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ObjectiveDespite medical therapy, damage occurs in patients with psoriatic arthritis (PsA) requiring musculoskeletal (MSK) surgery. We aimed to describe MSK surgery in patients with PsA and identify risk factors for undergoing first MSK surgery attributable to PsA.MethodsA single-center cohort identified patients with PsA fulfilling Classification Criteria for Psoriatic Arthritis who had MSK surgery between January 1978 and December 2019 inclusive. Charts were reviewed to confirm surgeries were MSK-related and attributable to PsA. Descriptive statistics determined MSK surgery prevalence and types. Cox proportional hazards models evaluated clinical variables for undergoing first MSK surgery using time-dependent covariates. Using a dataset with 1-to-1 matching on markers of PsA disease severity, a Cox proportional hazards model evaluated the effect of targeted therapies, namely biologics on time to first MSK surgery.ResultsOf 1574 patients, 185 patients had 379 MSK surgeries related to PsA. The total number of damaged joints (hazard ratio [HR] 1.03,P< 0.001), tender/swollen joints (HR 1.04,P= 0.01), presence of nail lesions (HR 2.08,P< 0.01), higher Health Assessment Questionnaire scores (HR 2.01,P< 0.001), elevated erythrocyte sedimentation rate (HR 2.37,P= 0.02), and HLA-B27 positivity (HR 2.22,P= 0.048) were associated with increased risk of surgery, whereas higher Psoriasis Area Severity Index (HR 0.88,P< 0.002) conferred a protective effect in a multivariate model. The effect of biologics did not reach statistical significance.ConclusionMSK surgery attributable to PsA is not rare, affecting 11.8% of patients. Markers of cumulative disease activity and damage are associated with a greater risk of requiring surgery.

To investigate the potential mineralising effects of calcium silicate-based dentine replacement material (Biodentine™) in comparison with glass-ionomer cement (GIC) (Fuji IX™) on different human dentine substrates using a multimodal non-invasive optical assessment.Cements were applied on artificially demineralised or naturally carious dentine and stored for 4 weeks in phosphate-rich media +/- tetracycline used for mineralisation labelling. Interfacial dentine was examined from the same sample and location before and after aging using two-photon fluorescence microscopy, fluorescence lifetime imaging (FLIM) and second harmonic generation (SHG) imaging. Additionally, Raman spectroscopy was used to detect changes in the mineral content of dentine.Significant changes in the fluorescence intensity and lifetime were detected in partially demineralised dentine and caries-affected dentine underneath both tested cements, after storage (p 0.001). This was associated with a significant increase in the mineral content as indicated by the increased intensity of the phosphate Raman peak located at 959 cm

Objective To investigate the incidence of and factors associated with SARS-CoV-2 testing and infection in immune mediated inflammatory diseases (IMIDs) versus matched non-IMIDs comparators from the general population. Methods We conducted a population-based, matched cohort study among adult residents from Ontario, Canada, from January to December 2020. We created cohorts for the following IMIDs: rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, systemic autoimmune rheumatic diseases, multiple sclerosis (MS), iritis, inflammatory bowel disease (IBD), polymyalgia rheumatica and vasculitis. Each patient was matched with five patients without IMIDs based on socio-demographic factors. We estimated the incidence of SARS-CoV-2 testing and infection in IMIDs and non-IMIDs patients. Multivariable logistic regressions assessed odds of SARS-CoV-2 infection. Results We studied 493,499 patients with IMIDs and 2,466,946 patients without IMIDs. Patients with IMIDs were more likely to have at least one SARS-CoV-2 test, versus patients without IMIDs (27.4% vs. 22.7%), but the proportion testing positive for SARS-CoV-2 was identical (0.9% in both groups). Overall, IMIDs patients had 20% higher odds of being tested for SARS-CoV-2 (odds ratio (OR) 1.20, 95% CI 1.19, 1.21). The odds of SARS-CoV-2 infection varied across IMIDs groups but was not significantly elevated for most IMID groups compared with non-IMIDs. The odds of SARS-CoV-2 infection was lower in IBD and MS and marginally higher in RA and iritis. Conclusions Patients across all IMIDs were more likely to be tested for SARS-CoV-2 versus those without IMIDs. The risk of SARS-CoV-2 infection varied across disease sub-groups.

To assess the incidence and risk factors for heart failure in patients with psoriatic disease and to describe their electrocardiographic and echocardiographic findings.A cohort analysis was conducted involving patients with psoriatic disease followed prospectively from 1978 to 2018. Participants were assessed according to a standard protocol every 6 to 12 months. The primary outcome was the time to first event of heart failure, further classified into ischemic and nonischemic heart failure (secondary outcomes). The association between cardiovascular risk factors, measures of disease activity, and heart failure events was assessed using Cox proportional hazards regression. Electrocardiographic and echocardiographic findings associated with heart failure events were described.A total of 1,994 patients with psoriatic disease were analyzed, with 64 incident heart failure events (38 ischemic, 26 nonischemic). The incidence rate of first heart failure event was 2.85 per 1,000 patient-years. In all events, the most common electrocardiographic findings were atrial fibrillation (22%) and bundle branch blocks (29%). Echocardiogram revealed 37% reduced ejection fraction and 63% preserved ejection fraction. In multivariable analysis, independent risk factors for all heart failure events were ischemic heart disease, adjusted mean tender joint count, adjusted mean swollen joint count, adjusted mean erythrocyte sedimentation rate, adjusted mean C-reactive protein level, and physical function (by Health Assessment Questionnaire) (all P 0.05). Minimal disease activity state was protective for all heart failure (P 0.05).Increased risk of heart failure is associated with a combination of known cardiovascular risk factors and measures of disease activity, particularly in nonischemic heart failure. The effect of inflammation on heart failure may be partially independent of atherosclerotic disease.

With the advent of personalized and stratified medicine, there has been much discussion about predictive modeling and the role of classical regression in modern medical research. We describe and distinguish the goals in these 2 frameworks for analysis.The assumptions underlying and utility of classical regression are reviewed for continuous and binary outcomes. The tenets of predictive modeling are then discussed and contrasted. Principles are illustrated by simulation and through application of methods to a neurosurgical study.Classical regression can be used for insights into causal mechanisms if careful thought is given to the role of variables of interest and potential confounders. In predictive modeling, interest lies more in accuracy of predictions and so alternative metrics are used to judge adequacy of models and methods; methods which average predictions over several contending models can improve predictive performance but these do not admit a single risk score.Both classical regression and predictive modeling have important roles in modern medical research. Understanding the distinction between the 2 frameworks for analysis is important to place them in their appropriate context and interpreting findings from published studies appropriately.

When hidden among pairs of individuals facing in the same direction, pairs of individuals arranged front-to-front are found faster in visual search tasks than pairs of individuals arranged back-to-back. Two rival explanations have been advanced to explain this search advantage for facing dyads. According to one account, the search advantage reflects the fact that front-to-front targets engage domain-specific social interaction processing that helps stimuli compete more effectively for limited attentional resources. Another view is that the effect is a by-product of the ability of individual heads and bodies to direct observers' visuospatial attention. Here, we describe a two-part investigation that sought to test these accounts. First, we found that it is possible to replicate the search advantage with nonsocial objects. Next, we employed a cuing paradigm to investigate whether it is the ability of individual items to direct observers' visuospatial attention that determines if an object category produces the search advantage for facing dyads. We found that the strength of the cuing effect produced by an object category correlated closely with the strength of the search advantage produced by that object category. Taken together, these results provide strong support for the directional cuing account. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

We assessed patterns of enteric infections caused by 14 pathogens, in a longitudinal cohort study of sequelae in British Columbia (BC) Canada, 2005–2014. Our population cohort of 5.8 million individuals was followed for an average of 7.5 years/person; during this time, 40 523 individuals experienced 42 308 incident laboratory-confirmed, provincially reported enteric infections (96.4 incident infections per 100 000 person-years). Most individuals (38 882/40 523; 96%) had only one, but 4% had multiple concurrent infections or more than one infection across the study. Among individuals with more than one infection, the pathogens and combinations occurring most frequently per individual matched the pathogens occurring most frequently in the BC population. An additional 298 557 new fee-for-service physician visits and hospitalisations for enteric infections, that did not coincide with a reported enteric infection, also occurred, and some may be potentially unreported enteric infections. Our findings demonstrate that sequelae risk analyses should explore the possible impacts of multiple infections, and that estimating risk for individuals who may have had a potentially unreported enteric infection is warranted We assessed patterns of enteric infections caused by 14 pathogens, in a longitudinal cohort study of sequelae in British Columbia (BC) Canada, 2005-2014. Our population cohort of 5.8 million individuals was followed for an average of 7.5 years/person; during this time, 40 523 individuals experienced 42 308 incident laboratory-confirmed, provincially reported enteric infections (96.4 incident infections per 100 000 person-years). Most individuals (38 882/40 523; 96%) had only one, but 4% had multiple concurrent infections or more than one infection across the study. Among individuals with more than one infection, the pathogens and combinations occurring most frequently per individual matched the pathogens occurring most frequently in the BC population. An additional 298 557 new fee-for-service physician visits and hospitalisations for enteric infections, that did not coincide with a reported enteric infection, also occurred, and some may be potentially unreported enteric infections. Our findings demonstrate that sequelae risk analyses should explore the possible impacts of multiple infections, and that estimating risk for individuals who may have had a potentially unreported enteric infection is warranted.

When encountering social scenes, there appears to be rapid and automatic detection of social interactions. Representations of interacting people appear to be bound together via a mechanism of joint attention, which results in enhanced memory, even when participants are unaware that memory is required. However, even though access is facilitated for socially bound representations, we predicted that the individual features of these representations are less efficiently encoded, and features can therefore migrate between the constituent interacting individuals. This was confirmed in Experiment 1, where overall memory for interacting compared with non-interacting dyads was facilitated but binding of features within an individual was weak, resulting in feature migration errors. Experiment 2 demonstrated the role of conscious strategic processing, where participants were aware that memory would be tested. With such awareness, attention can be focused on individual objects allowing the binding of features. The results support an account of two forms of processing: an initial automatic social binding process where interacting individuals are represented as one episode in memory facilitating access and a further stage where attention can be focused on each individual enabling the binding of features within individual objects.

Intensity-based multistate models provide a useful framework for characterizing disease processes, the introduction of interventions, loss to follow-up, and other complications arising in the conduct of randomized trials studying complex life history processes. Within this framework we discuss the issues involved in the specification of estimands and show the limiting values of common estimators of marginal process features based on cumulative incidence function regression models. When intercurrent events arise we stress the need to carefully define the target estimand and the importance of avoiding targets of inference that are not interpretable in the real world. This has implications for analyses, but also the design of clinical trials where protocols may help in the interpretation of estimands based on marginal features.

Propensity score methodology has become increasingly popular in recent years as a tool for estimating causal effects in observational studies. Much of the related research has been directed at settings with binary or discrete exposure variables with more recent work involving continuous exposure variables. In environmental epidemiology, a substantial proportion of individuals is often completely unexposed while others may experience heavy exposure leading to an exposure distribution with a point mass at zero and a heavy right tail. We suggest a new approach to handle this type of exposure data by constructing a propensity score based on a two-part model and show how this model can be used to more reliably adjust for covariates of a semi-continuous exposure variable. We also consider the case when a misspecified propensity score is used in a regression adjustment and derive an explicit form of the bias. We show that the potential bias gets smaller as the estimated propensity score gets closer to the true expectation of the exposure variable given a set of observed covariates. While this result pertains to a more general setting, we use it to evaluate the potential bias in settings in which the true exposure has a semi-continuous structure. We also evaluate and compare the performance of our proposed method through simulation studies relative to a simpler linear regression-based propensity score for a continuous exposure variable as well as through direct covariate adjustment. Overall, we find that using a propensity score constructed via a two-part model significantly improves the regression estimate when the exposure variable is semi-continuous in nature. Specifically when the proportion of non-exposed subjects is high and the effects of covariates on exposure and outcome are strong, the proposed two-part propensity score method outperforms the more standard competing methods. We illustrate our method using data from the Detroit Longitudinal Cohort Study in which the exposure variable reflects gestational alcohol exposure featuring zero values and a long tail.

In patients with psoriatic disease (PsD), we determined whether cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with carotid plaque burden and the development of cardiovascular events independent of the Framingham Risk Score (FRS).Among 1,000 patients with PsD, carotid total plaque area (TPA) was measured in 358 participants at baseline. Cardiac troponin I and NT-proBNP were measured using automated clinical assays. The association between cardiac biomarkers and carotid atherosclerosis was assessed by multivariable regression after adjusting for cardiovascular risk factors. Improvement in the prediction of cardiovascular events beyond the FRS was tested using measures of risk discrimination and reclassification.In univariate analyses, cTnI (β coefficient 0.52 [95% confidence interval (95% CI) 0.3, 0.74], P 0.001) and NT-proBNP (β coefficient 0.24 [95% CI 0.1, 0.39], P0.001) were associated with TPA. After adjusting for cardiovascular risk factors, the association remained statistically significant for cTnI (adjusted β coefficient 0.21 [95% CI 0, 0.41], P = 0.047) but not for NT-proBNP (P = 0.21). Among the 1,000 patients with PsD assessed for cardiovascular risk prediction, 64 patients had incident cardiovascular events. When comparing a base model (with the FRS alone) to expanded models (with the FRS plus cardiac biomarkers), there was no improvement in predictive performance.In patients with PsD, cTnI may reflect the burden of atherosclerosis, independent of traditional cardiovascular risk factors. Cardiac troponin I and NT-proBNP are associated with incident cardiovascular events independent of the FRS, but further study of their role in cardiovascular risk stratification is warranted.

Russia has enlisted the Russian Orthodox Church (ROC) and instrumentalised it as part of what can be described as a dynamic ‘soft-power offensive’. Its aim is to consolidate hierarchical power as a...

Genetic studies of two related survival outcomes of a pleiotropic gene are commonly encountered but statistical models to analyze them are rarely developed. To analyze sequencing data, we propose mixed effect Cox proportional hazard models by functional regressions to perform gene-based joint association analysis of two survival traits motivated by our ongoing real studies. These models extend fixed effect Cox models of univariate survival traits by incorporating variations and correlation of multivariate survival traits into the models. The associations between genetic variants and two survival traits are tested by likelihood ratio test statistics. Extensive simulation studies suggest that type I error rates are well controlled and power performances are stable. The proposed models are applied to analyze bivariate survival traits of left and right eyes in the age-related macular degeneration progression.

Objectives To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD). Methods PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD. Results 2051 patients (PsD) were included of whom 228 (11%) developed cancer. 168 patients developed cancer after first clinic visit and are included in this report. Overall SIR for malignancy was 0.83 (0.68, 1.00), SIR for females was 1.06 (0.80, 1.37), and for males was 0.67 (0.50, 0.88). The most common malignancies were skin, breast, and hematological. Skin cancer was the only specific cancer that had a higher incidence than the general population with SIR = 3.37 (1.84, 5.66). There was insufficient evidence to suggest an increased risk of malignancy associated with biologics use. Conclusions In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.

ObjectivesTo compare isolated axial psoriatic arthritis (PsA), axial PsA with peripheral involvement and isolated axial ankylosing spondylitis (AS) with psoriasis. To evaluate predictors for developing peripheral disease from isolated axial PsA over time.MethodsTwo PsA and AS cohorts identified patients with PsA with axial disease and isolated axial patients with AS with psoriasis. Logistic regression compared isolated axial PsA to axial PsA with peripheral involvement and isolated axial AS with psoriasis. Cox proportional hazards model evaluated predictors for developing peripheral disease from isolated axial PsA.ResultsOf 1576 patients with PsA, 2.03% had isolated axial disease and 29.38% had axial and peripheral disease. human leucocyte antigen HLA-B*27 positivity (OR 25.00, 95% CI 3.03 to 206.11) and lower Health Assessment Questionnaire scores (OR 0.004, 95% CI 0.00 to 0.28) were associated with isolated axial disease. HLA-B*27 also predicted peripheral disease development over time (HR 7.54, 95% CI 1.79 to 31.77). Of 1688 patients with AS, 4.86% had isolated axial disease with psoriasis. Isolated axial patients with PsA were older at diagnosis (OR 1.06, 95% CI 1.01 to 1.13), more likely to have nail lesions (OR 12.37, 95% CI 2.22 to 69.07) and less likely to have inflammatory back pain (OR 0.12, 95% CI 0.02 to 0.61) compared with patients with isolated axial AS with psoriasis.ConclusionsIsolated axial PsA and AS with psoriasis are uncommon. HLA-B*27 positivity is associated with isolated axial PsA and may identify those who develop peripheral disease over time. Isolated axial PsA is associated with better functional status. Isolated axial PsA appears clinically distinct from isolated axial AS with psoriasis.

Family studies routinely employ biased sampling schemes in which individuals are randomly chosen from a disease registry and genetic and phenotypic data are obtained from their consenting relatives. We view this as a two-phase study and propose the use of an efficient selection model for the recruitment of families to form a phase II sample subject to budgetary constraints. Simple random sampling, balanced sampling and use of an approximately optimal selection model are considered where the latter is chosen to minimize the variance of parameters of interest. We consider the setting where family members provide current status data with respect to the disease and use copula models to address within-family dependence. The efficiency gains from the use of an optimal selection model over simple random sampling and balanced sampling schemes are investigated as is the robustness of optimal sampling to model misspecification. An application to a family study on psoriatic arthritis is given for illustration.

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of –10%. This trial is registered with ClinicalTrials.gov, NCT01621204. Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49–55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI –2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. Funding: GlaxoSmithKline and Novartis.

The nature of the perceptual deficit seen in developmental prosopagnosia remains poorly understood. One possibility is that these individuals experience face recognition difficulties because they fail to process faces holistically; they may be less able to analyze distal regions in parallel and therefore struggle to integrate information from different regions into a unified perceptual whole. Consequently, developmental prosopagnosics may be forced to base perceptual decisions on a slow, effortful piecemeal analysis of local facial features. In the present study, we sought to test this view by comparing the face recognition of developmental prosopagnosics and typical observers under two viewing conditions: when target faces were briefly presented in their entirety, and when they were inspected region-by-region through a dynamic aperture. If developmental prosopagnosics are forced to base perceptual decisions on information accumulated from a serial piecemeal analysis, one would expect little if any decrement in performance when target faces are viewed through apertures. Contrary to this prediction, however, developmental prosopagnosics showed strong aperture effects comparable with typical observers; their perceptual decisions were more accurate in the whole-face condition than when targets were viewed through the aperture. As expected, the developmental prosopagnosics were less accurate than typical controls when judging briefly presented faces shown in their entirety. Strikingly, however, they were also less able to accumulate perceptual evidence from a serial region-by-region analysis, than typical observers. Our results suggest that the perceptual problems seen in this population arise from imprecise descriptions of local regions, not aberrant holistic processing.

Introduction This case series highlights the condition juvenile spongiotic gingivitis; how to recognise it, where it lies in a list of differential diagnoses and why conservative management is the authors' recommended treatment.Case series The authors present ten cases that were successfully managed conservatively on the Joint Oral Medicine Paediatric Dentistry Clinic at Guy's and St Thomas' NHS Foundation Trust over a six-year period. Follow-ups reached up to 5 years and 11 months to date, with no adverse outcomes observed in any of the cases.Conclusion The pathogenesis of this benign condition and its ideal management is not well understood. Recurrence can occur after surgical treatment and the condition is likely to spontaneously resolve or regress with age. Therefore, particularly in asymptomatic cases, conservative management is recommended.

In 2015, the Liquor Control Board of Ontario (LCBO) authorized sale of alcohol in some Ontario grocery stores. This research evaluates the impact of the new policy on alcohol use patterns of youth in a quasi-experimental setting with two control groups.The sample consists of 2267 grade 9 students attending 60 secondary schools across Ontario (n = 56) and Alberta (n = 4), who provided 4-year linked longitudinal data (2013-2014 to 2016-2017) in the COMPASS study. The study used the frequency of drinking and the frequency of binge drinking to characterize alcohol use behaviours.Latent transition analysis found four statuses of alcohol use: abstainer, periodic drinker, low-risk drinker, and high-risk regular drinker. The new policy had no negative impact among periodic and low-risk drinkers, but the risk of transitioning from the abstainer (lowest risk status) to high-risk regular drinker (highest risk status) among the exposed cohort was 1.71 times greater post-policy than pre-policy change, compared with those of Ontario-unexposed (0.50) and Alberta-unexposed cohorts (1.00). The probability of sustaining high-risk drinking among the exposed cohort increased by a factor of 1.76, compared with 1.13-fold and 0.89-fold among the Ontario-unexposed and Alberta-unexposed cohorts, respectively.Youth are more likely to transition from abstinence to high-risk regular drinking, and high-risk regular drinkers are more likely to maintain their behaviours in the jurisdictions exposed to the latest change in LCBO policy authorizing grocery stores to sell alcohol. When formulating policy interventions, youth access to alcohol should be considered in order to reduce their harmful alcohol consumption.RéSUMé: OBJECTIFS: Depuis 2015, la Régie des alcools de l’Ontario (LCBO) autorise la vente d’alcool dans certaines épiceries de la province. Nous évaluons ici l’incidence de la nouvelle politique sur les habitudes de consommation d’alcool des jeunes dans un milieu quasi-expérimental avec deux groupes témoins. MéTHODE: Notre échantillon est constitué de 2 267 élèves de 9

Background/Objectives Mortality studies in psoriatic arthritis (PsA) have provided inconsistent results. This study aimed to: 1) Estimate trends in mortality rates among PsA patients over calendar time; 2) Evaluate cause-specific mortality rates in patients with PsA compared to the general population; 3) Identify predictors for mortality in PsA. Methods The study was carried out at the University of Toronto Psoriatic Arthritis Clinic where patients are followed prospectively according to a standard protocol at 6- to 12- month intervals. Standardized mortality ratios (SMRs) were calculated overall, by age, and by sex with reference to the Ontario population. Causes of death were recorded by ICD9 and ICD10 codes and cause-specific SMRs were computed. Cox regression models were used to identify predictors for mortality among PsA patients. Results Among 1490 patients followed over 15062.8 patient-years, 225 (15%) confirmed deaths were recorded (111 females, 114 males). The overall SMR was 0.92 (95% CI: 0.81-1.05), the sex-specific SMRs were 1.08 (95% CI: 0.89-1.30) for females and 0.81 (95% CI: 0.66-0.97) for males. The age-specific SMRs were 3.36 (95% CI: 1.61-6.18), 0.97 (95% CI: 0.68-1.34), 0.88 (95% CI: 0.73-1.06) and 0.86 (95% CI: 0.66-1.11) for 20-39, 40-59, 60-79 and above 80 years of age, respectively. Major causes of death included malignant neoplasms (n=61; SMR=0.97, 95% CI: 0.72-1.28), acute myocardial infarction (n=32; SMR=1.11, 95% CI: 0.74-1.58), and pneumonia (n=14; SMR=2.46, 95% CI: 1.27-4.31). Factors found to be associated with increased mortality include elevated acute phase reactants, presence of comorbidities such as heart disease and cancer, and lower education level. Conclusion Young patients with PsA are at increased mortality risk. Better control of comorbidities may reduce this risk.

This is the peer reviewed version of the following invited article: Richard J. Cook and Jerald F. Lawless, Failure time studies with intermittent observation and losses to follow-up, Scandinavian Journal of Statistics (2020), 47(4): 1035–1063 which has been published in final form at https://doi.org/10.1111/sjos.12471.

Objective.To describe the pattern of musculoskeletal (MSK) symptoms and their correlation with clinical and sonographic findings among psoriasis patients with suspected psoriatic arthritis (PsA).Methods.Patients with psoriasis and no prior diagnosis of PsA were referred for assessment of their MSK complaints. The study included the following steps: (1) assessment by an advanced practice physiotherapist, (2) targeted MSK ultrasound, and (3) assessment by a rheumatologist. In addition, patients were asked to complete questionnaires about the nature and duration of their MSK symptoms and to mark the location of their painful joints on a homunculus. Each patient was classified by a rheumatologist as “Not PsA,” “Possible PsA,” or “PsA”. MSK symptoms and patient-reported outcomes (PRO) were compared between patients with PsA and Possible/Not PsA. Agreement between modalities was assessed using κ statistics.Results.Two hundred three patients with psoriasis and MK symptoms were enrolled (8.8% PsA, 23.6% Possible PsA). Patients classified as PsA had worse scores on the PsA Impact of Disease (P = 0.004) and Functional Assessment of Chronic Illness Therapy–Fatigue scale (P = 0.02). There was no difference between the 2 groups in the presence, distribution, and duration of MSK symptoms. Analysis of agreement in physical examination between modalities revealed the strongest agreement between the rheumatologist and physiotherapist (κ = 0.28). The lowest levels of agreement were found between ultrasound and patient (κ = 0.08) and physiotherapist and ultrasound (κ = 0.08).Conclusion.The results of this study suggest that the intensity, rather than the type, duration, or distribution of MSK symptoms, is associated with PsA among patients with psoriasis.

Summary We develop methods for assessing the predictive accuracy of a given event time model when the validation sample is comprised of case $K$ interval-censored data. An imputation-based, an inverse probability weighted (IPW), and an augmented inverse probability weighted (AIPW) estimator are developed and evaluated for the mean prediction error and the area under the receiver operating characteristic curve when the goal is to predict event status at a landmark time. The weights used for the IPW and AIPW estimators are obtained by fitting a multistate model which jointly considers the event process, the recurrent assessment process, and loss to follow-up. We empirically investigate the performance of the proposed methods and illustrate their application in the context of a motivating rheumatology study in which human leukocyte antigen markers are used to predict disease progression status in patients with psoriatic arthritis.

Interval-censored failure times arise when the status with respect to an event of interest is only determined at intermittent examination times. In settings where there exists a sub-population of individuals who are not susceptible to the event of interest, latent variable models accommodating a mixture of susceptible and nonsusceptible individuals are useful. We consider such models for the analysis of bivariate interval-censored failure time data with a model for bivariate binary susceptibility indicators and a copula model for correlated failure times given joint susceptibility. We develop likelihood, composite likelihood, and estimating function methods for model fitting and inference, and assess asymptotic-relative efficiency and finite sample performance. Extensions dealing with higher-dimensional responses and current status data are also described.

Cox regression models are routinely fitted to examine the association between time-dependent markers and a failure time when analyzing data from clinical registries. Typically, the marker values are measured periodically at clinic visits with the recorded value carried forward until the next assessment. We examine the asymptotic behavior of estimators from Cox regression models under this observation and data handling scheme when the true relationship is based on a Cox model using the current value of the marker. Specifically, we explore the impact of the marker process dynamics, the clinic visit intensity, and the marginal failure rate on the limiting value of the estimator of the marker effect from the Cox model. We also illustrate how a joint multistate model that accommodates intermittent observation of the time-varying marker can be formulated. Simulation studies demonstrate that the finite sample performance of the naive estimator aligns with the asymptotic results and shows good performance of the estimators from the joint model. We apply both methods to data from a study of bone markers and their effect on the development of skeletal complications in metastatic cancer.

Intra-articular corticosteroid (IAS) injections are often used for the immediate relief of pain and inflammation in the joint of psoriatic arthritis (PsA) patients. However, studies identifying factors that predict response to the IAS injections are lacking. We aimed to assess the usefulness of serine proteinase activity measurements in PsA synovial fluid (SF) samples obtained at the time of injection in predicting clinical response. The PsA patients with available SF samples from the knee joint were identified from the University of Toronto PsA cohort. Clinical response was defined as an absence of tenderness or swelling in the injected joint at the first post-injection visit, at either 3 or 6 months. SF proteinase activity was determined by measuring cleavage of fluorogenic tri-peptide substrates for trypsin-like (VPR-AMC and VLK-AMC) and chymotrypsin-like (AAPF-AMC) serine proteinases. Generalized estimating equation (GEE) models were used to investigate factors associated with response. A total of 32 patients with 60 injected joints and data available for follow-up at 3 or 6 months were included in the analysis, with 25 (41.7%) injected joints resulting in clinical response. Age, sex, active joint count, systemic medications and SF serine proteinase activity at the time of injection were included as covariates. Only treatment with biologics was significantly associated with response at 3 or 6 months in the multivariate reduced model (OR 3.02, p = 0.027). We could not demonstrate an association between SF serine proteinase activity and response to IAS injection. Biologic agents significantly improve the likelihood of achieving clinical response.

Grappling with the contemporary topos of a Sino-Russian Entente, Kazakhstan is caught between a delicate long-term peer-competition and potentially a structural rivalry involving the two Eurasian Leviathans, China and Russia. Acknowledging this perspective, Nur-Sultan is inducing hedging dynamics, fishing for a better range of net benefits, while playing a significant fulcrum role central to the regional geopolitical and geo-economic matrix. Although Russia is retaining the prevailing role in the security domain, China is catching up with Russia in various economic indices, notably generated by the Belt and Road Initiative. Utilizing the conceptualization of hierarchy in international relations adapted from the work of David A. Lake, this paper outlines how Nur-Sultan’s interests and preferences are acknowledged by the respective dominants, as a basis for social contracting processes to generate a dual hierarchical order in Central Asia.

We consider the setting in which a categorical exposure variable of interest can only be measured subject to misclassification via surrogate variables. These surrogate variables may represent the c...

When the upper half of one face (‘target region’) is spatially aligned with the lower half of another (‘distractor region’), the two halves appear to fuse together perceptually, changing observers’ subjective perception of the target region. This ‘composite face illusion’ is regarded as a key hallmark of holistic face processing. Importantly, distractor regions bias observers’ subjective perception of target regions in systematic, predictable ways. For example, male and female distractor regions make target regions appear masculine and feminine; young and old distractor regions make target regions appear younger and older. In the present study, we first describe a novel psychophysical paradigm that yields precise reliable estimates of these perceptual biases. Next, we use this novel procedure to establish a clear relationship between observers’ susceptibility to the age and gender biases induced by the composite face illusion. This relationship is seen in a lab-based sample (N = 100) and is replicated in an independent sample tested online (N = 121). Our findings suggest that age and gender variants of the composite illusion may be different measures of a common structural binding process, with an origin early in the face-processing stream. Electronic supplementary material The online version of this article (10.3758/s13423-019-01684-9) contains supplementary material, which is available to authorized users.

BackgroundOral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa. Currently there is no approved treatment for OLP. We report on the efficacy and safety of a novel mucoadhesive clobetasol patch (Rivelin®-CLO) for the treatment of OLP.MethodsPatients with confirmed OLP and measurable symptomatic ulcer(s) participated in a randomized, double-blind, placebo-controlled, multicenter clinical trial testing a novel mucoadhesive clobetasol patch (Rivelin®-CLO) in OLP across Europe, Canada, and the United States. Patients were randomized to placebo (nonmedicated), 1, 5, 20 µg Clobetasol/patch, twice daily, for 4 weeks. The primary endpoint was change in total ulcer area compared to baseline. Secondary endpoints included improvement from baseline in pain, disease activity, and quality of life.ResultsData were analyzed and expressed as mean [SD]. One hundred thirty-eight patients were included in the study; 99 females and 39 males, mean age was 61.1 [11.6] years. Statistical analyses revealed that treatment with 20-μg Rivelin®-CLO patches demonstrated significant improvement with ulcer area (p = 0.047), symptom severity (p = 0.001), disease activity (p = 0.022), pain (p = 0.012), and quality of life (p = 0.003) as compared with placebo. Improvement in OLP symptoms from beginning to the end of the study was reported as very much better (best rating) in the 20-µg group (25/32) patients compared to the placebo group (11/30), (p = 0.012). Adverse events were mild/moderate. Candidiasis incidence was low (2%).ConclusionsRivelin®-CLO patches were superior to placebo demonstrating statistically significant, clinically relevant efficacy in objective and subjective improvement and, with a favorable safety profile.

Studies of chronic disease often involve modeling the relationship between marker processes and disease onset or progression. The Cox regression model is perhaps the most common and convenient approach to analysis in this setting. In most cohort studies, however, biospecimens and biomarker values are only measured intermittently (e.g. at clinic visits) so Cox models often treat biomarker values as fixed at their most recently observed values, until they are updated at the next visit. We consider the implications of this convention on the limiting values of regression coefficient estimators when the marker values themselves impact the intensity for clinic visits. A joint multistate model is described for the marker-failure-visit process which can be fitted to mitigate this bias and an expectation-maximization algorithm is developed. An application to data from a registry of patients with psoriatic arthritis is given for illustration.