Which advanced treatment should be used following the failure of a first-line anti-TNF in patients with rheumatoid arthritis? 15 years of evidence from the Quebec registry RHUMADATA.

BACKGROUND: Since 2000, advanced therapies (AT) have revolutionized the treatment of moderate to severe rheumatoid arthritis (RA). Randomized control trials as well as observational studies together with medication availability often determine second-line choices after the failure of first Tumor Necrosis Factor inhibitors (TNFi). This led to the observation that specific sequences provide better long-term effectiveness. We investigated which alternative medication offers the best long-term sustainability following the first TNFi failure in RA. METHODS: Data were extracted from RHUMADATA from January2007. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. Kaplan-Meier and Cox regression models were used to compare discontinuation between groups. Missing data were imputed, and propensity scores were computed to reduce potential attribution bias. Complete, unadjusted, and propensity score-adjusted imputed data analyses were produced. RESULTS: 611 patients (320 treated with a TNFi and 291 treated with molecules having another mechanism of action (OMA)) were included. The mean age at diagnosis was 44.5 and 43.9 years, respectively. The median retention was 2.84 and 4.48 years for TNFi and OMAs groups. Using multivariable analysis, the discontinuation rate of the OMA group was significantly lower than TNFi (adjHR: 0.65; 95% CI: 0.44-0.94). This remained true for the PS-adjusted MI Cox models. In a stratified analysis, rituximab (adjHR: 0.39; 95% CI: 0.18-0.84) had better retention than TNFi after adjusting for patient characteristics. CONCLUSION: Switching to an OMA, especially rituximab, in patients with failure to a first TNFi appears to be the best strategy as a second line of therapy.

Impact of anti-rheumatic treatment on the individual components of the ACR composite score in patients with rheumatoid arthritis: real-world data.

OBJECTIVES: Standard criteria for measuring treatment efficacy in patients with rheumatoid arthritis (RA) include American College of Rheumatology (ACR) response rates, which require meeting a threshold of ≥20/50/70% improvement in several physician- and patient-reported measures. We aimed to evaluate the impact of csDMARDs, TNF inhibitors (TNFi), and tofacitinib (TOFA) on ACR components in real-life practice. METHODS: Clinical data of RA patients with a CDAI >10 at the time they started a treatment were pooled from two registries: Ontario Best Practices Research Initiative (OBRI) and RHUMADATA. Endpoints included proportions of patients achieving: ACR20/50/70 responses, ≥20/50/70% improvements and mean percentage improvement in individual ACR components at Month 6. We also adjusted for potential confounders to compare impact of these medications on outcomes of interest. RESULTS: A total of 669 patients were included (csDMARD, n=157, TNFi, n=252; TOFA, n=260). An overall higher proportion in all three-medication groups achieved ≥20/50/70% improvement in primary ACR components vs. secondary components. Among secondary components, ≥20/50/70% improvement rates were numerically highest for PhGA and lowest for HAQ-DI and pain. Among ACR20/50/70 responders for all medications, the mean percentage improvement was more than 80% for primary components, and ranged from 30% to 80% for secondary components. A significantly lower proportion of patients in TNFi group achieved to at least 50% improvement in pain compared to TOFA after adjusting. CONCLUSIONS: In this real-world practice, physician-reported measures contribute slightly more to overall ACR20/50/70 responses. Pain was the most important factor in achieving an ACR50 TOFA users, possibly reflecting the different effects of JAKi on pain.

Biologics initiation in moderate versus severe rheumatoid arthritis: real-world experience from a Canadian registry.

OBJECTIVES: To evaluate the treat-to-target experience, and quality of life measures of moderate and severe rheumatoid arthritis (RA) patients initiating a biologic in a real-world setting of a publicly funded payer system. METHODS: Biologic naive RA patients who had initiated their first biologic while enrolled in the Ontario Best Practices Research Initiative registry from 2008 to 2020 were selected if they had moderate (DAS28 >3.2 to ≤5.1) or severe (DAS28 >5.1) RA. Remission, LDA, DAS28, HAQ-DI, fatigue, sleep, drug persistence and characteristics associated with remission were assessed at 12 months post biologic initiation. RESULTS: Overall, 838 patients initiated their first biologic, 264 had moderate RA and 219 had severe RA. After 12 months, 44% moderate RA vs. 21% severe RA achieved remission (p<0.0001), and 59% moderate RA vs. 35% severe RA reached LDA (p<0.0001). Mean change (SD) from baseline in DAS28 was 2.2 (1.5) in severe RA vs. 1.4 (1.3) in moderate RA (p<0.0001), in fatigue score was 1.11 (3.2) in severe RA vs. 0.98 (3.2) in moderate RA (p<0.0001). Moderate disease at a biologic initiation was positively associated with remission (p=0.0016). Female gender (p=0.0170), and a higher HAQ-DI score at baseline (p=0.0042) were negatively associated with remission. Biologic persistence was 77% for moderate, and 73% for severe (p=0.2444). CONCLUSIONS: Severe RA patients had higher mean score improvements in DAS28, sleep and fatigue. Moderate RA was more likely to reach remission or LDA. Both groups had similar biologic persistence at 12 months. These findings highlight the importance of the treat-to-target approach and its potential underutilisation in the real-world setting.

Factors affecting the discrepancy between patient and physician global assessment in early rheumatoid arthritis: The Ontario Best Practices Research Initiative.

OBJECTIVES: We aimed to assess the prevalence and factors affecting the discrepancy between patient global assessment (PtGA) and physician global assessment of disease activity (PhGA) in patients with early rheumatoid arthritis (RA) at enrolment and after one year. METHODS: Patients from the Ontario Best Practices Research Initiative (OBRI) were included. The discrepancy between PtGA and PhGA was calculated by simple subtraction (PtGA-PhGA). An absolute value ≥30 was considered discordant. Linear regression analysis was used to assess factors affecting PtGA, PhGA, and PtGA-PhGA discrepancy at enrolment and 1-year follow-up. RESULTS: A total of 531 patients with mean disease duration of 0.3 years were analysed. The discordance prevalence was 22.4% at enrolment and 20.3% after one year. PtGA was higher in the majority of the discordant cases. Multivariable regression analysis showed higher PtGA was significantly associated with higher pain score, tender joint counts (TJC28), ESR, and fatigue at enrolment and 1-year follow-up while PtGA was associated with higher swollen joint counts (SJC28) only at enrolment. Similar associations were found for PhGA, with the exception of fatigue, which was not a significant factor at one year. Multivariable analysis showed that higher discrepancy between PtGA-PhGA was associated with lower SJC28 and higher pain score at enrolment and lower SJC28 and higher pain and fatigue score at 1-year follow-up. CONCLUSIONS: Significant PtGA-PhGA discrepancy was found in approximately one-quarter of early RA patients. In the majority of these patients, PtGA was higher than PhGA. The main predictors of PtGA and PhGA remained the same after one year.

Medical cannabis use by rheumatology patients in routine clinical care: results from The Ontario Best Practices Research Initiative.

OBJECTIVES: Medical cannabis is often used to alleviate common symptoms in patients with chronic conditions. With cannabis legalisation in Canada and easier access, it is important that rheumatologists understand its potential impact on their practice. Among patients attending rheumatology clinics in Ontario we assessed: the prevalence of medical cannabis use; symptoms treated; rheumatologists' perceptions. METHODS: Eight rheumatology clinics recruited consecutive adult patients in a 3-part medical cannabis survey: the first completed by rheumatologists; the second by all patients; the third by medical cannabis users. Student's t-test and Chi-square test were used to compare medical cannabis users to never users. RESULTS: 799 patients participated, 163 (20.4%) currently using medical cannabis or within <2 years and 636 never users; most had rheumatoid arthritis (37.8%) or osteoarthritis (34.0%). Compared to never users, current/past-users were younger; more likely to be taking opioids/anti-depressants, have psychiatric/gastrointestinal disorders, and have used recreational cannabis (p<0.05); had higher physician (2.9 vs. 2.1) and patient (6.0 vs. 4.2) global scores, and pain (6.2 vs. 4.7) (p<0.0001). Pain (95.5%), sleeping (82.3%) and anxiety (58.9%) were the most commonly treated symptoms; 78.2% of current/past-users reported medical cannabis was at least somewhat effective. Most rheumatologists reported being uncomfortable to authorise medical cannabis, primarily due to lack of evidence, knowledge, and product standardisation. CONCLUSIONS: Medical cannabis use among rheumatology patients in Ontario was two-fold higher than that reported for the general population of similar age. Use was associated with more severe disease, pain, and prior recreational use. Reported lack of research, knowledge, and product standardisation were barriers for rheumatologist use authorisation.

Investigating the tendency to use COVID-19 vaccine booster dose in Iran.

INTRODUCTION: Vaccine hesitancy is recognized as a significant public health threats, characterized by delays, refusals, or reluctance to accept vaccinations despite their availability. This study, aimed to investigate the willingness of Iranians to receive booster shots, refusal rate, and their preferred type of COVID-19 vaccine. MATERIALS AND METHODS: This cross-sectional study was conducted over a month from August 23 to September 22, 2022 using an online questionnaire distributed through WhatsApp and Telegram online communities. The questionnaire assessed participants' intent to accept COVID-19 booster vaccination and had no exclusion criteria. Data analysis involved using SPSS version 16.0, with t-tests and chi-square tests used to assess the bivariate association of continuous and categorical variables. A multivariate logistic regression model was built to examine the association between Health Belief Model (HBM) tenets and COVID-19 vaccination intent. The Hosmer Lemeshow Goodness of Fit statistic was used to assess the model's fit, with a p-value > 0.05 indicating a good fit. RESULTS: The survey was disseminated to 1041 adults and the findings revealed that 82.5% of participants expressed a desire to receive the booster dose. Participants who intended to be vaccinated were generally older (46.4 ± 10.9), mostly female (53.3%), single (78.9%), had received a flu vaccine (45.8%). The findings indicated that the HBM items, including perception of COVID-19 disease, perceived benefits of COVID-19 vaccines, COVID-19 safety/cost concerns, preference of COVID-19 vaccine alternatives, and prosocial norms for COVID-19 vaccination, received higher scores among individuals intending to be vaccinated compared to vaccine-hesitant individuals, with statistical significance (p < 0.05). However, the "COVID-19 risk-reduction habits" item had a higher score but did not reach statistical significance (p = 0.167). CONCLUSION: Factors such as lack of trust in the effectiveness of the vaccine, trust in specific vaccine manufacturers, and concerns about side effects of COVID-19 vaccine are among the most important factors. These findings have implications for national vaccination policies, emphasizing the need for policymakers in the health sector to address these factors as vital considerations to ensure the continuity of vaccination as one of the most important strategies for controlling the pandemic.

The Proportion of Patients With Rheumatoid Arthritis Achieving ACR20/50/70; Consistent Patterns of a 60/40/20 as Demonstrated by a Systematic Review and Meta-analysis.

OBJECTIVES: We aimed to demonstrate that the proportion of rheumatoid arthritis patients achieving 20%/50%/70% improvement in American College of Rheumatology (ACR20/50/70) responses to Food and Drug Administration-approved biologic disease-modifying antirheumatic drugs (bDMARDs) after an inadequate response to methotrexate (MTX) and after failure of the first bDMARDs followed a consistent pattern. METHODS: This systematic review and meta-analysis was performed in accordance with MECIR (Methodological Expectations for Cochrane Intervention Reviews) standards. Two separate groups of randomized controlled trials were included: the first group included studies with biologic-naive patients who added bDMARD to MTX as intervention arm compared with the placebo plus MTX group. The second group included biologic-irresponsive (IR) patients who used a second bDMARD plus MTX after the first bDMARD failure compared with placebo plus MTX group. Primary outcome was defined as the proportion of rheumatoid arthritis patients achieving ACR20/50/70 responses at 24 ± 6 weeks. RESULTS: Twenty-one studies initiated between 1999 and 2017 were included: 15 studies for the biologic-naive group and 6 studies for the biologic-IR group. For the biologic-naive group, the proportions of patients achieving ACR20/50/70 were 61.4% (95% confidence interval [CI], 58.7%-64.1%), 37.8% (95% CI, 34.8%-40.8%), and 18.8% (95% CI, 16.1%-21.4%), respectively. For the biologic-IR group, proportions of patients achieving ACR20/50/70 were 48.5% (95% CI, 42.2%-54.8%), 27.3% (95% CI, 21.6%-33.0%), and 12.9% (95% CI, 11.3%-14.8%), respectively. CONCLUSION: We were able to systematically demonstrate that ACR20/50/70 responses to biologic-naive follow a consistent pattern of 60%, 40%, and 20%, respectively. We also demonstrated that the ACR20/50/70 responses to a biologic IR follow a certain pattern of 50%, 25%, and 12.5%, respectively.

Does the Type of Failure and the Choice of the Second Biologic Influence Response and Persistence on Medication in Rheumatoid Arthritis?

BACKGROUND: The type of failure may predict response to a second biologic. We evaluated the response to a second tumor necrosis factor inhibitor (TNFi) or non-TNFi in patients failing their initial TNFi, either primarily or secondarily. METHODS: Patients with rheumatoid arthritis who were biologic-naive and had a Clinical Disease Activity Index (CDAI) >10, who started their first TNFi for ≥3 months and then switched to a second biologic, were included in the study. Secondary failure was defined as 2 consecutive low-CDAI visits and then switching to a second biologic while they had moderate/severe CDAI. Primary failure was defined if it did not meet the definition of secondary failure, or if they had at least 1 moderate/severe CDAI after 3 months on treatment. We used multivariable logistic regression comparing primary versus secondary failure for achievement of CDAI ≤10 (primary outcome) and minimal clinically important differences (secondary outcome) at 6 months after switch. RESULTS: Of the 462 patients included, 64.3% and 35.7% stopped the first TNFi because of a primary and secondary failure, respectively. Patients with primary failure had a more severe disease (CDAI mean, 26.39 vs. 21.61; p < 0.001). The likelihood of achieving CDAI ≤10 (odds ratio, 4.367; 95% confidence interval, 2.428-7.856) and minimal clinically important difference (odds ratio, 2.851; 95% confidence interval, 1.619-5.020) was significantly higher for secondary than primary failure regardless of choice of a second agent. CONCLUSION: Patients with rheumatoid arthritis with secondary failure to a first TNFi responded better to a second biologic agent, regardless of the choice of biologic.

The comparison of stress and strain between custom-designed bone plates (CDBP) and locking compression plate (LCP) for distal femur fracture.

BACKGROUND: Distal femur fracture is considered one of the most common fractures due to high-energy traumas such as car accidents or low-energy traumas such as osteoporosis. Locking plates are orthopedic implants used for stabilized femur fracture. Thus, designing a bone plate fitted exactly with the patient's bone and correctly fixing bone segments are required for better fracture healing. OBJECTIVES: This study aims to design a bone plate based on anthropometric characteristics of patients' femurs and compare performing custom-designed bone plates (CDBP) with the locking compression plate (LCP) by finite element method. MATERIALS AND METHODS: In this analytical study, a 3D model of four patients' femur and CDBP were firstly designed in MIMICS 19.0 based on the patient's femur anatomy. After designing the bone plate, the CDBPs and LCP were fixed on the bone and analyzed by finite element method (FEM) in ANSYS, and stress and strain of bone plates were also compared. RESULTS: The maximum principal stress for all 3D models of patients' fracture femur by CDBPs was stabilized better than LCP with a decrease by 39.79, 12.54, 9.49, and 20.29% in 4 models, respectively. Also, in all models, the strain of CDBPs is less than LCP. Among the different thicknesses considered, the bone plate with 5 mm thickness showed better stress and strain distribution than other thicknesses. CONCLUSION: Customized bone plate designed based on patient's femur anatomical morphology shows better bone-matching plate, resulting in increasing the quality of the fracture healing and fails to any need for additional shaping. TRIAL REGISTRATION NUMBER: Design and analysis of an implant were investigated in this study. There was no intervention in the diagnosis and treatment of patients and the study was not a clinical trial.

Differential influence of Clinical Disease Activity Index components based on disease state in rheumatoid arthritis patients: real-world results from the Ontario Best Practices Research Initiative.

OBJECTIVES: The Clinical Disease Activity Index (CDAI) is routinely used in clinical care when treating-to-target RA patients. Previous validation studies have looked at CDAI's overall performance; this analysis aimed at evaluating its properties by disease state and identifying drivers of variance. METHODS: RA patients enrolled in the OBRI registry, with available follow-up of ≥6 months were included. Construct validity of CDAI was assessed with principal component analysis; internal consistency with Cronbach's alpha (α); correlational validity with Spearman's rho (ρ); agreement in disease state classification with the kappa statistic. Stratification by disease states was performed. RESULTS: CDAI correlation with DAS28 was strong when CDAI>10 (ρ=0.79), moderate when CDAI≤10 (ρ=0.56) or 2.810, CDAI was able to be reduced to a single component with patient global assessment (PtGA) having the lowest loading. When CDAI≤10, two distinct components were identified: (1) PtGA and physician global assessment; (2) SJC28 and TJC28. Moderate levels (α=0.71) of internal consistency were observed when CDAI>10 but low when CDAI≤10 (α=0.23), 2.8

Time to remission in swollen joints is far faster than patient reported outcomes in rheumatoid arthritis: results from the Ontario Best Practices Research Initiative (OBRI).

OBJECTIVES: RA patients are often not in remission due to patient global assessment of disease activity (PtGA) included in disease activity indices. The aim was to assess the lag of patient-reported outcomes (PROs) after remission measured by clinical disease activity index (CDAI) or swollen joint count (SJC28). METHODS: RA patients enrolled in the Ontario Best Practices Research Initiative registry not in low disease state at baseline with at ≥6 months of follow-up, were included. Low disease state was defined as CDAI ≤ 10, SJC28 ≤ 2, PtGA ≤ 2cm, pain score ≤ 2cm, or fatigue ≤ 2cm. Remission included CDAI ≤ 2.8, SJC28 ≤ 1, PtGA ≤ 1cm, pain score ≤ 1cm, or fatigue ≤ 1cm. Time to first low disease state/remission based on each definition was calculated overall and stratified by early vs established RA. RESULTS: A total of 986 patients were included (age 57.4 (12.9), disease duration 8.3 (9.9) years, 80% women). The median (95% CI) time in months to CDAI ≤ 10 was 12.4 (11.4, 13.6), SJC28 ≤ 2 was 9 (8.2, 10), PtGA ≤ 2cm was 18.9 (16.1, 22), pain ≤ 2cm was 24.5 (19.4, 30.5), and fatigue ≤ 2cm was 30.4 (24.8, 31.7). For remission, the median (95% CI) time in months to CDAI ≤ 2.8 was 46.5 (42, 54.1), SJC28 ≤ 1 was 12.5 (11.4, 13.4), PtGA ≤ 1cm was 39.6 (34.6, 44.8), pain ≤ 1cm was 54.7 (43.6, 57.5) and fatigue ≤ 1cm was 42.6 (36.8, 48). Time to achieving low disease state and remission was generally significantly shorter in early RA compared with established RA with the exception of fatigue. CONCLUSION: Time to achieving low disease state or remission based on PROs was considerably longer compared with swollen joint count. Treating to a composite target in RA could lead to inappropriate changes in DMARDs.

Treatment patterns in rheumatoid arthritis after discontinuation of methotrexate: data from the Ontario Best Practices Research Initiative (OBRI).

OBJECTIVES: In active rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX), guidelines support adding or switching to another conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) and/or a biologic DMARD (bDMARD). The purpose of this analysis was to describe treatment practices in routine care and to evaluate determinants of regimen selection after MTX discontinuation. METHODS: Biologic-naïve patients in the Ontario Best Practice Research Initiatives registry discontinuing MTX due to primary/secondary failure, adverse events, or patient/physician decision were included. RESULTS: Of 313 patients discontinuing MTX, 102 (32.6%) were on MTX monotherapy, 156 (49.8%) on double, and 55 (17.6%) on multiple csDMARDs. Patients on MTX monotherapy were older than patients on double or multiple csDMARDs (p=0.013), less likely to have joint erosions (p=0.009) and had lower patient global assessment (p=0.046) at MTX discontinuation. Post-MTX discontinuation, 169 (54.0%) transitioned to, or added new DMARD(s) (new csDMARD(s): 139 [44.4%]; bDMARD: 30 [9.6%]), and 144 (46.0%) opted for no new DMARD treatment. Patients on MTX monotherapy transitioning monotherapy, whereas patients on combination csDMARDs switched more to new csDMARDs and bDMARD combination therapy. Early RA (adjOR [95%CI]: 3.07 [1.40-6.72]) and treatment with multiple csDMARDs vs. MTX monotherapy (4.15 [1.35-12.8]) at MTX discontinuation were significant predictors of transitioning to or adding new csDMARD(s)/bDMARD treatment versus opting for no new DMARD treatment. CONCLUSIONS: Differences in subsequent treatment patterns exist between patients discontinuing MTX when used as monotherapy versus in combination with other csDMARDs where the former are more likely to use a subsequent monotherapy treatment.

Oral glucocorticoid therapy and all-cause and cause-specific mortality in patients with rheumatoid arthritis: a retrospective cohort study.

Previous studies of glucocorticoid (GC) therapy and mortality have had inconsistent results and have not considered possible perimortal bias-a type of protopathic bias where illness in the latter stages of life influences GC exposure, and might affect the observed relationship between GC use and death. This study aimed to investigate all-cause and cause-specific mortality in association with GC therapy in patients with rheumatoid arthritis (RA), and explore possible perimortal bias. A retrospective cohort study using the primary care electronic medical records. Oral GC exposure was identified from prescriptions. Mortality data were obtained from the UK Office for National Statistics. Multivariable Cox proportional hazards regression models assessed the association between GC use models and death. Several methods to explore perimortal bias were examined. The cohort included 16,762 patients. For ever GC use there was an adjusted hazard ratio for all-cause mortality of 1.97 (95 % CI 1.81-2.15). Current GC dose of below 5 mg per day (prednisolone equivalent dose) was not associated with an increased risk of death, but a dose-response association was seen for higher dose categories. The association between ever GC use and all-cause mortality was partly explained by perimortal bias. GC therapy was associated with an increased risk of mortality for all specific causes considered, albeit to a lesser extent for cardiovascular causes. GC use was associated with an increased risk of death in RA, at least partially explained by perimortal bias. Importantly, GC doses below 5 mg were not associated with an increased risk of death.

Retention of triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine compared to combination methotrexate and leflunomide in rheumatoid arthritis.

OBJECTIVE: There are various combination conventional synthetic disease-modifying-antirheumatic drug (csDMARD) treatment strategies used in rheumatoid arthritis (RA). A commonly used csDMARD combination is triple therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ). Another approach is double therapy with MTX and leflunomide (LEF). We compared the real-world retention of these two treatment combinations. METHODS: Patients with RA from the Ontario Best Practices Research Initiative (OBRI) who received triple or double therapy on or after OBRI enrolment were included. Retention rates were compared between these two groups. We also analyzed which medication in the combination was discontinued and the reasons for treatment discontinuation. Disease activity was assessed at baseline, 6 and 12 months after treatment initiation as well as at time of discontinuation. Risk factors for treatment discontinuation were also examined. RESULTS: Six hundred and ninety-two patients were included (258 triple and 434 double therapy). There were 175 (67.8%) discontinuations in the triple therapy group and 287 (66.1%) discontinuations in patients on double therapy. The median survival for triple therapy was longer (15.1 months; 95% CI: 11.2-21.2) compared to double therapy (9.6 months; 95%CI: 7.03-12.2). However, this was not statistically significant. Disease activity at 6 and 12 months, measured by 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) was lower with triple therapy (mean DAS28 at 6 months 3.4 vs. 3.9, P<0.0001 and at 12 months 3.2 vs. 3.5, P=0.0005). CONCLUSION: Patients on triple therapy remained on treatment longer than patients on double therapy. However, this difference was not statistically significant.

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Cardiovascular Risk Factors and the Risk of Discontinuation of Advanced Therapies Due to Treatment Failure in Rheumatoid Arthritis: Results From the Ontario Best Practices Research Initiative.

OBJECTIVES: Our goal was to investigate whether cardiovascular disease (CVD) risk factors are associated with the retention of biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted-synthetic DMARDs (tsDMARDs) in patients with rheumatoid arthritis (RA). METHODS: We included participants in the Ontario Best Practices Initiative RA registry who initiated their first bDMARD or tsDMARD. Participants were grouped by the number of baseline CVD risk factors (0, 1, or ≥2). The primary outcome was time-to-discontinuation of therapy for any reason. Secondary outcomes included discontinuation for primary failure, secondary failure, or due to adverse events. Competing risks hazards model, adjusted for clinically important confounders, estimated the association between CVD risk factors and treatment retention. RESULTS: The sample included 872 patients, of which 58% (n = 508) discontinued their b/tsDMARD after a median of 13 months from the time of initiation. The most common causes for treatment discontinuation were primary failure (n = 72), secondary failure (n = 126), or adverse events (n = 133). Patients with no CVD risk factors experienced significantly longer treatment survival compared to patients with 1 or ≥2 CVD risk factors. In multivariable-adjusted analysis, there was no association between all-cause discontinuation and CVD risk factors. However, there was a significant association between the presence of >1 CVD risk factor and treatment discontinuation, notably due to secondary treatment failure, but not due to adverse events. CONCLUSION: Multiple CVD risk factors increase the risk of treatment failure in RA, particularly for secondary treatment failure. To improve patient outcomes, future research should focus on developing strategies to identify early treatment nonresponse and investigate the potential modifiability of this association.

Roadmap to recovery: Implemented and attitude toward school reopening strategies during the COVID-19 pandemic, a scoping review.

The novel coronavirus disease 2019 (COVID-19) has had various financial and life impacts on the world's population. Schools' regular activity and function during the pandemic require balancing the repercussions of suspending in-person education versus health threats. Furthermore, children are one of the prominent victims of the restricted quarantine strategies' effects, which may make them vulnerable to various mental health problems. In this study, we reviewed previously reported strategies and roadmaps regarding the reopening of schools during the COVID-19 pandemic. The following databases were searched from October to December 2021, via multi-step search strategies for "COVID-19," "coronavirus," "school reopening," "roadmaps," "reopening," and "reopening strategies": Google Scholar, PubMed, Scopus, and Web of Science. A total of five papers with roadmaps focusing on reopening schools were included in this study. Fundamental issues and principles of these reviewed roadmaps were: 1) protecting the high-risk students and staff physically and mentally, 2) accelerating the vaccination of essential workers, staff, parents, and students, and 3) improving the COVID-19 testing capacity. Roadmaps for the reopening of the schools should describe some phases and steps for their strategies. Current roadmaps have not mentioned any phases and timelines for this process. Describing some health metrics in the roadmaps for progressing to the next step or returning to the previous ones is also necessary for all roadmaps and should be considered in further studies.

A Hardware-Software System for Accurate Segmentation of Phonocardiogram Signal.

Background: Phonocardiogram (PCG) signal provides valuable information for diagnosing heart diseases. However, its applications in quantitative analyses of heart function are limited because the interpretation of this signal is difficult. A key step in quantitative PCG is the identification of the first and second sounds (S1 and S2) in this signal. Objective: This study aims to develop a hardware-software system for synchronized acquisition of two signals electrocardiogram (ECG) and PCG and to segment the recorded PCG signal via the information provided in the acquired ECG signal. Material and Methods: In this analytical study, we developed a hardware-software system for real-time identification of the first and second heart sounds in the PCG signal. A portable device to capture synchronized ECG and PCG signals was developed. Wavelet de-noising technique was used to remove noise from the signal. Finally, by fusing the information provided by the ECG signal (R-peaks and T-end) into a hidden Markov model (HMM), the first and second heart sounds were identified in the PCG signal. Results: ECG and PCG signals from 15 healthy adults were acquired and analyzed using the developed system. The average accuracy of the system in correctly detecting the heart sounds was 95.6% for S1 and 93.4% for S2. Conclusion: The presented system is cost-effective, user-friendly, and accurate in identifying S1 and S2 in PCG signals. Therefore, it might be effective in quantitative PCG and diagnosing heart diseases.

Epidemiology and Survival of Systemic Sclerosis-Sarcoidosis Overlap Syndrome.

OBJECTIVE: We evaluated the epidemiology, manifestations, serology, comorbidities, and survival among patients with systemic sclerosis (SSc) with and without sarcoidosis. METHODS: We conducted a retrospective cohort study comparing patients with SSc with and without sarcoidosis. All patients fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc. Sarcoidosis was based on physician diagnosis and/or confirmatory biopsy. The primary outcome was time from diagnosis to all-cause mortality. Survival was evaluated using Kaplan-Meier curves. RESULTS: We included 1977 patients (1971 with SSc, 6 with SSc-sarcoidosis) with a SSc-sarcoidosis prevalence of 0.30%. Sarcoidosis frequently preceded SSc (66.66%). The most frequent sarcoidosis manifestations were pulmonary (66.66%), lymphadenopathy (66.66%), arthritis (50%), cutaneous (33.33%), and hepatic (16.66%). Patients with SSc and SSc-sarcoidosis had female to male sex ratios of 4.5:1 vs 5:1 and median ages of SSc onset of 48.3 vs 43.8 years, respectively. Interstitial lung disease (35% vs 66.66%) and pulmonary hypertension (24.91% vs 50%) tended to occur more frequently whereas abnormal nailfold capillaries (34.7% vs 16.66%) and digital ulcers (33.33% vs 16.66%) tended to occur less frequently among patients with SSc-sarcoidosis, but the differences were not significant. There was an increased frequency of stroke among the patients with SSc-sarcoidosis (relative risk 8.59, 95% CI 1.02-72.00). The median survival times were 23.4 years for SSc-sarcoidosis and 18.6 years for SSc, with no differences in survival curves (log-rank test, P = 0.55). CONCLUSION: Sarcoidosis in SSc is rare but appears to occur more frequently than in the general population. It is associated with pulmonary, lymph node, cutaneous, joint, and hepatic involvement. Stroke occurs more frequently in patients with SSc-sarcoidosis but with no differences in survival.

Discontinuation of tofacitinib and TNF inhibitors in patients with rheumatoid arthritis: analysis of pooled data from two registries in Canada.

OBJECTIVES: The similarity in retention of tumour necrosis factor inhibitors (TNFi) and tofacitinib (TOFA) was previously reported separately by the Ontario Best Practices Research Initiative and the Quebec cohort Rhumadata. However, because of small sample sizes in each registry, we aimed to confirm the findings by repeating the analysis of discontinuation of TNFi compared with TOFA, using pooled data from both these registries. DESIGN: Retrospective cohort study. SETTING: Pooled data from two rheumatoid arthritis (RA) registries in Canada. PARTICIPANTS: Patients with RA starting TOFA or TNFi between June 2014 and December 2019 were included. A total of 1318 patients were included TNFi (n=825) or TOFA (n=493). OUTCOME MEASURES: Time to discontinuation was assessed using Kaplan-Meier survival and Cox proportional hazards regression analysis. Propensity score (PS) stratification (deciles) and PS weighting were used to estimate treatment effects. RESULTS: The mean disease duration in the TNFi group was shorter (8.9 years vs 13 years, p<0.001). Prior biological use (33.9% vs 66.9%, p<0.001) and clinical disease activity index (20.0 vs 22.1, p=0.02) were lower in the TNFi group.Discontinuation was reported in 309 (37.5%) and 181 (36.7%) TNFi and TOFA patients, respectively. After covariate adjustment using PS, there was no statistically significant difference between the two groups in discontinuation due to any reason HR=0.96 (95% CI 0.78 to 1.19, p=0.74)) as well as discontinuation due to ineffectiveness only HR=1.08 (95% CI 0.81 to 1.43, p=0.61)).TNFi users were less likely to discontinue due to adverse events (AEs) (adjusted HRs: 0.46, 95% CI 0.29 to 0.74; p=0.001). Results remained consistent for firstline users. CONCLUSIONS: In this pooled real-world data study, the discontinuation rates overall were similar. However, discontinuation due to AEs was higher in TOFA compared with TNFi users.