirmed that LLDAS is an attainable early treatment target for SLE. Though with more difficulty, RONT can be achieved in two-thirds of our patients. ROFT may not be an ideal treatment target at present as it is only attained in few patients.

A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy.

OBJECTIVES: To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. METHODS: Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. RESULTS: A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. CONCLUSION: Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry.

OBJECTIVE: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. METHODS: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. RESULTS: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. CONCLUSIONS: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Salivary gland ultrasound integrated with 2016 ACR/EULAR classification criteria improves the diagnosis of primary Sjögren's syndrome.

OBJECTIVES: To evaluate the utility of salivary gland ultrasound (SGUS) in the diagnosis of primary Sjögren's syndrome (pSS) singly or integrated with 2016 ACR/EULAR classification criteria. METHODS: Patients with suspected pSS were enrolled in the study. SGUS semi-quantitative scoring was used to assess salivary gland. Clinical characteristics were recorded, including autoantibodies, ophthalmic tests, salivary glands scintigraphy (SGS) and labial biopsy. The diagnostic accuracy of SGUS score and complementary value of SGUS to 2016 ACR/EULAR criteria were analysed. RESULTS: 282 patients were included for analysis. 161 were diagnosed as pSS and 121 as non-SS. SGUS score≥5 showed 64.7% sensitivity and 81.4% specificity for the diagnosis of pSS. Positive anti-SSA, abnormal SGS and SGUS score were significantly higher in pSS than non-SS group (80.1% vs. 14.0%, p<0.01; 91.3% vs. 57.0%, p<0.01; 8.4±6.6 vs. 2.6±3.2, p<0.01 respectively). A weighted score [(anti-SSA×16.5) + (SGS×14.5) + (SGUS×4.5)] was constructed. The score ≥17.5 could improve the sensitivity, and almost keep the specificity comparing to 2016 ACR/EULAR criteria (89.9% vs. 85.6% and 79.5% vs. 82.2%). When replacing labial biopsy by SGUS in 2016 ACR/EULAR criteria, both sensitivity and specificity were a bit decreased (85.0% vs. 85.6% and 79.8% vs. 82.2%). When adding SGUS to 2016 ACR/EULAR criteria, it showed better performance by improving the sensitivity (90.8% vs. 85.6%), while not losing the specificity (83.7% vs. 82.2%). CONCLUSIONS: Adding SGUS score to the 2016 ACR/EULAR criteria can improve the diagnosis utility of pSS. SGUS may be a feasible and prospective tool in the diagnosis of pSS.

Real-World Clinical Equivalence of Generic and Branded Tofacitinib: A Prospective Longitudinal Cohort Study in Patients With Rheumatoid Arthritis.

OBJECTIVES: To explore the clinical efficacy and safety of generic tofacitinib vs brand name tofacitinib in patients with rheumatoid arthritis (RA) in a single-center comparative study based on a prospective real-world cohort. METHODS: Patients with RA receiving tofacitinib, either generic (Kelejia) or branded (Xeljanz), from March 2017, to December 31, 2022, were enrolled. The primary outcome was the simplified disease activity index (SDAI)-defined remission rate at month 6. Secondary outcomes included the rates of remission and low disease activity defined by other composite scores; European Alliance of Associations for Rheumatology response rate, and ultrasonic synovitis scores at months 1, 3, 6, and 12. Cost-effectiveness was investigated. Propensity score-based inverse probability of treatment weighting was adopted to reduce selection bias. RESULTS: A total of 204 patients were enrolled: 59 in the generic group and 145 in the branded group. An SDAI-defined remission was achieved in 41.1% and 39.2% of patients in the generic and branded groups, respectively, at month 6 (P=.85). Rates of remission and low disease activity achievement, changes in clinical disease activity scores, and power Doppler and gray scale synovitis scores at months 1, 3, 6, and 12 were comparable between the 2 groups. Similar proportions of patients in the groups achieved moderate/good response at months 1, 3, 6, and 12. Rates of drug retention and adverse effects were also similar in the 2 groups. Both Kelejia and Xeljanz were cost-effective, but Kelejia had a lower average cost-effectiveness ratio. CONCLUSION: Generic tofacitinib (Keljia) had equivalent clinical efficacy and safety and better cost-effectiveness compared with its originator (Xeljanz).

B cell pathway dual inhibition for systemic lupus erythematosus: a prospective single-arm cohort study of telitacicept.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B-cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor-Fc fusion protein, which can neutralize both B-cell lymphocyte stimulator and a proliferation-inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty-seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI-4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti-dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow-up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT-Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B-cell lymphoma were occurred. In our first prospective real-world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository ("Registry").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. PATIENTS/METHODS: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. RESULTS: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). CONCLUSION: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

The mTOR pathway in the antiphospholipid syndrome.

This perspective discussed the available evidence on the involvement of mTOR pathway in antiphospholipid syndrome (APS), from the aspects of endothelial cells, platelets, monocytes and anti-phospholipid antibodies (PLs), which may lead to future therapeutic applications of mTOR inhibition in APS.

CellCover Defines Conserved Cell Types and Temporal Progression in scRNA-seq Data across Mammalian Neocortical Development.

Accurate identification of cell classes across the tissues of living organisms is central in the analysis of growing atlases of single-cell RNA sequencing (scRNA-seq) data across biomedicine. Such analyses are often based on the existence of highly discriminating "marker genes" for specific cell classes which enables a deeper functional understanding of these classes as well as their identification in new, related datasets. Currently, marker genes are defined by methods that serially assess the level of differential expression (DE) of individual genes across landscapes of diverse cells. This serial approach has been extremely useful, but is limited because it ignores possible redundancy or complementarity across genes, that can only be captured by analyzing several genes at the same time. We wish to identify discriminating panels of genes. To efficiently explore the vast space of possible marker panels, leverage the large number of cells often sequenced, and overcome zero-inflation in scRNA-seq data, we propose viewing panel selection as a variation of the "minimal set-covering problem" in combinatorial optimization which can be solved with integer programming. In this formulation, the covering elements are genes, and the objects to be covered are cells of a particular class, where a cell is covered by a gene if that gene is expressed in that cell. Our method, CellCover, identifies a panel of marker genes in scRNA-seq data that covers one class of cells within a population. We apply this method to generate covering marker gene panels which characterize cells of the developing mouse neocortex as postmitotic neurons are generated from neural progenitor cells (NPCs). We show that CellCover captures cell class-specific signals distinct from those defined by DE methods and that CellCover's compact gene panels can be expanded to explore cell type specific function.Transfer learning experiments exploring these covering panels across in vivo mouse, primate, and human scRNA-seq datasets demonstrate that CellCover identifies markers of conserved cell classes in neurogenesis, as well as markers of temporal progression in the molecular identity of these cell types across development of the mammalian neocortex. The gene covering panels we identify across cell types and developmental time can be freely explored in visualizations across all the public data we use in this report at with NeMo Analytics [1] through https://nemoanalytics.org/p?l=CellCover . The code for CellCover is written in R and the Gurobi R interface and is available at [2].

Comparison of the Effectiveness and Safety of Mycophenolate Mofetil and Cyclophosphamide in Lupus Nephritis: Evidence from a Real-World Study.

INTRODUCTION: Both mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC) have been recommended in the induction therapy of lupus nephritis (LN) for years; nevertheless, their effectiveness and safety in a real-world setting are extremely lacking. Therefore, we decided to conduct this real-world study. METHODS: A total of 195 Chinese patients with LN who were initially treated with MMF (n = 98), or intravenous CYC (n = 97) as induction therapy were enrolled. All of the patients were followed up to 12 months. Complete renal remission (CRR) was defined as 24-h urinary protein (24 h-UTP) < 0.5 g, and partial renal remission (PRR) was defined as ≥ 50% reduction in 24 h-UTP to the subnephrotic level, however > 0.5 g, both with a change of serum creatinine (SCr) within 10% from baseline. The proportions of CRR, PRR, and total renal remission (TRR), as well as adverse events, were compared by Chi-square test and Kaplan-Meier analysis (log-rank test). Inverse probability of treatment weighting (IPTW) was used for propensity score matching and multivariable logistic regression analyses were employed. RESULTS: The cumulative proportion of TRR in 6 months (79.4 vs. 63.8%, p = 0.026) and CRR in 12 months (72.8 vs. 57.6%, p = 0.049) in MMF group were significantly higher than CYC group, and the above conclusions were further confirmed by IPTW. The proportions of PRR, CRR, and TRR at other time points were equivalent between two groups. Further subgroup analysis in 111 patients with biopsy-proven III-V LN also showed a significantly higher proportion of TRR at 6 months in the MMF group than in the CYC group (78.3 vs. 56.9%, p = 0.026). In the Kaplan-Meier analysis and after IPTW, the MMF group showed better TRR and CRR responses than CYC group in 12 months. Multivariable logistic regression analyses revealed that MMF use was the only predictor of CRR (HR 2.12, 95% CI 1.90-4.09, p = 0.026), while low complement level was also a predictor, albeit risk was reduced (HR 0.38, 95% CI 0.17-0.86, p = 0.019). Moreover, compared to the CYC group, MMF group patients were more likely to have significantly lower SCr (µmol/l) [72.5 (62.5, 86.5) vs. 79.0 (71.1, 97.5), p = 0.001] and daily dose of prednisone (mg/day) (15.7 ± 5.2 vs. 18.6 ± 11.3, p = 0.022) at 6 months; lower 24 h-UTP (g) [0.1 (0.1, 0.3) vs. 0.2 (0.1, 0.9), p = 0.005] and daily dose of prednisone (mg/day) (9.6 ± 3.3 vs. 11.2 ± 5.5, p = 0.023) at 12 months. Infection was the most common adverse event. Pneumonia and gastrointestinal discomfort were more frequently observed in the CYC group. CONCLUSIONS: Real-world data are a key component of the evidence supporting the effectiveness of drugs and are of interest to all stakeholders. Our comparative study demonstrated the effectiveness of MMF in LN induction therapy was at least equivalent to intravenous CYC, with superior tolerance.

Presence of tophi and carotid plaque were risk factors of MACE in subclinical artherosclerosis patients with gout: a longitudinal cohort study.

Background: Patients with gout carry an excess risk for cardiovascular disease (CVD), but the contribution of subclinical atherosclerosis to the CVD risk has never been reported. In this study, we aimed to explore the predictive factors for incident major adverse cardiovascular events (MACE) in gout patients without a previous history of CVD or cerebral vascular disease. Methods: A single-center, long-term follow-up cohort analysis was performed to assess subclinical atherosclerosis at baseline since 2008. Patients with a previous history of CVD or cerebrovascular disease were excluded. The outcome of the study was the first MACE. The presence of subclinical atherosclerosis was assessed by carotid plaque (CP), and carotid intima-media thickness (CMIT) was determined by ultrasound. An ultrasound scan of bilateral feet and ankles was performed at baseline. The association between tophi, carotid atherosclerosis, and the risk of developing incident MACE was evaluated using Cox proportional hazards models with adjustment for the CVD risk scores. Results: A total of 240 consecutive patients with primary gout were recruited. Their mean age was 44.0 years, with male predominance (238, 99.2%). During a median follow-up of 10.3 years, incident MACE was ascertained in 28 (11.7%) patients. In a Cox hazards model, controlling for the CV risk scores, the presence of at least two tophi (HR, 2.12-5.25, p < 0.05) and carotid plaque (HR, 3.72-4.01, p < 0.05) were identified as independent predictors of incident MACE in gout patients. Conclusions: The presence of at least two tophi and carotid plaque on an ultrasound could independently predict MACE in addition to conventional cardiovascular risk factors in gout patients.

Flare and change in disease activity among patients with stable rheumatoid arthritis following coronavirus disease 2019 vaccination: A prospective Chinese cohort study.

BACKGROUND: Vaccination has been shown effective in controlling the global coronavirus disease 2019 (COVID-19) pandemic and reducing severe cases. This study was to assess the flare and change in disease activity after COVID-19 vaccination in patients with stable rheumatoid arthritis (RA). METHODS: A prospective cohort of RA patients in remission or with low disease activity was divided into a vaccination group and a non-vaccination group based on their COVID-19 vaccination status. Each of them was examined every 3 to 6 months. In the vaccination group, disease activity was compared before and after vaccination. The rates of flare defined as disease activity scores based on 28-joint count (DAS28) >3.2 with ΔDAS28 ≥0.6 were compared between vaccination and non-vaccination groups. RESULTS: A total of 202 eligible RA patients were enrolled. Of these, 98 patients received no vaccine shot (non-vaccination group), and 104 patients received two doses of vaccine (vaccination group). The median time interval from pre-vaccination visit to the first immunization and from the second dose of vaccine to post-vaccination visit was 67 days and 83 days, respectively. The disease activity scores at pre-vaccination and post-vaccination visits in the vaccination group patients were similar. At enrollment, gender, RA disease course, seropositivity, and disease activity were comparable across the two groups. Flare was observed in five (4.8%) of the vaccination group patients and nine (9.2%) of the non-vaccination group patients at post-vaccination assessment ( P  = 0.221). In terms of safety, 29 (27.9%) patients experienced adverse events (AEs) after vaccination. No serious AEs occurred. CONCLUSIONS: COVID-19 vaccinations had no significant effect on disease activity or risk of flare in RA patients in remission or with low disease activity. Patients with stable RA should be encouraged to receive the COVID-19 vaccination.