Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression changes have been identified, but many have not been replicated and ...have unknown functions. We identified groups of genes whose expressions varied together, that is co-expression modules, then tested them for association with SCZ. Using weighted gene co-expression network analysis, we show that two modules were differentially expressed in patients versus controls. One, upregulated in cerebral cortex, was enriched with neuron differentiation and neuron development genes, as well as disease genome-wide association study genetic signals; the second, altered in cerebral cortex and cerebellum, was enriched with genes involved in neuron protection functions. The findings were preserved in five expression data sets, including sets from three brain regions, from a different microarray platform, and from BD patients. From those observations, we propose neuron differentiation and development pathways may be involved in etiologies of both SCZ and BD, and neuron protection function participates in pathological process of the diseases.
Low Ag dose promotes induction and persistence of regulatory T cells (Tregs) in mice, yet few studies have addressed the role of Ag dose in the induction of adaptive CD4(+)FOXP3(+) Tregs in humans. ...To this end, we examined the level of FOXP3 expression in human CD4(+)CD25(-) T cells upon activation with autologous APCs and varying doses of peptide. Ag-specific T cells expressing FOXP3 were identified by flow cytometry using MHC class II tetramer (Tmr). We found an inverse relationship between Ag dose and the frequency of FOXP3(+) cells for both foreign Ag-specific and self Ag-specific T cells. Through studies of FOXP3 locus demethylation and helios expression, we determined that variation in the frequency of Tmr(+)FOXP3(+) T cells was not due to expansion of natural Tregs, but instead, we found that induction, proliferation, and persistence of FOXP3(+) cells was similar in high- and low-dose cultures, whereas proliferation of FOXP3(-) T cells was favored in high Ag dose cultures. The frequency of FOXP3(+) cells positively correlated with suppressive function, indicative of adaptive Treg generation. The frequency of FOXP3(+) cells was maintained with IL-2, but not upon restimulation with Ag. Together, these data suggest that low Ag dose favors the transient generation of human Ag-specific adaptive Tregs over the proliferation of Ag-specific FOXP3(-) effector T cells. These adaptive Tregs could function to reduce ongoing inflammatory responses and promote low-dose tolerance in humans, especially when Ag exposure and tolerance is transient.
Lung transplantation, in patients with end-stage lung disease, is limited by chronic rejection, which occurs with an incidence and severity exceeding most other transplanted organs. Alloimmune ...responses play an important role in progression to chronic rejection that manifests as bronchiolitis obliterans syndrome (BOS), but no biomarker can currently predict the progression to BOS. Studies in animal models suggest that intragraft T regulatory cells (Tregs) are important in maintaining transplantation tolerance, and FoxP3 is the protoypic Treg marker.
Leukocytes in blood and bronchoalveolar lavage (BAL) fluid were compared for expression of FoxP3 by flow cytometry in 14 stable lung transplant recipients and 6 lung transplant recipients who eventually developed BOS.
Stable patients, compared with patients who subsequently developed BOS, consistently had a significantly increased percentage of FoxP3 cells among CD4 cells in BAL and greater levels of the Treg-attracting chemokine CCL22. These differences were observed in limited sequential analyses, before, at the time of acute rejection, and postacute rejection. In this pilot study, a threshold of 3.2% CD4/FoxP3 cells in the BAL distinguished stable recipients from those subsequently developing BOS within the first 2 years posttransplantation.
The proportion of FoxP3 cells among CD4 cells in BAL may help to predict lung allograft outcome and guide therapeutic immunosuppression in lung transplant recipients.
To assess the features and level of health literacy (HL) of available medication adherence apps and to create a searchable website to assist health care providers (HCP) and patients identify quality ...adherence apps.
Medication nonadherence continues to be a significant problem and leads to poor health outcomes and avoidable health care expense. The average adherence rate for chronic medications, regardless of disease state, is approximately 50% leaving significant room for improvement.
Smartphone adherence apps are a novel resource to address medication nonadherence. With widespread smartphone use and the growing number of adherence apps, both HCP and patients should be able to identify quality adherence apps to maximize potential benefits.
Assess the features, functionality and level of HL of available adherence apps and create a searchable website to help both HCP and patients identify quality adherence apps.
Online marketplaces (iTunes, Google Play, Blackberry) were searched in June of 2014 to identify available adherence apps. Online descriptions were recorded and scored based on 28 author-identified features across 4 domains. The 100 highest-scoring apps were user-tested with a standardized regimen to evaluate their functionality and level of HL.
461 adherence apps were identified. 367 unique apps were evaluated after removing "Lite/Trial" versions. The median initial score based on descriptions was 15 (max of 68; range: 3 to 47). Only 77 apps of the top 100 highest-scoring apps completed user-testing and HL evaluations. The median overall user-testing score was 30 (max of 73; range: 16 to 55).
App design, functionality, and level of HL varies widely among adherence apps. While no app is perfect, several apps scored highly across all domains. The website www.medappfinder.com is a searchable tool that helps HCP and patients identify quality apps in a crowded marketplace.
•Utilising residual chlamydia specimens is a feasible method for HPV surveillance in Australia.•HPV results of 362 residual specimens were matched with demographic and vaccine registry data for ...98.6%•We detected HPV 16/18 in 3% women, and HPV 31/33/45/52/58 in 19%; 7.8% had a positive chlamydia test.
Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women.
De-identified residual specimens from women aged 16–24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay.
Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5–5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6–23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6–52.0%) of women.
HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.
Abstract Background Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the ...identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. Methods We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). Results The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT ( p =8.9×10−8 for rs4854912) with a secondary peak in the adjacent FXR1 gene ( p =1.2×10−6 for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis ( p =3.5×10−7 and 4.3×10−6 , respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. Limitations While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. Conclusions These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness.
Abstract
Long-term survival of lung allograft recipients can be hindered by the development of obliterative bronchiolitis (OB), a condition that has been linked to acute rejection. CD8+ T cells ...contribute to acute rejection by inducing lung epithelial injury; however, the mechanisms for mitigating this type of injury are unclear. Using an in vivo model of CD8-mediated lung rejection, we have found bystander CD4+ T cells are required for resolution of acute inflammation. The percentage of CD4+Foxp3+ Treg is significantly higher in inflamed lungs compared to controls, and the majority of these cells are ICOSHi in inflamed lungs. To determine the role ICOS expression plays in the ability of Treg to control inflammation, we investigated Treg cytokine expression levels and found WT Treg express more Il10 than Icos-/- Treg when stimulated in vitro. IL-10 production is also enhanced in WT Treg compared to Icos-/- Treg. Additionally, we saw WT Treg have enhanced proliferation compared to Icos-/- Treg. In vivo, we found Icos-/- CD4+ T cells are not sufficient for resolution of acute inflammation; however, addition of WT Treg rescues this defect. Together, these data suggest ICOS-expressing Treg are required for resolution of CD8-mediated lung injury due to a possible increase in IL-10 production or an enhanced ability to proliferate in vivo. Augmenting ICOS function on Treg after transplantation may protect the lung from acute rejection and prevent OB.
This paper considers patient and public involvement (PPI) in health economics research and how this might be facilitated. PPI refers to research carried out ‘with’ or ‘by’ members of the public and ...is now an important aspect of health research policies internationally. Patients and members of the public can be involved in all stages of the research cycle, from establishing whether the topic is important to influencing details of study design, wording of patient-facing documentation and interpretation and dissemination of findings. PPI has become commonplace in health services research. In the context of clinical trials, it has become imperative, with, for example, patients and members of the public informing the selection of outcome measures and recruitment methods, and qualitative research is frequently steered by PPI input regarding the content of interview topic guides and the interpretation of study findings. It is less common for PPI to be explicitly reported in the economic components of health services research. However, we argue that involvement is no less important in this area. The fundamental rationale for involving people in research is that it promotes democratic principles, research quality and relevance to service users. These arguments equally apply to health economics as to other health research disciplines. Our overarching aim in this paper is to show how health economic research might be informed by PPI. We report our experiences of PPI via case studies in child health, reflect on our learnings, and make suggestions for future research practice.
Plain Language Summary
This paper considers how to involve patients and members of the public in health economics research.
Health economists often carry out research into the value for money (sometimes called ‘cost effectiveness’) of new ways of treating people. This can help in decisions about which treatments are publically funded. In an economic evaluation, the economist identifies and values the key things used to treat someone who is unwell. They also have to measure how unwell that person is and whether their health changes with treatment. They do this by asking them questions about how they rate specific aspects of their health. Economists compare costs and health outcomes of different treatments. Patient and public involvement in health research is really important because the public fund health systems (through taxation in the UK) and benefit from healthcare. This paper shares our ideas on and experiences involving the public in health economic research studies. All our examples come from the involvement of children and/or parents. We think our approaches would also apply to adults.
Nonadherence produces considerable health consequences and economic burden to patients and payers. One approach to improve medication nonadherence that has gained interest in recent years is the use ...of smartphone adherence apps. The development of smartphone adherence apps has increased rapidly since 2012; however, literature evaluating the clinical app and effectiveness of smartphone adherence apps to improve medication adherence is generally lacking.
The aims of this study were to (1) provide an updated evaluation and comparison of medication adherence apps in the marketplace by assessing the features, functionality, and health literacy (HL) of the highest-ranking adherence apps and (2) indirectly measure the validity of our rating methodology by determining the relationship between our app evaluations and Web-based consumer ratings.
Two independent reviewers assessed the features and functionality using a 4-domain rating tool of all adherence apps identified based on developer claims. The same reviewers downloaded and tested the 100 highest-ranking apps including an additional domain for assessment of HL. Pearson product correlations were estimated between the consumer ratings and our domain and total scores.
A total of 824 adherence apps were identified; of these, 645 unique apps were evaluated after applying exclusion criteria. The median initial score based on descriptions was 14 (max of 68; range 0-60). As a result, 100 of the highest-scoring unique apps underwent user testing. The median overall user-tested score was 31.5 (max of 73; range 0-60). The majority of the user tested the adherence apps that underwent user testing reported a consumer rating score in their respective online marketplace. The mean consumer rating was 3.93 (SD 0.84). The total user-tested score was positively correlated with consumer ratings (r=.1969, P=.04).
More adherence apps are available in the Web-based marketplace, and the quality of these apps varies considerably. Consumer ratings are positively but weakly correlated with user-testing scores suggesting that our rating tool has some validity but that consumers and clinicians may assess adherence app quality differently.
PDF
