Osteoarthritis consumers as co-researchers: identifying consumer insights to improve osteoarthritis management by co-designing translational research solutions.

INTRODUCTION: Co-design is a consumer-driven approach that facilitates consumer participation in creating meaningful solutions to complex problems. Poor uptake of core management strategies for osteoarthritis suggests there is a missing link in translation between research and practice. We partnered with osteoarthritis consumers as 'co-researchers' to identify translational research solutions to improve uptake of core management strategies that are grounded in lived experiences. OBJECTIVE: To transparently describe a theory-driven, generative co-design approach using an integrated conceptual framework to collaborate with consumers at the equal partnership level. DESIGN: We used co-design workshops with a non-hierarchical participatory framework. Three workshops with six co-researchers [2 female, mean age 68.7 (9.8) years, 3-30 years symptom duration] were conducted using activities to encourage creative thinking, promote deep reflection on personal/societal beliefs and minimise sensitivities around sharing personal beliefs (e.g., establishing a safe space, prompting questions, perspective-taking, counter-stereotypical exemplars). RESULTS: All six co-researchers actively participated in the workshops. Achievement of an equal collaborative partnership was evidenced by co-researchers challenging a project proposed by the research team and making alternative recommendations that have been implemented in prospective decision-making - representing a complete change in research focus driven by consumer input. A key suggested solution was to develop a scalable knowledge translation intervention that targets misconceptions about osteoarthritis and its management at the societal-level. CONCLUSIONS: Through an innovative co-design approach in partnership with co-researchers, we identified meaningful areas on which to focus translational research for osteoarthritis. Discordance between existing research priorities and novel solutions proposed by co-researchers highlights the value of co-design.

Chinese and South Asian ethnicity, immigration status, and clinical cancer outcomes in the Ontario Cancer System.

BACKGROUND: In the United States, certain minority groups have been shown to have inferior cancer outcomes compared with the white majority population. However, to the authors' knowledge, the majority of research has not separated ethnicity from immigration status. The objective of the current study was to determine the impact of ethnicity, independent of immigration status, on cancer outcomes in Chinese and South Asian populations in Ontario, Canada. METHODS: The authors conducted a population-based retrospective cohort study using administrative databases in Ontario, Canada. Incident cancer cases were captured in Canadian-born Chinese and South Asian individuals, Chinese and South Asian immigrants, and the general Ontario reference population (non-Chinese/non-South Asian and non-immigrant) between 2000 and 2012. Subjects were followed until death (all-cause and cancer-specific), and Cox proportional hazard models were used to estimate the impact of Chinese and South Asian ethnicity on cancer outcomes after adjusting for explanatory variables. RESULTS: A total of 423,678 cancer cases were identified; at total of 6631 cases were identified in Canadian-born Chinese individuals and 2752 cases in Canadian-born South Asian individuals. After adjustment, the rate of all-cause mortality was lower for Canadian-born Chinese (hazard ratio [HR], 0.829; 95% confidence interval [95% CI], 0.795-0.865), Canadian-born South Asian (HR, 0.856; 95% CI, 0.797-0.919), and Chinese immigrant (recent immigrant: HR, 0.661 [95% CI, 0.610-0.716] and non-recent immigrant: HR, 0.853 [95% CI, 0.803-0.906]) populations compared with the general Ontario population. A similar effect was found for cancer-specific mortality. CONCLUSIONS: Chinese and South Asian ethnic groups appear to have lower cancer mortalities compared with the general Ontario population. After removing the well-documented protective effect of immigration, Chinese and South Asian ethnicities were found to be associated with a cancer survival advantage in Ontario, Canada. Cancer 2018;124:1473-82. © 2018 American Cancer Society.

IL-6 promotes CD4+ T-cell and B-cell activation during Plasmodium infection.

Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4+ T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6-/- mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138+ plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4+ T cells, as well as their localization close to splenic B cells, but was not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4+ T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production.

Response to sensory uncertainty in Parkinson's disease: a marker of cerebellar dysfunction?

Motor performance is profoundly influenced by sensory information, yet sensory input can be noisy and uncertain. The basal ganglia and the cerebellum are important in processing sensory uncertainty, as the basal ganglia incorporate the uncertainty of predictive reward cues to reinforce motor programs, and the cerebellum and its connections mitigate the effect of ambiguous sensory input on motor performance through the use of forward models. Although Parkinson's disease (PD) is classically considered a primary disease of the basal ganglia, alterations in cerebellar activation are also observed, which may have consequences for the processing of sensory uncertainty. The aim of this study was to investigate the effect of visual uncertainty on motor performance in 15 PD patients and ten age-matched control subjects. Subjects performed a visually guided tracking task, requiring large-amplitude arm movements, by tracking with their index finger a moving target along a smooth trajectory. To induce visual uncertainty, the target position randomly jittered about the desired trajectory with increasing amplitudes. Tracking error was related to target ambiguity to a significantly greater degree in PD subjects off medication compared with control subjects, indicative of susceptibility to visual uncertainty in PD. l-Dopa partially ameliorated this deficit. We interpret our findings as suggesting an inability of PD subjects to create adequate forward models and/or de-weight less informative visual input. As these computations are normally associated with the cerebellum and connections, we suggest that alterations in normal cerebellar functioning may be a significant contributor to altered motor performance in PD.

Dyskinetic Parkinson's disease patients demonstrate motor abnormalities off medication.

The pathophysiology of L-dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) remains poorly understood. The presence of superimposed LIDs clearly differentiates motor performance of dyskinetic from non-dyskinetic PD subjects when they are on medication, but here, we investigated whether their respective motor performance differs while subjects are off L-dopa medication and LIDs are not apparent. We assessed the motor performance of nine dyskinetic and ten non-dyskinetic PD subjects off L-dopa, and of ten age-matched control subjects, during a visually guided tracking task. As previous studies have suggested that linear dynamical system (LDS) models are useful to assess motor performance in PD in addition to overall tracking error, we used LDS models to assess the damping ratio parameter of motor behavior while controlling for disease severity. While overall tracking error did not significantly differ across groups, dyskinetic PD subjects demonstrated a significantly decreased mean damping ratio compared with control and non-dyskinetic PD subjects. For both groups, greater disease severity significantly predicted a lower damping ratio, but even after controlling for disease severity, the damping ratio for dyskinetic subjects was significantly lower. Our results demonstrate, somewhat counter-intuitively, that motor performance of dyskinetic and non-dyskinetic PD subjects differ, even off L-dopa when no dyskinesias are seen. A decreased damping ratio is indicative of a tendency to overshoot a target during motor performance, similar to the dysmetria found in cerebellar patients. We discuss the possibility of motor abnormalities in dyskinetic PD patients off medication in relation to altered functional cerebellar changes described in PD.

Effect of the structure of cholesterol-based tethered bilayer lipid membranes on ionophore activity.

Tethered bilayer lipid membranes (tBLM) are formed on 1) pure tether lipid triethyleneoxythiol cholesterol (EO(3)C) or on 2) mixed self-assembled monolayers (SAMs) of EO(3)C and 6-mercaptohexanol (6MH). While EO(3)C is required to form a tBLM with high resistivity, 6MH dilutes the cholesterol content in the lower leaflet of the bilayer forming ionic reservoirs required for submembrane hydration. Here we show that these ionic reservoirs are required for ion transport through gramicidin or valinomycin, most likely due to the thermodynamic requirements of ions to be solvated once transported through the membrane. Unexpectedly, electrochemical impedance spectroscopy (EIS) shows an increase of capacitance upon addition of gramicidin, while addition of valinomycin decreases the membrane resistance in the presence of K(+) ions. We hypothesise that this is due to previously reported phase separation of EO(3)C and 6MH on the surface. This results in ionic reservoirs on the nanometre scale, which are not fully accounted for by the equivalent circuits used to describe the system.

Improved survival in overweight and obese patients with aggressive B-cell lymphoma treated with rituximab-containing chemotherapy for curative intent.

The association between obesity and survival in non-Hodgkin lymphoma is unclear. Using the Ontario Cancer Registry we conducted a retrospective analysis of incident cases of aggressive-histology B-cell lymphoma treated with a rituximab-containing regimen with curative intent between 2008-2016. 6246 patients were included. On multivariable analysis the rate of all-cause mortality was lower for the overweight body mass index (BMI 25-29.9 kg/m2) (HR 0.85; 95%CI 0.77-0.95) and obese BMI (≥30 kg/m2) (HR 0.75; 95%CI 0.67-0.85) groups compared to the normal weight group (18.5-24.9 kg/m2). Binomial logistic regression analysis revealed a lower odds ratio (OR) of admission to hospital during treatment in the overweight (OR 0.84; 95%CI 0.75-0.95) compared to normal weight BMI group. In the largest cohort to date of aggressive-histology B-cell lymphoma patients treated with rituximab, increased BMI is associated with a survival advantage, and the magnitude of this effect increases from overweight to obese BMI.

Deaminatively generated carbocations as initiators of styrene polymerization.

[reaction: see text] Addition polymerization is readily accomplished via free radicals and carbanions but conventional initiations via carbocations are limited principally by low initiator reactivity. Thermolyses of N-nitrosamides produce nitrogen-separated ion-pairs (NSIPs) containing exceedingly reactive carbocations. We report here the novel use of this facile mode of carbocation generation in the polymerization of styrene. Polystyrene of viscosity average molecular weight approximately 10(6) was obtained.

Immunohistological study of human lungs by immunoperoxidase technique.

An unlabelled antibody peroxidase-antiperoxidase method for the detection of IgG, IgM, complement (C3 and Clq), fibrinogen and albumin was applied to routinely processed paraffin sections of lung from 27 cases. The results in 11 cases were compared with those obtained by immunofluorescence using frozen sections. Tissue was obtained from surgical specimens of cases with interstitial pneumonia comprising 10 of the usual type (UIP) and three of the desquamative type (DIP). Tissue was also obtained from the specimens of cases with sarcoidosis (two cases) and granulomatous inflammation of unknown cause (one case). There were 11 control cases, nine with primary carcinoma of the lung and two with metastatic tumours of the lung. Immunoglobulins of various types and complement were seen in diseased lung tissue. Although most of these deposits were probably due to a non-immunological mechanism there was evidence of the possible implication of immune complexes in three cases of UIP and in the interstitial pneumonia present in the two cases of sarcoidosis. The immunoperoxidase technique is a more sensitive method than immunofluorescence and has the additional advantage of the easy identification of the precise sites of the various deposits.

Immunohistological study of oestrogen receptors in breast carcinomas that are biochemically receptor negative.

The reliability of an immunohistological method, applied to paraffin wax sections, was assessed for determination of oestrogen receptor content of biochemically oestrogen receptor negative breast carcinomata. Sixty consecutive tumours with oestrogen receptor concentrations of less than 10 fmol/mg cytosol protein, as estimated by dextran-coated charcoal biochemical assay, were examined. Paraffin wax sections were treated with DNAse before applying a peroxidase-anti-peroxidase method using ER-ICA monoclonal antibodies. Fifty one cases (85%) were negative, six (10%) weakly positive, and three (5%) were moderately positive. No strongly positive cases were seen. It is suggested that cases with weakly positive staining, especially when localised to a small area, should be regarded as negative. On the other hand, as the three moderately stained cases included two small tubular carcinomas and an invasive ductal carcinoma with high progesterone receptor concentrations, it is more likely that the biochemical assay in these cases represented false negative results due to sampling error or inclusion of fibrous or other non-neoplastic tissue in the assayed samples. It is concluded that the immunohistological method used here is fairly reliable and would be especially valuable for determination of oestrogen receptor content in small, mammographically detected tumours from which no tissue would be available for biochemical assay or frozen section examination.

Oestrogen receptors in mucinous carcinoma of the breast: an immunohistological study using paraffin wax sections.

An immunohistological method (Shintaku-Said method) for the demonstration of oestrogen receptors in routinely processed paraffin wax embedded tissue was applied to 19 cases of mucinous carcinoma of the breast. Seventeen (89%) tumours showed variable degrees of positivity and two were negative. In eight cases the receptors were also assayed biochemically using a dextran-coated charcoal method, and the results of the two methods showed good correlation. No difference in the distribution of positive and negative cases was noted between pure and mixed mucinous tumours, and in the latter group the pattern of staining of the mucinous elements was similar to that seen in the solid elements. It is concluded that the major advantage of this method is its ability to offer for study the distribution of the receptors in individual cells and specific histological structures. The results also indicate that most mucinous carcinomas of the breast are oestrogen receptor positive, irrespective of whether they are pure or mixed type.

Excessive Sensitivity to Uncertain Visual Input in L-DOPA-Induced Dyskinesias in Parkinson's Disease: Further Implications for Cerebellar Involvement.

UNLABELLED: When faced with visual uncertainty during motor performance, humans rely more on predictive forward models and proprioception and attribute lesser importance to the ambiguous visual feedback. Though disrupted predictive control is typical of patients with cerebellar disease, sensorimotor deficits associated with the involuntary and often unconscious nature of l-DOPA-induced dyskinesias in Parkinson's disease (PD) suggests dyskinetic subjects may also demonstrate impaired predictive motor control. METHODS: We investigated the motor performance of 9 dyskinetic and 10 non-dyskinetic PD subjects on and off l-DOPA, and of 10 age-matched control subjects, during a large-amplitude, overlearned, visually guided tracking task. Ambiguous visual feedback was introduced by adding "jitter" to a moving target that followed a Lissajous pattern. Root mean square (RMS) tracking error was calculated, and ANOVA, robust multivariate linear regression, and linear dynamical system analyses were used to determine the contribution of speed and ambiguity to tracking performance. RESULTS: Increasing target ambiguity and speed contributed significantly more to the RMS error of dyskinetic subjects off medication. l-DOPA improved the RMS tracking performance of both PD groups. At higher speeds, controls and PDs without dyskinesia were able to effectively de-weight ambiguous visual information. CONCLUSION: PDs' visually guided motor performance degrades with visual jitter and speed of movement to a greater degree compared to age-matched controls. However, there are fundamental differences in PDs with and without dyskinesia: subjects without dyskinesia are generally slow, and less responsive to dynamic changes in motor task requirements, but in PDs with dyskinesia, there was a trade-off between overall performance and inappropriate reliance on ambiguous visual feedback. This is likely associated with functional changes in posterior parietal-ponto-cerebellar pathways.

Ferritin and lysozyme distribution in normal and abnormal duodenal mucosae.

The distribution of ferritin and lysozyme in 19 normal and abnormal duodenal biopsies was studied by an immunoperoxidase technique. The abnormal biopsies included cases of chronic duodenitis with gastric metaplasia, gastric heterotopia, villous atrophy, and a case of hemochromatosis. Ferritin is demonstrated in duodenal absorptive cells, with the staining being most intense in the hemochromatosis case. It was absent in duodenal cells showing gastric metaplasia and in the surface epithelial cells of most biopsies with villous atrophy and gastric heterotopia. Lysozyme-positive mononuclear inflammatory cells were markedly increased in all abnormal biopsies. Not all lysozyme-positive cells were ferritin positive. The latter were especially abundant in areas with gastric metaplasia. It is suggested that this abundance may be related to passive diffusion of intestinal contents, particularly iron, through the metaplastic areas, and consequently there may be a relationship between the presence of duodenal gastric metaplasia and uncontrolled iron absorption.

Mucinous carcinoma of the breast: further characterization of its three subtypes.

Nineteen cases of mucinous carcinoma of the breast were studied. Twelve tumours were of the pure type, and seven were mixed. All had abundant neutral and acidic mucin, and stained strongly with CAM 5.2. Of the 12 pure mucinous tumours, six were devoid of argyrophilic granules and were S-100 negative, and only one was CEA positive. All six patients are alive with no evidence of recurrence (mean follow-up 42 months). The other six pure mucinous tumours were rich in argyrophilic granules. Five of these showed S-100 positivity and all were CEA positive. One patient developed local recurrence and one died of myocardial infarction with no evidence of tumour recurrence (mean follow-up 80 months). Of the seven mixed tumours, only one contained an occasional cell with argyrophilic granules and four had variable degrees of CEA positivity. Two patients died and one developed bony metastasis (mean follow-up 40 months). Our findings emphasise the microscopic and prognostic differences between the three subtypes of mucinous carcinoma of the breast, and support the concept of dividing pure mucinous tumours into two distinct subtypes. We suggest that the latter subtyping can be qualitatively made on the basis of the presence or absence of argyrophilic granules in the tumour cells.