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Job stress has many negative effects on correctional staff. We proposed and tested a path model of transactional, procedural, and distributive justice’s direct and indirect effects on the job stress of 322 surveyed correctional staff, including 219 correctional officers, at a maximum security Southern prison. Findings indicated that procedural, distributive, and transactional justice affected job stress. Specifically, the proposed path model was supported, such that procedural justice had an indirect effect on job stress through distributive justice, and transactional and distributive justice had direct, negative effects on job stress. Transactional justice also had indirect effects on job stress through procedural and distributive justice. Taken together, the results suggest that organizational justice plays an important role in reducing correctional staff job stress.

Police organizations are tasked with a wide variety of duties, and officers often encounter stressful situations. Past studies have indicated that job stressors are negatively related to job involvement, which, in turn, is positively related to several beneficial outcomes. The present study empirically tested the job demands model with data obtained from a police agency in India. Survey data was collected from 827 police officers in the Indian state of Haryana. Analysis was carried out to determine the impact of job stressors (role overload, role underload, repetitiveness, role ambiguity, fear of victimization, and role conflict) on job involvement. Findings indicate that all stressors except fear of victimization had a negative effect on job involvement. The implications of the findings, for organizations in general and the police in particular, include the need to reduce workplace stressors and improve the work environment.

The 2011–12 Schools and Staffing Survey (SASS) was used to examine occupational stress, occupational commitment, and intention to remain in teaching in a nationally representative sample of U.S. kindergarten teachers (n = 744). Teachers who perceived classroom resources as sufficient to meet demands, tended to report they would become a teacher again (86.5%) and reported intentions to remain in the profession (87.6%). However, of teachers who perceived classroom resources as insufficient to meet classroom demands, only 50.2% reported they would become teachers again, and only 61.4% reported they intended to remain in the profession. Logistic regression was used to examine teacher responses to these items while controlling for school- and teacher-level covariates. Teachers perceiving sufficient resources were more likely to report they would become teachers again and intended to remain in teaching (odds ratios = 2.612, 1.863) while teachers perceiving insufficient resources were much less likely (odds ratios = 0.324, 0.327).

There is a growing body of research that has explored how workplace factors affect prison staff, although empirical research specifically aimed at how organizational justice affects correct...

Job stress is a problem in corrections. Although the very nature of correctional work is stressful, workplace variables also contribute to correctional staff job stress. The job demands-resource model holds that job demands increase negative outcomes (e.g., job stress) and decrease positive outcomes (e.g., job satisfaction), whereas job resources help increase positive outcomes and decrease negative outcomes. An ordinary least squares regression analysis of self-reported survey data from 322 staff at a Southern prison indicated that input into decision-making and quality supervision had statistically significant negative effects on job stress, whereas role overload and fear of victimization had significant positive effects. Instrumental communication, views of training, and role clarity all had nonsignificant associations with stress from the job in the multivariate analysis. The results partially supported the job demands-resources model; however, the specific work environment variables varied in terms of their statistical significance. Correctional administrators need to be aware of the contribution that workplace variables have on job stress and make changes to reduce staff job stress.

Research using the National Teacher and Principal Survey (NTPS) has consistently demonstrated that teachers' reported working conditions are related to both intentions to leave the profession and attrition (Tickle, Chang, and Kim, 2011). However, limited research evaluates teacher appraisals of job-related demands and resources as an antecedent to job dissatisfaction. We tested for differential item functioning (DIF) using a partial credit model approach within a Rasch modeling context to examine whether elementary and secondary teachers with similar overall stress levels respond to the NTPS Demands and Resources items in similar ways. For the Demands items, seven of the items displayed differences that were negligible, four were intermediate, and three items indicated large DIF contrasts. For the Resources items, 10 items displayed differences that were negligible, two were intermediate, and zero items indicated large DIF contrasts. These results indicate elementary and secondary teachers exhibit different appraisal patterns, suggesting implications for the development and use of survey data in public school settings in general, and for the use of the NTPS data in particular.

Objective Perception of touch is expected at the location where it is applied. However, there are indications that being touched may be perceived on the contralateral side when seen as a reflection in a mirror at midline. Such inter-lateral referral of sensation (RS) lacks evidence, as mirror therapy research usually focusses on movement-based techniques. This study aimed to map out existing research across disciplines regarding the effect of RS in health and disease, and to understand whether there is rehabilitation potential in RS. Method A scoping review was conducted to map out concepts and keywords across disciplines interested in this topic, using keywords in several languages, and a wide range of databases and additional sources. Results The review revealed mostly cross-sectional experiments and included over 486 participants: healthy, or with stroke, complex regional pain syndrome, amputation, nerve graft surgery or radial fracture. Procedures varied regarding stimulation tool, time and location, with two stimulating replacements, one the face and one a variety of areas. Response rates ranged from 0 to 100%. In general, RS was regarded as a phenomenon or even as a predictor of maladaptive neuroplasticity. There was little research into using RS stimulation as a modulatory tool to improve sensory perception. Conclusions RS challenges the understanding of touch perception and elicits a range of questions regarding neuro-processing. A modulatory approach using RS has not been described, requires investigation and, if promising, development as an intervention.

Background Incomplete suicidality coding in administrative claims data is a known obstacle for observational studies. With most of the negative outcomes missing from the data, it is challenging to assess the evidence on treatment strategies for the prevention of self-harm in bipolar disorder (BD), including pharmacotherapy and psychotherapy. There are conflicting data from studies on the drug-dependent risk of self-harm, and there is major uncertainty regarding the preventive effect of monotherapy and drug combinations. Objective The aim of this study was to compare all commonly used BD pharmacotherapies, as well as psychotherapy for the risk of self-harm, in a large population of commercially insured individuals, using self-harm imputation to overcome the known limitations of this outcome being underrecorded within US electronic health care records. Methods The IBM MarketScan administrative claims database was used to compare self-harm risk in patients with BD following 65 drug regimens and drug-free periods. Probable but uncoded self-harm events were imputed via machine learning, with different probability thresholds examined in a sensitivity analysis. Comparators included lithium, mood-stabilizing anticonvulsants (MSAs), second-generation antipsychotics (SGAs), first-generation antipsychotics (FGAs), and five classes of antidepressants. Cox regression models with time-varying covariates were built for individual treatment regimens and for any pharmacotherapy with or without psychosocial interventions (“psychotherapy”). Results Among 529,359 patients, 1.66% (n=8813 events) had imputed and/or coded self-harm following the exposure of interest. A higher self-harm risk was observed during adolescence. After multiple testing adjustment (P≤.012), the following six regimens had higher risk of self-harm than lithium: tri/tetracyclic antidepressants + SGA, FGA + MSA, FGA, serotonin-norepinephrine reuptake inhibitor (SNRI) + SGA, lithium + MSA, and lithium + SGA (hazard ratios [HRs] 1.44-2.29), and the following nine had lower risk: lamotrigine, valproate, risperidone, aripiprazole, SNRI, selective serotonin reuptake inhibitor (SSRI), “no drug,” bupropion, and bupropion + SSRI (HRs 0.28-0.74). Psychotherapy alone (without medication) had a lower self-harm risk than no treatment (HR 0.56, 95% CI 0.52-0.60; P=8.76×10-58). The sensitivity analysis showed that the direction of drug-outcome associations did not change as a function of the self-harm probability threshold. Conclusions Our data support evidence on the effectiveness of antidepressants, MSAs, and psychotherapy for self-harm prevention in BD. Trial Registration ClinicalTrials.gov NCT02893371; https://clinicaltrials.gov/ct2/show/NCT02893371

Transactions of the London and Middlesex Archaeological Society, 1.6, 123-189

In recent years, G protein vs. &beta, arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of &micro, opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe-pCF3-Phe-Asp]NH2 (F-81), and the &beta, arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35S]GTP&gamma, S binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure &beta, arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand&ndash, receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or &beta, arrestin.

Transactions of the London and Middlesex Archaeological Society, 1.6, 74-84

No corner of the world is completely safe from terrorist attacks. Both India and the United States have suffered horrific acts of terrorist-inspired violence. While views of terrorism vary for different reasons, culture certainly plays a role. A total of 918 undergraduate college students, composed of 434 Indian students and 484 U.S. students, were surveyed on their views of terrorism, responses to terrorism, and appropriate punishment of terrorists. Ordered ordinal regression results indicated a significant difference on 20 of the 26 items by nationality. Indian participants were more likely to express strong views on the problem of terrorism for society and to see terrorists as more similar to common criminals than their U.S. counterparts. Indian students were also more likely to feel that the government should do whatever was necessary to win against terrorists, while U.S. students were more likely to view winning against terrorists as difficult. Further, Indian respondents were more likely to feel that terrorists needed to be punished harshly and the death penalty would deter them, while U.S. respondents more likely to feel convicted terrorists should be able to appeal their sentences. The results suggest that culture plays a role in shaping terrorism views.

BackgroundThe web-based Spondyloarthritis Research Consortium of Canada (SPARCC) real-time iterative calibration (RETIC) modules for scoring MRI lesions in axial spondyloarthritis (axSpA) have been created by SPARCC developers to enable remote training of readers to appropriately use the SPARCC MRI inflammation and structural damage instruments and to attain adequate scoring proficiency.ObjectivesWe aimed to test the performance of these modules in enhancing scoring proficiency in comparison to SPARCC developers.MethodsThe SPARCCRETIC SIJ inflammation and structural damage modules are each comprised of 50 DICOM axSpA cases with baseline and follow up scans and an online scoring interface based on SIJ quadrants. Continuous visual real-time feedback regarding concordance/discordance of scoring per SIJ quadrant with expert readers is provided by a color-coding scheme. Reliability is assessed in real-time by intra-class correlation coefficient (ICC), ICC data being provided every 10 cases, which are scored until proficiency targets for ICC are attained. In the present exercise, participants (n=15) from the EuroSpA Imaging project were randomized, stratified by reader expertise in scoring with SPARCC, to one of two reader training strategies (groups A and B) that each comprised 3 stages (25 patients per stage, 2 timepoints, blinded to chronology; independent assessment of Inflammatory and structural lesions): Group A. 1. Review of original SPARCC manuscript describing scoring method. 2. Review of PowerPoint summary of SPARCC method plus completion of SPARCCRETIC module. 3. Re-review of PowerPoint summary. Group B. Same 3-step strategy as A except SPARCCRETIC module completed at stage 3. The reliability of scoring was compared to an expert radiologist (SPARCC developer).ResultsVery good scoring proficiency for status and change scores was evident for SPARCC BME even by non-experienced readers with similar levels of reliability irrespective of prior expertise. The beneficial impact of the SPARCCRETIC module on scoring proficiency was most consistently evident for the scoring of structural lesions and for Strategy B, where the impact was evident for all structural lesions, level of reader expertise, and status as well as change scores (Table 1). Scoring proficiency improved the most for the least experienced readers (Figure 1).Table 1.Inter-rater reliability (Status/Change ICC) compared to radiologist SPARCC developerMRI LesionReader expertiseStrategy AStrategy BStage 1 cases (n=25)Stage 2 cases (n=25)Stage 3 cases (n=25)Stage 1 cases (n=25)Stage 2 cases (n=25)Stage 3 cases (n=25)BMENone (n=4)0.91 / 0.940.83/0.820.77/0.780.82/0.880.65/0.820.88/0.90Intermediate (n=6)0.88/0.880.90/0.900.85/0.900.93/0.940.78/0.800.83/0.80Experienced (n=5)0.92/0.940.90/0.880.92/0.930.83/0.880.84/0.900.89/0.89ANKYLOSISNone (n=4)0.86/0.660.83/0.280.86/0.780.66/0.410.69/0.340.88/0.80Intermediate (n=6)0.89/0.570.83/0.370.92/0.810.82/0.680.74/0.470.93/0.84Experienced (n=5)0.96/0.760.93/0.640.94/0.860.97/0.240.83/0.410.91/0.79BACKFILLNone (n=4)-0.08/-0.050.38/0.220.59/0.380.64/0.130.05/-0.090.47/0.27Intermediate (n=6)0.41/0.130.44/0.420.69/0.390.50/0.220.30/0.300.70/0.42Experienced (n=5)0.82/0.380.55/0.400.91/0.640.65/0.240.21/0.260.71/0.30EROSIONNone (n=4)0.13/-0.080.67/0.420.51/0.330.34/0.330.23/0.080.38/0.37Intermediate (n=6)0.42/0.180.56/0.120.51/0.440.33/0.270.45/0.180.53/0.39Experienced (n=5)0.61/0.330.64/0.340.64/0.420.51/0.270.58/0.110.62/0.31FAT METAPLASIANone (n=4)0.62/0.540.30/0.170.57/0.290.43/0.530.38/0.070.83/0.63Intermediate (n=6)0.49/0.380.59/0.300.79/0.510.57/0.780.50/0.420.81/0.47Experienced (n=5)0.75/0.620.81/0.340.91/0.700.84/0.900.56/0.130.78/0.37ConclusionAttaining scoring proficiency for MRI structural lesions in axSpA is difficult but can be consistently improved by using the SPARCCRETIC module, even for experienced readers.Figure 1.Disclosure of InterestsWalter P Maksymowych Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer Ingelheim, Celgene, Eli-Lilly, Galapagos, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Novartis, Pfizer, UCB, Anna Enevold Fløistrup Hadsbjerg Grant/research support from: Novartis, Mikkel Østergaard Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Gilead, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, UCB, Grant/research support from: AbbVie, BMS, Merck, Celgene, Novartis, Raphael Micheroli: None declared, Susanne Juhl Pedersen Grant/research support from: Novartis, Adrian Ciurea: None declared, Nora Vladimirova Grant/research support from: Novartis, Michael J Nissen Speakers bureau: Eli-Lilly, Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli-Lilly, Janssen, Novartis, Pfizer, Kristyna Bubova: None declared, Stephanie Wichuk: None declared, Manouk de Hooge: None declared, Ashish Jacob Mathew Grant/research support from: Novartis, Karlo Pintaric: None declared, Monika Gregová: None declared, Ziga Snoj: None declared, Marie Wetterslev: None declared, Karel Gorican: None declared, Joel Paschke: None declared, Iris Eshed: None declared, Robert G Lambert Paid instructor for: Novartis

BackgroundIxekizumab (IXE) has demonstrated clinical efficacy in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) together with significant repair of structural lesions in the sacroiliac joint (SIJ) on MRI. There is, however, a paucity of data as to which patients may be most responsive.ObjectivesWe aimed to evaluate whether patients’ gender, HLA-B27 status, and presence of MRI inflammation impacted the effect of treatment with IXE versus placebo (PBO) on MRI structural lesions in the SIJ in patients with nr-axSpA.MethodsPatients with active nr-axSpA, biologic-naïve (COAST-X, NCT02757352) were randomized 1:1:1 to ixekizumab 80 mg every 4 (Q4W) or 2 weeks (Q2W) or PBO. Structural lesions on SIJ MRI were assessed by the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ structural score (SSS). Treatment comparisons used analysis of covariance based on observed cases. SPARCC SSS subgroup analyses were performed according to baseline gender, HLA-B27 status, and SPARCC MRI SIJ bone marrow oedema (BME) ResultsOf 303 randomized patients, 266 patients (Q4W: n=85, Q2W: n=91, PBO: n=90) had an MRI scan at baseline and week 16. At baseline, SPARCC scores were consistently higher in males, and mostly higher in HLA-B27 and BME≥4 positive subgroups. Significant differences between patients treated with IXE versus PBO were observed for male patients, HLA-B27 positives, and those with baseline SPARCC BME ≥4. Numerically similar changes were observed in female patients, patients with negative HLA-B27, and patients with SPARCC BMEConclusionEffects of IXE on structural repair are most evident in males, HLA-B27 positives, and patients with definite MRI inflammation at baseline.Table 1.MRI SIJ Structural Lesion Outcomes.LesionAnalysisPBOIXE Q4WIXE Q2WMale (n=39)Female (n=51)Male (n=44)Female (n=41)Male (n=43)Female (n=48)ErosionBL mean5·1671·9803·5452·8173·5232·594LS mean CFB (SE)0·51 (0·20)-0·11 (0·17)-0·63 (0·18)-0·11 (0·19)-0·51 (0·18)-0·32 (0·17)P value vs PBONANApp>0·99pp=0·37FatBL mean2·0510·9122·0911·2931·4650·677LS mean CFB (SE)-0·02 (0·09)-0·03 (0·08)0·29 (0·08)0·03 (0·08)0·21 (0·08)0·04 (0·08)P value vs PBONANAp=0·01p=0·65p=0·062p=0·51BackfillBL mean1·1540·1670·6630·4150·7910·323LS mean CFB (SE)-0·20 (0·13)0·01 (0·11)0·39 (0·12)0·01 (0·12)0·34 (0·12)0·14 (0·11)P value vs PBONANApp>0·99p=0·002p=0·38LesionAnalysisHLA-B27+HLA-B27-HLA-B27+HLA-B27-HLA-B27+HLA-B27-(n=64)(n=25)(n=61)(n=23)(n=65)(n=26)ErosionBL mean3·8202·1003·4672·5433·5151·827LS mean CFB (SE)0·27 (0·15)-0·10 (0·24)-0·49 (0·15)-0·01 (0·25)-0·50 (0·15)-0·17 (0·24)P value vs PBONANApp=0·79pp=0·84FatBL mean1·5781·0201·3282·7831·2850·462LS mean CFB (SE)-0·06 (0·06)-0·06 (0·10)0·22 (0·06)0·01 (0·10)0·13 (0·06)0·10 (0·10)P value vs PBONANAp=0·002p=0·65p=0·027p=0·25BackfillBL mean0·7420·2400·5420·5650·7620LS mean CFB (SE)-0·12 (0·10)0·01 (0·16)0·28 (0·10)0 (0·17)0·27 (0·10)0·16 (0·16)P value vs PBONANAp=0·005p=0·96p=0·005p=0·52LesionAnalysisBME ≥4BME BME ≥4BME BME ≥4BME (n=40)(n=50)(n=27)(n=58)(n=38)(n=53)ErosionBL mean4·8632·1605·3522·1905·2761·425LS mean CFB (SE)0·42 (0·19)-0·06 (0·17)-0·70 (0·23)-0·23 (0·16)-0·71 (0·20)-0·19 (0·17)P value vs PBONANApp=0·47pp=0·57FatBL mean0·7751·9101·9261·6031·6710·604LS mean CFB (SE)-0·02 (0·08)-0·02 (0·07)0·54 (0·10)-0·01 (0·07)0·28 (0·08)0·01 (0·07)P value vs PBONANApp=0·90p=0·013p=0·74BackfillBL mean0·7500·4701·0190·3280·7630·387LS mean CFB (SE)-0·21 (0·12)0·01 (0·11)0·41 (0·15)0·11 (0·10)0·49 (0·13)0·05 (0·11)P value vs PBONANAp=0·002p=0·52pp=0·80CFB=change from BL. BL=baseline, LS=least squares.AcknowledgementsStudy was sponsored by Eli Lilly and CompanyDisclosure of InterestsWalter P Maksymowych Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB and is Chief Medical Officer of CARE Arthritis Ltd, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Xenofon Baraliakos Grant/research support from: Abbvie, Amgen, BMS, Chugai, Galapagos, Gilead, Eli Lilly and Company, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB, Robert G Lambert Consultant of: CARE Arthritis, Image Analysis Group, Parexel, and Pfizer, Robert B.M. Landewé Consultant of: AbbVie, Astra-Zeneca, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Gilead, Galapagos, Glaxo-Smith-Kline, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB; and is director of Imaging Rheumatology BV, which is a registered company under Dutch Law, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hilde Carlier Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jeffrey Lisse Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Maja Hojnik Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Mikkel Østergaard Speakers bureau: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly and Company, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly and Company, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Grant/research support from: AbbVie, BMS, Merck, Celgene, and Novartis

BackgroundThe lack of pediatric classification criteria for axial disease is a major impediment to the conduct of clinical trials for juvenile spondyloarthritis (JSpA).ObjectivesWe aimed to develop classification criteria for axial JSpA that will enable identification of a more homogeneous group representative of children with SpA and axial disease for entry into observational or clinical trials. These criteria are not intended to capture all possible subjects, but instead most patients with shared key features of axial disease. Treatment and diagnostic decisions should adhere to evidence-based recommendations.Methods304 cases with JSpA and suspected axial disease from 6 international centers were collected on a standardized case report form; all had an MRI that was reviewed by an independent team of experts in musculoskeletal imaging. Candidate criteria were developed in an earlier phase of the project through an iterative process that included an international Delphi exercise for item generation, systematic literature review, and an item reduction exercise. Using the preliminary candidate criteria, 14 international clinical SpA experts scored and rank-ordered 20 representative SpA cases. During four, 3-hour virtual meetings, the clinical expert panel reviewed the interrater reliability of case ranking, refined the criteria definitions and domain levels, and participated in a multi-criterion decision consensus methodology exercise to generate relative weights of the criteria. The expert panel assessed whether the criteria weighting was in accordance with their consensus clinical judgment as a test of face validation of the weighting/scoring system and revisions were made as necessary. Next, 30 cases from the derivation cohort were scored and ranked using the relative weights for each category and domain. Each expert independently determined the score or “threshold” below which they were no longer confident enough that a patient had axial disease to enroll the child in a Phase 3 randomized clinical trial of a drug with unclear efficacy and safety. Results of this exercise were discussed and a provisional threshold score for classification was achieved by consensus.ResultsThe preliminary axial disease criteria for JSpA included the PRINTO provisional criteria for enthesitis/spondylitis-related JIA or a rheumatologist diagnosis of SpA as obligatory entry criteria as well as additive weighted criteria for 7 domains (SIJ active inflammation on imaging, SIJ structural lesions on imaging, pain chronicity, pain pattern, pain location, morning stiffness, and genetics) (Figure 1). Interrater reliability of the pre-consensus meeting case rankings was poor (Kendall’s correlation coefficient was 0.20 for clinical data-only and 0.23 for clinical plus imaging data). The multi-criterion decision analysis was repeated for the imaging domains when the initial criteria weighting was not in accordance with the expert panel’s opinion. The multi-criterion decision analysis involved a total of 58 pairwise decisions agreed by expert consensus. After criteria weights and additive scores were re-calculated, experts reached consensus for axial disease in JSpA for all cases scoring 55 and greater.Figure 1.Axial juvenile spondyloarthritis (AxJSpA) classification criteria domains and levels. The first ring represents the domains and the items branching out are the levels moving from highest level (closest to center) to lowest level (farthest from center) in each domain. Assigned weights are shown below each item description.ConclusionUsing an iterative process, the JSpA axial disease criteria definitions were refined, preliminary weights were generated, and a provisional threshold score for classification was determined. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was necessary, but not sufficient without any clinical criterion, to surpass the axial disease classification threshold.Disclosure of InterestsPamela F. Weiss Consultant of: PfizerNovartisBiogenLilly(All < $5K in the past fiscal year), Timothy G. Brandon: None declared, Amita Aggarwal: None declared, Ruben Burgos-Vargas Speakers bureau: not in the last three yearsNovartis, Consultant of: Not in the last four yearsBMS, Lilly, Novartis, Robert A. Colbert: None declared, Gerd Horneff Speakers bureau: Pfizer, Novartis, Janssen, Chugai, Abbvie, Grant/research support from: Pfizer, Novartis, MSD, Chugai, Roche, Abbvie, Rik Joos Speakers bureau: Galapagos, Pfizer, AbbVie, Novartis, Amgen, BMS, Lilly, Grant/research support from: Pfizer, AbbVie, Roche, Ronald Laxer Consultant of: Abbvie, Novartis, Sobi, Sanofi, Eli Lilly Canada, Eli Lilly, Kirsten Minden Speakers bureau: Pfizer, Novartis, Consultant of: Pfizer, Novartis, Angelo Ravelli Speakers bureau: Abbvie, Novartis, SOBI, Angelini, Reckitt-Benkiser, Roche, Pfizer, Alexion, Grant/research support from: Novartis, Pfizer, Nicolino Ruperto Speakers bureau: NR has received honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers and Squibb, Celgene, inMed, Cambridge Healthcare Research, Domain Therapeutic, EMD Serono, Glaxo Smith Kline, Idorsia, Janssen, Eli Lilly, Novartis, Pfizer, Sobi, UCB., Consultant of: NR has received honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers and Squibb, Celgene, inMed, Cambridge Healthcare Research, Domain Therapeutic, EMD Serono, Glaxo Smith Kline, Idorsia, Janssen, Eli Lilly, Novartis, Pfizer, Sobi, UCB., Grant/research support from: The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions from the following industries in the last 3 years: Bristol Myers and Squibb, Eli-Lilly, F Hoffmann-La Roche, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Judith Smith Consultant of: Consulting panel of pediatric rheumatologists identifying issues in juvenile spondyloarthritis for Novartis. Paid < $5000, Matthew L. Stoll Consultant of: Currently consulting for Novartis, Shirley ML Tse: None declared, Filip van den Bosch Speakers bureau: Abbvie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB, Paid instructor for: Amgen, Eli Lilly, Consultant of: Abbvie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB, Walter P Maksymowych Speakers bureau: Abbvie, Eli-Lilly, Janssen, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB Pharma, Grant/research support from: Abbvie, Novartis, Pfizer, Robert G Lambert Paid instructor for: Novartis, Consultant of: CARE Arthritis, Calyx, Image Analysis Group, Novartis, David M. Biko Employee of: Employee of Merck from 1998 to 2000, Nancy A. Chauvin Employee of: Forest Pharmaceuticals - Research scientist (1996) and Novartis - Pharmaceutical sales representative (1997), Michael L. Francavilla: None declared, Jacob L Jaremko: None declared, Nele Herregods: None declared, Ozgur Kasapcopur Speakers bureau: Pfizer, Abbvie, Novartis and Roche, Mehmet YILDIZ: None declared, Alison M. Hendry: None declared

BackgroundMagnetic resonance tomography (MRI) plays a key role in the early diagnosis of axial spondyloarthritis (axSpA). However, the detection of changes indicative of axSpA requires specific expertise, which poses a challenge to non-specialized centers. Deep learning (an advanced machine learning method) based on training an artificial neural network may facilitate and support diagnostics in clinical practice.ObjectivesTo create a reliable deep learning tool for the detection of active inflammatory and structural changes indicative of axSpA on MRI of sacroiliac joints.MethodsIn this study, MRIs of sacroiliac joints from 477 patients from four cohorts (GESPIC-AS, GESPIC-Crohn, GESPIC-Uveitis and OptiRef comprising 266 patients with and 211 without axSpA) were used to develop a deep learning framework (randomly divided into training, n=404, and validation, n=73, datasets). MRIs from the ASAS cohort (n=116) were used for independent testing (test dataset). Each examination in the training/validation dataset was evaluated for the presence of active inflammatory and structural changes indicative of SpA by six experienced, trained and calibrated readers and by seven expert readers in the test dataset. The presence of the changes was defined as the majority vote amongst readers. Discordant cases in the training/validation dataset underwent consensus reading. In addition, the test dataset was evaluated by three radiologists not specifically trained in SpA. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity.ResultsThe prevalence of positive imaging findings for active inflammatory/structural changes indicative of axSpA was 41%/51% in the training/validation dataset and 22%/22% in the test dataset. The model for the detection of active inflammatory changes showed an AUC of 0.91 (0.83 – 0.97) – Figure 1 – and an accuracy of 84% on the validation dataset; the corresponding sensitivity and specificity were 96% and 76%, respectively. Despite a substantially lower prevalence of active inflammatory changes in the test dataset, the model showed good generalization with an AUC of 0.91 (0.84−0.97) and an accuracy of 75%; the sensitivity and specificity were 88% and 71%, respectively. The model demonstrated a similar performance on the validation and test datasets for the detection of active inflammatory changes fulfilling the ASAS definition. The model for the detection of structural changes indicative of axSpA showed good performance on the validation dataset with an AUC of 0.90 (0.82-0.96) for the detection of structural changes and an overall accuracy of 85%. The associated sensitivity and specificity were 95% and 75%, respectively. The model showed reasonable generalization to new data with an AUC of 0.89 (0.81−0.96) and an accuracy of 79%; the sensitivity and specificity were 85% and 78%, respectively. Overall, the model performed close to the individual human experts - Figure 1.ConclusionThe developed framework allowed the detection of active inflammatory and structural changes indicative of axSpA on MRI. This approach may be used as an assistant tool in the diagnostic workflow.AcknowledgementsGESPIC-AS has been financially supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung - BMBF). GESPIC-Crohn has been supported by the Clinical Research Unit grant from the Berlin Institute of Health (BIH). GESPIC-Uveitis has been supported by a research grant from AbbVie. OptiRef has been supported by a research grant from Novartis. The Assessment of Spondyloarthritis International Society (ASAS) has supported the project with a research grant and provided access to the MRI images of the ASAS calssifiaction cohort.We want to thank colleagues who performed annotation of the images from the ASAS classification cohort: Pedro Machado, Mikkel Ostergaard, Suzanne Juhl Pedersen, Ulrich Weber. Further, we thank Torsten Karge for the development of the MRI reading interface for GESPIC and OptiRef images, Joel Paschke for development of the scoring interface for ASAS images.LCA is grateful for her participation in the BIH Charité–Junior Clinician and Clinician Scientist Program and KKB is grateful for his participation in the BIH Charité Digital Clinician Scientist Program all funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. JR is grateful for her participation in the BIH Charité–Junior Clinician and Clinician Scientist Program.Disclosure of InterestsNone declared

Plasmodium falciparum (Pf) malaria is among the leading causes of childhood morbidity and mortality worldwide. During a natural infection, ingestion of the malarial parasite product, hemozoin (PfHz), by circulating phagocytic cells induces dysregulation in innate immunity and enhances malaria pathogenesis. Treatment of cultured peripheral blood mononuclear cells (PBMCs) from healthy, malaria-naïve donors with physiological concentrations of PfHz can serve as an in vitro model to investigate cellular processes. Although disruptions in host ubiquitination processes are central to the pathogenesis of many diseases, this system remains unexplored in malaria. As such, we investigated the impact of PfHz on the temporal expression patterns of 84 genes involved in ubiquitination processes. Donor PBMCs were cultured in the absence or presence of PfHz for 3-, 9-, and 24 h. Stimulation with PfHz for 3 h did not significantly alter gene expression. Incubation for 9 h, however, elicited significant changes for 6 genes: 4 were down-regulated (FBXO4, NEDD8, UBE2E3, and UBE2W) and 2 were up-regulated (HERC5 and UBE2J1). PfHz treatment for 24 h significantly altered expression for 14 genes: 12 were down-regulated (ANAPC11, BRCC3, CUL4B, FBXO4, MIB1, SKP2, TP53, UBA2, UBA3, UBE2G1, UBE2G2, and WWP1), while 2 were up-regulated (UBE2J1 and UBE2Z). Collectively, these results demonstrate that phagocytosis of PfHz by PBMCs elicits temporal changes in the transcriptional profiles of genes central to host ubiquitination processes. Results presented here suggest that disruptions in ubiquitination may be a previously undiscovered feature of malaria pathogenesis., Highlights • Phagocytosis of PfHz by PBMCs a viable in vitro model for severe malaria. • Altered mRNA expression of ubiquitination process genes seen in PfHz-treated PBMCs. • Gene expression in PfHz-stimulated PBMCs observed at 9 and 24 h post incubation. • 6 and 14 ubiquitination genes differentially expressed at 9 and 24 h, respectively. • Disrupted ubiquitination process, a pathophysiological mechanism for severe malaria.

The LocalControl R package implements novel approaches to address biases and confounding when comparing treatments or exposures in observational studies of outcomes. While designed and appropriate for use in comparative safety and effectiveness research involving medicine and the life sciences, the package can be used in other situations involving outcomes with multiple confounders. LocalControl is an open-source tool for researchers whose aim is to generate high quality evidence using observational data. The package implements a family of methods for non-parametric bias correction when comparing treatments in observational studies, including survival analysis settings, where competing risks and/or censoring may be present. The approach extends to bias-corrected personalized predictions of treatment outcome differences, and analysis of heterogeneity of treatment effect-sizes across patient subgroups.

Genetically encoded probes with red-shifted absorption and fluorescence are highly desirable for imaging applications because they can report from deeper tissue layers with lower background and because they provide additional colors for multicolor imaging. Unfortunately, red and especially far-red fluorescent proteins have very low quantum yields, which undermines their other advantages. Elucidating the mechanism of nonradiative relaxation in red fluorescent proteins (RFPs) could help developing ones with higher quantum yields. Here we consider two possible mechanisms of fast nonradiative relaxation of electronic excitation in RFPs. The first, known as the energy gap law, predicts a steep exponential drop of fluorescence quantum yield with a systematic red shift of fluorescence frequency. In this case the relaxation of excitation occurs in the chromophore without any significant changes of its geometry. The second mechanism is related to a twisted intramolecular charge transfer in the excited state, followed by an ultrafast internal conversion. The chromophore twisting can strongly depend on the local electric field because the field can affect the activation energy. We present a spectroscopic method of evaluating local electric fields experienced by the chromophore in the protein environment. The method is based on linear and two-photon absorption spectroscopy, as well as on quantum-mechanically calculated parameters of the isolated chromophore. Using this method, which is substantiated by our molecular dynamics simulations, we obtain the components of electric field in the chromophore plane for seven different RFPs with the same chromophore structure. We find that in five of these RFPs, the nonradiative relaxation rate increases with the strength of the field along the chromophore axis directed from the center of imidazolinone ring to the center of phenolate ring. Furthermore, this rate depends on the corresponding electrostatic energy change (calculated from the known fields and charge displacements), in quantitative agreement with the Marcus theory of charge transfer. This result supports the dominant role of the twisted intramolecular charge transfer mechanism over the energy gap law for most of the studied RFPs. It provides important guidelines of how to shift the absorption wavelength of an RFP to the red, while keeping its brightness reasonably high.

Genome wide association studies (GWAS) can reveal important genotype–phenotype associations, however, data quality and interpretability issues must be addressed. For drug discovery scientists seeking to prioritize targets based on the available evidence, these issues go beyond the single study. Here, we describe rational ranking, filtering and interpretation of inferred gene–trait associations and data aggregation across studies by leveraging existing curation and harmonization efforts. Each gene–trait association is evaluated for confidence, with scores derived solely from aggregated statistics, linking a protein-coding gene and phenotype. We propose a method for assessing confidence in gene–trait associations from evidence aggregated across studies, including a bibliometric assessment of scientific consensus based on the iCite Relative Citation Ratio, and meanRank scores, to aggregate multivariate evidence. This method, intended for drug target hypothesis generation, scoring and ranking, has been implemented as an analytical pipeline, available as open source, with public datasets of results, and a web application designed for usability by drug discovery scientists, at https://unmtid-shinyapps.net/tiga/.

Working as a correctional office is a unique occupation. Correctional officers are responsible for the care, custody, and control of the inmate population. The major goals of correctional officers are protecting the community by ensuring inmates remain incarcerated, to ensure the smooth and effective operation of the facility, to ensure a humane environment, and to assist inmates in developing a positive and productive lifestyle so they will successfully return to the community as law-abiding members. Officers face many challenges, including maintaining order, ensuring compliance by inmates, dealing with work strains and dangers, effectively dealing with job stress, and creating a better, healthier, and more positive work environment. While there are many challenges faced by the job, there are many positive aspects to being a correctional officer, including protecting the community and assisting inmates.

Purpose To report the case of a ten-year old girl with torpedo maculopathy with a complete vitelliform lesion and describe associated optical coherence tomography (OCT), OCT angiography (OCTA), multifocal electroretinogram (ERG) and adaptive optics ophthalmoscopy (AOO) imaging of the lesion. Observations An asymptomatic ten-year old girl with visual acuity of 20/15 OU was referred for evaluation of possible Best's disease of her left eye. The unilaterality, location, and shape of the lesion was consistent with torpedo maculopathy. OCT and autofluorescence (AF) revealed that the entire lesion was composed of subretinal hyperreflective material that was hyperautofluorescent, consistent with vitelliform material. Within the boundary of the lesion, OCTA showed reduced choriocapillaris density while adjacent to the lesion, the choriocapillaris density was slightly increased. Microperimetry demonstrated normal sensitivity in both eyes, electrooculograms (EOG) were normal and multifocal ERG showed symmetrical mildly supernormal amplitudes. Additionally, AOO demonstrated that nasal to the lesion there were clusters of hyper-reflective areas, and immediately adjacent to the lesion cones were poorly resolved. However, there was a return to more normal photoreceptor architecture outside of the lesion. Conclusions and Importance Torpedo maculopathy lesions typically present with outer retinal attenuation and retinal pigmented epithelium (RPE) atrophy. Vitelliform material was recently observed for the first time in association with Torpedo maculopathy in a case report that described small vitelliform material at the periphery of the lesion. We report the second case of torpedo maculopathy associated with a vitelliform lesion and the first description of a torpedo lesion composed fully of presumed vitelliform material. We also describe findings of OCTA, multifocal ERG and AOO imaging in torpedo maculopathy with vitelliform lesion.

Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I² value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Selfcontrolled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment.

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

Alendronate and raloxifene are among the most popular anti-osteoporosis medications. However, there is a lack of head-to-head comparative effectiveness studies comparing the two treatments. We conducted a retrospective large-scale multicenter study encompassing over 300 million patients across nine databases encoded in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The primary outcome was the incidence of osteoporotic hip fracture, while secondary outcomes were vertebral fracture, atypical femoral fracture (AFF), osteonecrosis of the jaw (ONJ), and esophageal cancer. We used propensity score trimming and stratification based on an expansive propensity score model with all pre-treatment patient characteritistcs. We accounted for unmeasured confounding using negative control outcomes to estimate and adjust for residual systematic bias in each data source. We identified 283,586 alendronate patients and 40,463 raloxifene patients. There were 7.48 hip fracture, 8.18 vertebral fracture, 1.14 AFF, 0.21 esophageal cancer and 0.09 ONJ events per 1,000 person-years in the alendronate cohort and 6.62, 7.36, 0.69, 0.22 and 0.06 events per 1,000 person-years, respectively, in the raloxifene cohort. Alendronate and raloxifene have a similar hip fracture risk (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.94–1.13), but alendronate users are more likely to have vertebral fractures (HR 1.07, 95% CI 1.01–1.14). Alendronate has higher risk for AFF (HR 1.51, 95% CI 1.23–1.84) but similar risk for esophageal cancer (HR 0.95, 95% CI 0.53–1.70), and ONJ (HR 1.62, 95% CI 0.78–3.34). We demonstrated substantial control of measured confounding by propensity score adjustment, and minimal residual systematic bias through negative control experiments, lending credibility to our effect estimates. Raloxifene is as effective as alendronate and may remain an option in the prevention of osteoporotic fracture.

PURPOSE Stickler syndrome is associated with open-angle glaucoma, but no reports exist of adults presenting with acute angle closure. Here, we report the clinical associations and short-term outcomes in 2 patients with Stickler syndrome who presented with acute angle closure at a single tertiary referral center. OBSERVATIONS A 36-year-old female with Stickler syndrome presented with acute onset of red and painful left eye with cloudy vision. Initial intraocular pressure (IOP) was measured to be 54 mm Hg. Gonioscopy revealed no angle structures or peripheral anterior synechiae in the left eye. Two laser peripheral iridotomies were created 5 days apart without adequate IOP lowering. Left eye cataract extraction with intraocular lens implantation and Ahmed glaucoma drainage device implantation were performed with resolution of ocular hypertension.A 35-year-old male with Stickler syndrome presented with intermittent right eye pain and blurry vision. IOP was 42 mm Hg and gonioscopy revealed 270 degrees of angle closure in the right eye. The patient underwent laser peripheral iridotomy in the right eye with resolution of ocular hypertension by the next day. CONCLUSIONS Recognizing angle closure as a potential feature of Stickler syndrome can help providers adequately screen and manage patients with Stickler syndrome presenting with acutely elevated IOP.

BackgroundHydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.MethodsNew user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine- azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22- 3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02- 1.45])ConclusionsShort-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.Trial registration numberRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine.Funding sourcesThis research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.

Journal article

Introduction: Previous studies have linked short sleep duration, poor sleep quality, and late sleep timing with lower health-related quality of life (HRQoL) in children. However, almost all studies relied solely on self-reported sleep information, and most studies were conducted in high-income countries. To address these gaps, we studied both device-measured and self-reported sleep characteristics in relation to HRQoL in a sample of children from 12 countries that vary widely in terms of economic and human development. Methods: The study sample included 6,626 children aged 9-11 years from Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. Waist-worn actigraphy was used to measure total sleep time, bedtime, wake-up time, and sleep efficiency on both weekdays and weekends. Children also reported ratings of sleep quantity and quality. HRQoL was measured by the KIDSCREEN-10 survey. Multilevel regression models were used to determine the relationships between sleep characteristics and HRQoL. Results: Results showed considerable variation in sleep characteristics, particularly duration and timing, across study sites. Overall, we found no association between device-measured total sleep time, sleep timing or sleep efficiency, and HRQoL. In contrast, self-reported ratings of poor sleep quantity and quality were associated with HRQoL. Conclusions: Self-reported, rather than device-based, measures of sleep are related to HRQoL in children. The discrepancy related to sleep assessment methods highlights the importance of considering both device-measured and self-reported measures of sleep in understanding its health effects. (c) 2019 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.

Successful police organizations rely on involved, satisfied, and committed workers. The concepts of job involvement (i.e., connection with the job), job satisfaction (i.e., affective feeling toward the job), and organizational commitment (i.e., bond with the employing organization) have been shown to significantly affect intentions and behaviors of employees. The current study used multivariate ordinary least squares (OLS) regression analysis on survey results from a sample of 827 Indian police officers to explore how perceptions of work environment factors affect officers’ job involvement, job satisfaction, and organizational commitment. Organizational support, formalization (i.e., level of codified written rules and guidelines), promotional opportunities, institutional communication (i.e., salient work information is transmitted), and input into decision-making (i.e., having a voice in the process) significantly influenced the job involvement, job satisfaction, and organizational commitment of Indian police officers. Specifically, in the multivariate analysis, perceptions of formalization and instrumental communication had a positive relationship with job involvement; perceptions of organizational support, promotional opportunities, instrumental communication, and input into decision-making had positive associations with job satisfaction; and perceptions of organizational support, formalization, promotional opportunities, instrumental communication, and input into decision-making had positive relationships with organizational commitment.

Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment. Funding National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Background and purpose: The nociceptin/orphanin FQ (N/OFQ) receptor (NOP) is a member of the opioid receptor family and is involved in a number of physiological responses, pain and immune regulation as examples. In this study, we conjugated a red fluorophore-ATTO594 to the peptide ligand N/OFQ (N/OFQATTO594 ) for the NOP receptor and explored NOP receptor function at high (in recombinant systems) and low (on immune cells) expression. Experimental approach: We assessed N/OFQATTO594 receptor binding, selectivity and functional activity in recombinant (CHO) cell lines. Live cell N/OFQATTO594 binding was measured in (i) HEK cells expressing NOP and NOPGFP receptors, (ii) CHO cells expressing the hNOPGαqi5 chimera (to force coupling to measurable Ca2+ responses) and (iii) freshly isolated human polymorphonuclear cells (PMN). Key results: N/OFQATTO594 bound to NOP receptor with nM affinity and high selectivity. N/OFQATTO594 activated NOP receptor by reducing cAMP formation and increasing Ca2+ levels in CHOhNOPGαqi5 cells. N/OFQATTO594 was also able to visualize NOP receptors at low expression levels on PMN cells. In NOP-GFP-tagged receptors, N/OFQATTO594 was used in a FRET protocol where GFP emission activated ATTO, visualizing ligand-receptor interaction. When the NOPGFP receptor is activated by N/OFQATTO594 , movement of ligand and receptor from the cell surface to the cytosol can be measured. Conclusions and implications: In the absence of validated NOP receptor antibodies and issues surrounding the use of radiolabels (especially in low expression systems), these data indicate the utility of N/OFQATTO594 to study a wide range of N/OFQ-driven cellular responses.

Background/Context It is widely understood that teachers are plagued by a myriad of challenges that ultimately affect their stress levels, job satisfaction, and effectiveness at work. Teacher stress can lead to burnout, lowered occupational commitment, and an eventual decision to leave the field. An important question for the field is how best to understand which teachers are most vulnerable to stress. This study used Lazarus and Folkman's transactional theory, which is the dominant model within the stress literature, to examine teachers’ stress vulnerability. Objective This study examined how elementary teacher appraisals of their classroom environment contribute to their risk for stress in the context of individual, classroom, and school characteristics, as well as state-level policy factors. Further, this study looked at how these factors are associated with teachers’ occupational stress, burnout, and commitment to teaching. Participants Participants were 11,850 full-time public school elementary teachers (Grades 1–5) who responded to the National Center for Education Statistics 2007/2008 Schools and Staffing Survey (SASS). Research Design Secondary data from the SASS were employed. The Rasch rating scale model was used to form scores on the Appraisal Index (teachers’ ratio of experiencing resources versus demands), as well as the Classroom Control and Burnout scales. Data Collection and Analysis Multilevel modeling was used. Each model had two levels with teachers nested within the state where they work. Two types of models were estimated using hierarchical linear modeling (HLM) software and restricted maximum likelihood procedures. The SASS teacher final sampling weight was then normalized and applied to all analyses within the HLM software. All results were reported with robust standard errors. Findings Teachers classified as at risk for stress based on SASS items about classroom demand and resources were found to be more likely to report lower job satisfaction and burnout symptoms, as well as reduced occupational commitment. Professional characteristics, school context, and the policy climate in which teachers work were also associated with teachers being at risk for stress. Conclusions/Recommendations Given these connections between occupational stressors, teacher appraisals of the classroom environment, and occupational outcomes, these results suggest that education stakeholders should be mindful of the climate and context in which public policies are enacted.

Staff are an obvious and important resource for correctional organizations across the globe. One important area that concerns staff is job involvement (i.e., the psychosocial bonds between staff members and their jobs). The majority of the limited research on how work environment factors affect correctional personnel has examined U.S. staff. To fill this void, the current study used the job demands-resource model to explore how various personal characteristics and work environment variables affected the job involvement of staff at two prisons in southern China. The specific personal characteristics were age, tenure, gender, educational level, and assigned prison. The job demand variables were fear of victimization and role overload, and the job resource variables were instrumental communication, job autonomy, transactional justice, procedural justice, distributive justice, job variety, and supervision. Tenure, fear of victimization, transactional justice, distributive justice, job variety, and supervision had significant effects on job involvement in a multivariate regression analysis, while the other variables did not. Except for fear of victimization, which had a negative association, the other significant variables had positive associations with job involvement.

Past research among U.S. correctional staff has found that work–family conflict has negative outcomes such as decreasing job satisfaction, decreasing organizational commitment, and increasing job stress. Little empirical research has addressed the association of the specific types of work–family conflict with job involvement. The present study contributes to the literature by separately analyzing the relationship of the four specific major types of work–family conflict (time-based conflict, strain-based conflict, behavior-based conflict, and family-on-work conflict) with job involvement among surveyed staff at two Chinese prisons. Job involvement varied by the type of work–family conflict. Specifically, time-based conflict and strain-based conflict had nonsignificant association with job involvement, but behavior-based and family-based conflicts had significant negative associations.

The measurement properties of any assessment system should be rigorously examined as long as the measure is in use. Authentic formative assessments are not immune to this process. Messick provided a comprehensive theory of test validation that conceptualized validity as a unitary construct. He identified six distinct types of evidence that can support the inferences made from assessment scores, all of which are applied to the process of validating authentic formative assessment measures. The validation argument for direct summative assessments is compared to the distinct aspects of a validity argument to support formative assessments for young children. Specific sources of construct irrelevant variance in the information provided by authentic formative assessments are also outlined. The complex constellation of purposes for which authentic formative assessments have been developed is unified by a single underlying principle: usefulness to teachers.