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ObjectiveTo compare clinical characteristics and treatment of patients with rheumatoid arthritis (RA) across 4 Canadian cohorts.MethodsThe 4 longitudinal cohorts included the following: the Canadian Early Arthritis Cohort (CATCH; n = 2878), Ontario Best Practices Research Initiative (OBRI; n = 3734), RHUMADATA (Quebec, n = 2890), and the Rheum4U Precision Health Registry (Calgary, Alberta, n = 709). Data were from cohort inception (range 1998–2016) to 2020. Clinical characteristics and drug treatments were summarized descriptively.ResultsIn total, 10,211 patients with RA were included. The percentage of patients who entered the cohort with early RA (2 yrs of disease at enrollment) ranged from 29% (Rheum4U) to 100% (CATCH). Mean age (55 yrs), sex (74% female), and seropositivity (69%) were similar between cohorts. At the time of initial disease-modifying antirheumatic drug (DMARD) use, median Disease Activity Score in 28 joints (DAS28) varied, ranging from 2.99 (Rheum4U) to 5.19 (CATCH), but were more similar at the time of the first DMARD switch (range 3.57–5.03), first biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) use (range 4.01–4.67), and second bDMARD or tsDMARD (range 3.71–4.39). The initial DMARD was most commonly methotrexate, either in monotherapy (32%, range 18–40%) or dual therapy (34%, range 29–42%). The first DMARD switch was to another DMARD monotherapy in 20% (range 10–32%), dual therapy in 49% (range 39–56%), and bDMARD or tsDMARD in 24% (range 15–28%). The first bDMARD was an anti–tumor necrosis factor in 79% (range 78–82%).ConclusionCanadian RA cohorts demonstrate some heterogeneity in treatment, which could reflect differences in inclusion criteria, calendar year, or regional differences. This project is a first step toward conducting harmonized analyses across Canadian RA cohorts.

Introduction In collaboration with the Alberta Medical Association’s Physician Learning Program we developed individualized physician reports and held a group feedback session on rheumatoid arthritis (RA) performance measures (PM) to facilitate treat-to-target (T2T) strategies and evaluated physician experiences with this process. Methods 5 PMs addressing T2T concepts from an established Canadian quality framework were operationalized for physician practice reports at 2 university-affiliated rheumatology clinics. Rheum4U, a quality improvement and research platform, was the data source. The audit results were reviewed in a facilitated group feedback session. Rheumatologists provided experiential feedback on the process through survey and/or an interview. Transcripts from interviews were analyzed using a 6-step thematic analysis. Results 11 of 12 eligible rheumatologists consented to receive practice reports and provided feedback through surveys (n = 5) and interviews (n = 6). The practice reports from Rheum4U (n = 448 patients) revealed high rates of yearly follow-up (> 85%, PM1) and 100% performance on documentation of disease activity at ≥ 50% of visits (PM2). Only 34% of patients were seen within 3 months if not in remission (PM3) with 62% (2017) and 69% (2018) of those with active RA achieving a LDA state within 6 months (PM4). Approximately 70% of patients were in remission at any time point (PM5). All survey respondents agreed or strongly agreed comparison to peers was valuable and helped them reflect on their practice. Several strategies for improvement were identified, including but not limited to, leveraging of electronic records for future audit and feedback reports, providing additional granularity of results, additional stratification of results, and using high-performing peers as the comparator rather than the group mean. Conclusions Audit and feedback was perceived by clinicians as a useful strategy for evaluating T2T efforts in RA. Future work will focus on longitudinal evaluation of the clinical impact of this quality improvement initiative. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00237-0) contains supplementary material, which is available to authorized users.

OBJECTIVE The aim of this study was to examine the effects of sex and menopausal status on depot-specific estrogen signaling in white adipose tissue (AT) in age-matched men and women with morbid obesity. METHODS A total of 28 premenopausal women, 16 postmenopausal women, and 27 age-matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins. RESULTS With the exception of fasting nonesterified fatty acids being higher in women (P

Extracellular vesicle (EV) biology involves understanding the cellular and molecular mechanisms of cell communication. Studies conducted so far with various bacterial infection models demonstrate the release of various types of EVs that include exosomes and microvesicles. Depending upon the infection and cell type, EV cargo composition changes and ultimately might impact the host immune response and bacterial growth. The mechanisms behind the EVs release, cargo composition, and impact on the immune system have not been fully investigated. Future research needs to include in vivo models to understand the relevance of EVs in host immune function during bacterial infection, and to determine aspects that are shared or species-specific in the host. This would aid in the development of EVs as therapeutics or as markers of disease.

Introduction Lifespans after the occurrence of a stroke have been lengthening, but most stroke survivors will experience chronic impairment. Directed, repetitive practice may reduce deficits, but clinical access is often limited by a variety of factors, such as transportation. Purpose of the Study To introduce a multiuser virtual reality platform that can be used to promote therapist-client interactions when the client is at home. Methods The Virtual Environment for Rehabilitative Gaming Exercises encourages exploration of the hand workspace by enabling multiple participants, located remotely and colocated virtually, to interact with the same virtual objects in the shared virtual space. Each user controls an avatar by corresponding movement of his or her own body segments. System performance with stroke survivors was evaluated during longitudinal studies in a laboratory environment and in participants' homes. Active arm movement was tracked throughout therapy sessions for both studies. Results Stroke survivors achieved considerable arm movement while using the system. Mean voluntary hand displacement, after accounting for trunk displacement, was greater than 350 m per therapy session for the Virtual Environment for Rehabilitative Gaming Exercises system. Compliance for home-based therapy was quite high, with 94% of all scheduled sessions completed. Having multiple players led to longer sessions and more arm movement than when the stroke survivors were trained alone. Conclusions Multiuser virtual reality offers a relatively inexpensive means of extending clinical therapy into home and enabling family and friends to support rehabilitation efforts, even when physically remote from each other.

ObjectivesThe objective of this study is to evaluate the effect of policy change disallowing body checking in adolescent ice hockey leagues (ages 15–17) on reducing rates of injury and concussion.MethodsThis is a prospective cohort study. Players 15–17 years-old were recruited from teams in non-elite divisions of play (lower 40%–70% by division of play depending on year and city of play in leagues where policy permits or prohibit body checking in Alberta and British Columbia, Canada (2015–18). A validated injury surveillance methodology supported baseline, exposure-hours and injury data collection. Any player with a suspected concussion was referred to a study physician. Primary outcomes include game-related injuries, game-related injuries (>7 days time loss), game-related concussions and game-related concussions (>10 days time loss).Results44 teams (453 player-seasons) from non-body checking and 52 teams (674 player-seasons) from body checking leagues participated. In body checking leagues there were 213 injuries (69 concussions) and in non-body checking leagues 40 injuries (18 concussions) during games. Based on multiple multilevel mixed-effects Poisson regression analyses, policy prohibiting body checking was associated with a lower rate of injury (incidence rate ratio (IRR): 0.38 (95% CI 0.24 to 0.6)) and concussion (IRR: 0.49; 95% CI 0.26 to 0.89). This translates to an absolute rate reduction of 7.82 injuries/1000 game-hours (95% CI 2.74 to 12.9) and the prevention of 7326 injuries (95% CI 2570 to 12083) in Canada annually.ConclusionsThe rate of injury was 62% lower (concussion 51% lower) in leagues not permitting body checking in non-elite 15–17 years old leagues highlighting the potential public health impact of policy prohibiting body checking in older adolescent ice hockey players.

Objective Decision aids are being developed to support guideline-based rheumatology care in Canada. The study objective was to identify barriers to decision aid use in rheumatoid arthritis (RA) within a behavior change model to inform an implementation strategy. Methods Perspectives from Canadian health care providers (HCPs) and patients living with RA were obtained on an early RA decision aid and on perceived facilitators and barriers to decision aid implementation. Data were collected through semistructured interviews, transcribed, and then analyzed by inductive thematic analysis. The lessons learned were then mapped to the behavior change wheel COM-B system (C = capability, O = opportunity, and M = motivation interact to influence B = behavior) to inform key elements of a national implementation strategy. Results Fifteen HCPs and fifteen patients participated. The analysis resulted in five lessons learned: 1) paternalistic decision-making is a dominant practice in early RA, 2) patients need emotional support and access to educational tools to facilitate participation in shared decision-making (SDM), 3) there are many logistical barriers to decision aid implementation in current care models, 4) flexibility is necessary for successful implementation, and 5) HCPs have limited interest in further training opportunities about decision aids. Implementation recommendations included the following: 1) making the decision aids directly available to patients (O) and providing SDM education (C/M), 2) creating an SDM rheumatology curriculum (C/O/M), 3) using "decision coaches" or patient partners as peer support (C/O/M), 4) linking decision aids to "living" rheumatology guidelines (M), and 5) designing trials of patient decision aid/SDM interventions to evaluate patient-important outcomes (O/M). Conclusion A multifaceted strategy is suggested to improve uptake of decision aids.

Increased arterial stiffness and vascular remodeling precede and are consequences of hypertension. They also contribute to the development and progression of life-threatening cardiovascular diseases. Yet, there are currently no agents specifically aimed at preventing or treating arterial stiffening and remodeling. Previous research indicates that vascular smooth muscle actin polymerization participates in the initial stages of arterial stiffening and remodeling, and that LIM kinase promotes F-actin formation and stabilization via cofilin phosphorylation and consequent inactivation. Herein, we hypothesize that LIM kinase inhibition is able to prevent vasoconstriction- and hypertension-associated arterial stiffening and inward remodeling. We found that small visceral arteries isolated from hypertensive subjects are stiffer and have greater cofilin phosphorylation than those from non-hypertensives. We also show that LIM kinase inhibition prevents arterial stiffening and inward remodeling in isolated human small visceral arteries exposed to prolonged vasoconstriction. Using cultured vascular smooth muscle cells, we determined that LIM kinase inhibition prevents vasoconstrictor agonists from increasing cofilin phosphorylation, F-actin volume and cell cortex stiffness. We further show that localized LIM kinase inhibition prevents arteriolar inward remodeling in hypertensive mice. This indicates that hypertension is associated with increased vascular smooth muscle cofilin phosphorylation, cytoskeletal stress fiber formation and heightened arterial stiffness. Our data further suggest that pharmacological inhibition of LIM kinase prevents vasoconstriction-induced arterial stiffening, in part via reductions in vascular smooth muscle F-actin content and cellular stiffness. Accordingly, LIM kinase inhibition should represent a promising therapeutic means to stop the progression of arterial stiffening and remodeling in hypertension.

Chlamydia trachomatis is the leading cause of sexually transmitted infections that may progress to pelvic inflammatory disease and infertility. No effective vaccine exists for Chlamydia, nor are there biomarkers available that readily predict disease progression. In this cross-sectional pilot study, we recruited symptomatic and asymptomatic women with C. trachomatis (CT) infection and asymptomatic, uninfected control women from an urban sexually transmitted disease clinic to determine if there were differences in microRNA (miRNA) expression. Infected women with signs and/or symptoms (CTSS) have distinct miRNA profiles compared to asymptomatic infected women (CTNS). In the CTSS group, miR-142 and -147 showed 2.2- to 6.9-fold increases in expression. In the CTNS group, miR-449c, -6779, -519d, -449a, and -2467 showed 3.9- to 9.0-fold increases in expression. In the CTNS group, cyclins and cell cycle regulation and IL-17 pathways were likely downregulated, while the same signaling pathways were upregulated in the CTSS group. In addition, in the CTSS group, additional inflammatory pathways associated with TNFR1 and IL-8 appear to be upregulated. The miRNA expression patterns differ between CT-infected symptomatic and asymptomatic women, and these differences may warrant further study.

ObjectiveTo compare rates of injury and concussion among non-elite (lowest 60% by division of play) Bantam (ages 13–14 years) ice hockey leagues that disallow body checking to non-elite Bantam leagues that allow body checking.MethodsIn this 2-year cohort study, Bantam non-elite ice hockey players were recruited from leagues where policy allowed body checking in games (Calgary/Edmonton 2014–2015, Edmonton 2015–2016) and where policy disallowed body checking (Kelowna/Vancouver 2014–2015, Calgary 2015–2016). All ice hockey game-related injuries resulting in medical attention, inability to complete a session and/or time loss from hockey were identified using valid injury surveillance methodology. Any player suspected of having concussion was referred to a study physician for diagnosis and management.Results49 body checking (608 players) and 33 non-body checking teams (396 players) participated. There were 129 injuries (incidence rate (IR)=7.98/1000 hours) and 54 concussions (IR=3.34/1000 hours) in the body checking teams in games. After policy change, there were 31 injuries (IR=3.66/1000 hours) and 17 concussions (IR=2.01/1000 hours) in games. Policy disallowing body checking was associated with a lower rate of all injury (adjusted incidence rate ratio (IRR)=0.44; 95% CI: 0.27 to 0.74). The point estimate showed a lower rate of concussion (adjusted IRR=0.6; 95% CI: 0.31 to 1.18), but this was not statistically significant.ConclusionPolicy change disallowing body checking in non-elite Bantam ice hockey resulted in a 56% lower rate of injury. There is growing evidence that disallowing body checking in youth ice hockey is associated with fewer injuries.

Background Breastfeeding is associated with a variety of positive health outcomes in children and is recommended exclusively for the first 6 months of life; however, 50–70 % of infants in the US are formula-fed. To test the hypothesis that immune system development and function in neonates and infants are significantly influenced by diet, 2-day old piglets were fed soy or milk formula (n = 6/group/gender) until day 21 and compared to a sow-fed group (n = 6/gender). Methods Histomorphometric analyses of ileum, jejunum and Peyer’s patches were carried out, to determine the inflammation status, mRNA and protein expression of pro-inflammatory, anti-inflammatory and growth-related chemokines and cytokines. Results In formula-fed animals, increases in ileum and jejunum villus height and crypt depth were observed in comparison to sow-fed animals (jejunum, p

This study explores interactions between judges and caseworkers in child maltreatment cases. We examined the extent to which judges demonstrated therapeutic jurisprudence principles (TJ) in their courtroom interactions in light of past findings linking such practices with positive outcomes. Ninety-four child maltreatment proceedings were observed over a one-year period between 2012 and 2013. We found that while some judges created respectful, empathetic, and supportive environments that included caseworkers, other interactions were more negative. Although caseworkers had the most knowledge of, and experience with families, their participation was limited, and conversations were often directed through the attorneys. Shaming rituals also occurred, with judges criticizing workers for the quality of their work, the slowness of the bureaucracy, and other deficiencies. The findings highlight the importance of applying the principles of TJ to all court actors, especially in the family court milieu, where courtrooms are populated by a team of professionals who share the common goal of rehabilitating families when appropriate.

Acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) is thought to be crucial for dietary fat absorption. Indeed, mice lacking the enzyme (Mogat2(-/-)) are resistant to obesity and other metabolic disorders induced by high-fat feeding. However, these mice absorb normal quantities of fat. To explore whether a high level of dietary fat is an essential part of the underlying mechanism(s), we examined metabolic responses of Mogat2(-/-) mice to diets containing varying levels of fat. Mogat2(-/-) mice exhibited 10-15% increases in energy expenditure compared with wild-type littermates; although high levels of dietary fat exacerbated the effect, this phenotype was expressed even on a fat-free diet. When deprived of food, Mogat2(-/-) mice expended energy and lost weight like wild-type controls. To determine whether MGAT2 deficiency protects against obesity in the absence of high-fat feeding, we crossed Mogat2(-/-) mice with genetically obese Agouti mice. MGAT2 deficiency increased energy expenditure and prevented these mice from gaining excess weight. Our results suggest that MGAT2 modulates energy expenditure through multiple mechanisms, including one independent of dietary fat; these findings also raise the prospect of inhibiting MGAT2 as a strategy for combating obesity and related metabolic disorders resulting from excessive calorie intake.

An important question in the study of chlamydial genital tract disease is why some women develop severe upper tract disease while others have mild or even “silent” infections with or without pathology. Animal studies suggest that the pathological outcome of an infection is dependent upon both the composition of the infecting chlamydial population and the genotype of the host, along with host physiological effects, such as the cyclical production of reproductive hormones and even the size of the infecting inoculum or the number of repeated infections. In this study, we compared two variants of Chlamydia caviae , contrasting in virulence, with respect to their abilities to ascend the guinea pig genital tract. We then determined the effect of combining the two variants on the course of infection and on the bacterial loads of the two variants in the genital tract. Although the variants individually had similar infection kinetics in the cervix, SP6, the virulent variant, could be isolated from the oviducts more often and in greater numbers than the attenuated variant, AZ2. SP6 also elicited higher levels of interleukin 8 (IL-8) in the lower genital tract and increased leukocyte infiltration in the cervix and uterus compared to AZ2. When the two variants were combined in a mixed infection, SP6 outcompeted AZ2 in the lower genital tract; however, AZ2 was able to ascend the genital tract as readily as SP6. These data suggest that the ability of SP6 to elicit an inflammatory response in the lower genital tract facilitates the spread of both variants to the oviducts.

Volume 5, no. 3, doi:10.1128/mBio.01241-14, 2014. After careful review, it was noted that Table 2 is missing data for the number of BALB/c mice positive for hydrosalpinx/total number …

It is not currently possible to predict the probability of whether a woman with a chlamydial genital infection will develop pelvic inflammatory disease (PID). To determine if specific biomarkers may be associated with distinct chlamydial pathotypes, we utilized two Chlamydia muridarum variants (C. muridarum Var001 [CmVar001] and CmVar004) that differ in their abilities to elicit upper genital tract pathology in a mouse model. CmVar004 has a lower growth rate in vitro and induces pathology in only 20% of C57BL/6 mouse oviducts versus 83.3% of oviducts in CmVar001-infected mice. To determine if chemokine and cytokine production within 24 h of infection is associated with the outcome of pathology, levels of 15 chemokines and cytokines were measured. CmVar004 infection induced significantly lower levels of CXCL1, CXCL2, tumor necrosis factor alpha (TNF-α), and CCL2 in comparison to CmVar001 infection with similar rRNA (rs16) levels for Chlamydiae. A combination of microRNA (miRNA) sequencing and quantitative real-time PCR (qRT-PCR) analysis of 134 inflammation-related miRNAs was performed 24 h postinfection to determine if the chemokine/cytokine responses would also be reflected in miRNA expression profiles. Interestingly, 12 miRNAs (miR-135a-5p, miR298-5p, miR142-3p, miR223-3p, miR299a-3p, miR147-3p, miR105, miR325-3p, miR132-3p, miR142-5p, miR155-5p, and miR-410-3p) were overexpressed during CmVar004 infection compared to CmVar001 infection, inversely correlating with the respective chemokine/cytokine responses. To our knowledge, this is the first report demonstrating that early biomarkers elicited in the host can differentiate between two pathological variants of chlamydiae and be predictive of upper tract disease., IMPORTANCE It is apparent that an infecting chlamydial population consists of multiple genetic variants with differing capabilities of eliciting a pathological response; thus, it may be possible to identify biomarkers specific for a given virulence pathotype. miRNAs are known to regulate genes that in turn regulate signaling pathways involved in disease pathogenesis. Importantly, miRNAs are stable and can reflect a tissue response and therefore have the potential to be biomarkers of disease severity. Currently, with respect to chlamydial infections, there is no way to predict whether an infected patient is more or less likely to develop PID. However, data presented in this study indicate that the expression of a specific miRNA profile associated with a virulent variant early in the infection course may be predictive of an increased risk of pelvic inflammatory disease, allowing more aggressive treatment before significant pathology develops.

The mechanism by which chlamydiae persist in vivo remains undefined; however, chlamydiae in most animals persist in the gastrointestinal tract (GI) and are transmitted via the fecal–oral route. Oral infection of mice with Chlamydia muridarum was previously shown to establish a long-term persistent infection in the GI tract. In this study, BALB/c, DBA/2, and C57Bl/6 mice, infected orally with C. muridarum , were infected in the cecum for as long as 100 days in the absence of pathology. The primary target tissue was the cecum although the large intestine was also infected in most animals. A strong serum IgG and cecal IgA antibody response developed. Lymphocyte proliferation assays to chlamydial antigen on mesenteric lymph node cells were positive by day 10 and peaked on days 15–21, but the response returned to baseline levels by 50 days, despite the ongoing presence of the organism in the cecum. Because studies have shown that women and men become infected orally with chlamydiae, we propose that the GI tract is a site of persistent infection and that immune down-regulation in the gut allows chlamydiae to persist indefinitely. As a result, women may become reinfected via contamination of the genital tract from the lower GI tract.

Currently, with respect to chlamydial infections, one cannot predict the probability of an infected patient developing pelvic inflammatory disease. To determine if specific biomarkers may be associated with distinct chlamydial pathotypes, we utilized two Chlamydia muridarum variants (M4, M9) that showed differences in the development of upper tract pathology. M4 has a slower growth rate in vitro, induces pathology in 6 of 30 C57Bl/6 oviducts versus 25 of 30 oviducts in M9-infected mice. To determine if chemokine cytokine production within 24 h of infection will define the outcome of pathology, 15 chemokines and cytokines were measured. M4 infection induced significantly lower levels of CXCL 1, CXCL 2, TNF-α and CCL 2 in comparison to M9 infection with similar ribosomal RNA (rs16) levels for chlamydiae. To understand if chemokine cytokine responses would also be reflected in miRNA expression profile within 24 h of infection, 134 inflammation-related miRNAs were measured. Interestingly, 12 miRNAs (miR-135a-5p, miR155-5p, miR325-3p, miR338-5p, miR105, miR132-3p, miR142-3p, miR142-5p, miR147-3p, miR223-3p, miR298-5p and miR299a-3p) were expressed significantly higher during M4 infection than M9 infection, inversely correlating with the respective chemokine/cytokine responses. To our knowledge this is the first report demonstrating that early biomarkers elicited in the host could differentiate between two pathologic variants of chlamydiae and be predictive of upper tract disease.