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Emulation of the \"target trial\" (TT), a hypothetical pragmatic randomized controlled trial (RCT), using observational data can be used to mitigate issues commonly encountered in comparative effectiveness research (CER) when randomized trials are not logistically, ethically, or financially feasible. However, cardiovascular (CV) health research has been slow to adopt TT emulation. Here, we demonstrate the design and analysis of a TT emulation using electronic health records to study the comparative effectiveness of the addition of a disease-modifying anti-rheumatic drug (DMARD) to a regimen of methotrexate on CV events among rheumatoid arthritis (RA) patients. We used data from an electronic medical records-based cohort of RA patients from Northwestern Medicine to emulate the TT. Follow-up began 3 months after initial prescription of MTX (2000-2020) and included all available follow-up through June 30, 2020. Weighted pooled logistic regression was used to estimate differences in CVD risk and survival. Cloning was used to handle immortal time bias and weights to improve baseline and time-varying covariate imbalance. We identified 659 eligible people with RA with average follow-up of 46 months and 31 MACE events. The month 24 adjusted risk difference for MACE comparing initiation vs non-initiation of a DMARD was -1.47% (95% confidence interval [CI]: -4.74, 1.95%), and the marginal hazard ratio (HR) was 0.72 (95% CI: 0.71, 1.23). In analyses subject to immortal time bias, the HR was 0.62 (95% CI: 0.29-1.44). In this sample, we did not observe evidence of differences in risk of MACE, a finding that is compatible with previously published meta-analyses of RCTs. Thoughtful application of the TT framework provides opportunities to conduct CER in observational data. Benchmarking results of observational analyses to previously published RCTs can lend credibility to interpretation.

The authors identify in patients with rheumatoid arthritis a pathogenic subset of CD4+ T cells that augments B cell responses within inflamed tissues. Peripheral helper T cells in rheumatoid arthritis Michael Brenner and colleagues identify a subset of pathogenically activated PD-1 hi CD4-positive T cells in patients with rheumatoid arthritis, and show that it promotes B-cell responses in tertiary lymphoid structures. The cells, which the authors designate as 'peripheral helper' T cells, differ from follicular helper cells in that they lack CXCR5, have altered BCL6 expression, and express chemokine receptors that direct migration to inflamed sites. CD4 + T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4 + T cells within affected tissues may be identified by expression of markers of recent activation 1 . Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population 2 . This approach revealed a markedly expanded population of PD-1 hi CXCR5 − CD4 + T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1 hi CXCR5 − ‘peripheral helper’ T (T PH ) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1 hi CXCR5 + T follicular helper cells, T PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3 , 4 ). However, global transcriptomics highlight differences between T PH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in T PH cells. T PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, \"Sleep Insufficiency, Circadian Misalignment, and the Immune Response,\" to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ∼24-hour rhythms. The clock of cyanobacteria is driven by a three-protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator.

The Technology Acceptance Model (TAM) is widely used in many areas but is rarely applied to determine the link between tourists’ perceptions of tourism development and environmental sustainability. Therefore, this study aimed to (1) explore the relationships among tourism development, tourists’ perceptions, and environmental sustainability, (2) examine the mediating role of blockchain technology in these relationships, and (3) analyze the use of the TAM for sustainable practices in tourism. Data were collected from tourists on their perceptions of the impact of tourism on the environment, their use of information technology (IT) during their visits, and their willingness to pay for sustainable tourism practices. The data collected from 473 respondents were analyzed using partial least squares structural equation modeling (PLS-SEM). The findings reveal that tourism development and perceptions have a significant impact on environmental sustainability. Furthermore, blockchain technology directly affects environmental sustainability and partially mediates the relationship between tourism development and tourists’ perception constructs on environmental sustainability. This study contributes to the understanding of the relationships among tourism development, tourist perceptions, and environmental sustainability, analyzed through the lens of the TAM. Although the TAM has been used in several technology adoption and behavioral studies, this is its first application in the context of sustainable tourism, specifically used in exploring perceptions of environmental sustainability, limited to the environmentally rich Gilgit-Baltistan region in Pakistan.

ObjectiveLong-term opioid prescribing has increased amid concerns over effectiveness and safety of its use. We examined long-term prescription opioid use among patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), compared with patients with hypertension (HTN).MethodsWe used Truven MarketScan, a US commercial claims database (2003–2014) and identified RA, SLE, PsA and AS cohorts, each matched by age and sex to patients with HTN. We compared long-term opioid prescription use during 1 year of follow-up and used multivariable Poisson regression model to estimate the relative risk (RR) of receiving opioid prescriptions based on underlying disease cohort.ResultsWe identified 181 710 RA (mean age 55.3±13.1, 77% female), 45 834 SLE (47.1±13.1, 91% female), 30 307 PsA (49.7±11.5, 51% female), 7686 AS (44.6±12.0, 39% female) and parallel numbers of age-matched and sex-matched patients with HTN. The proportion of patients receiving long-term opioid prescriptions, and other measures of opioid prescriptions were higher among rheumatic disease cohorts and highest in patients with AS. AS was associated with the highest RR of receiving long-term opioid prescriptions (RR 2.73, 95% CI 2.60 to 2.87) versus HTN, while RRs were 2.21 (2.16 to 2.25) for RA, 1.94 (1.87 to 2.00) for PsA and 1.82 (1.77 to 1.88) for SLE.ConclusionsPatients with rheumatic disease have higher rates of long-term opioid prescriptions, and patients with AS have the highest risk of receiving opioid prescriptions versus patients with HTN. Further studies investigating the effectiveness of disease-targeted treatments on decreasing opioid use in these four rheumatic diseases may provide strategies for reducing prescription opioids.

We investigated the effects of lithium disilicate ceramic thickness and translucency on the degree of polymerization of light-cured resin cement using the measure of hardness. Lithium disilicate specimens of three translucencies (low, medium and high) were prepared to four thicknesses (0.5, 1.0, 2.0 and 3.0 mm). A light-cured resin cement was cured through each of the ceramic specimens using a handheld curing light for 50 s. A 3D printed jig was used to achieve a uniform thickness of the resin cement. Directly cured resin cement was used as the control. Hardness was measured using nano-indentation to determine the degree of polymerization of the resin cement. Two-way ANOVA and Tukey post hoc tests were used to evaluate interaction between translucency and thickness. Hardness values from control specimens were assessed using the two-tailed t-test with the Bonferroni approach. The translucency of the specimens significantly influenced the hardness (p < 0.001), where a negative linear relationship between cement hardness and ceramic thickness was present for low translucency and high translucency. However, at a 0.5 mm thickness, all specimens showed similar hardness regardless of the translucency. The translucency of ceramics affected the hardness, and hence polymerization, of light-cure resin cement. However, the effect of increased thickness was a more significant factor.

The pathogenic variant c.144T>G (p.N48K) in the clarin1 gene (CLRN1) results in progressive loss of vision and hearing in Usher syndrome IIIA (USH3A) patients. CLRN1 is predicted to be an essential protein in hair bundles, the mechanosensory structure of hair cells critical for hearing and balance. When expressed in animal models, CLRN1 localizes to the hair bundle, whereas glycosylation-deficient CLRN1N48K aggregates in the endoplasmic reticulum, with only a fraction reaching the bundle. We hypothesized that the small amount of CLRN1N48K that reaches the hair bundle does so via an unconventional secretory pathway and that activation of this pathway could be therapeutic. Using genetic and pharmacological approaches, we find that clarin1 knockout (clrn1KO/KO ) zebrafish that express the CLRN1c.144T>G pathogenic variant display progressive hair cell dysfunction, and that CLRN1N48K is trafficked to the hair bundle via the GRASP55 cargo-dependent unconventional secretory pathway (GCUSP). On expression of GRASP55 mRNA, or on exposure to the drug artemisinin (which activates GCUSP), the localization of CLRN1N48K to the hair bundles was enhanced. Artemisinin treatment also effectively restored hair cell mechanotransduction and attenuated progressive hair cell dysfunction in clrn1KO/KO larvae that express CLRN1c.144T>G , highlighting the potential of artemisinin to prevent sensory loss in CLRN1c.144T>G patients.