Impact of Political Economy on Population Health: A Systematic Review of Reviews.

Background. Although there is a large literature examining the relationship between a wide range of political economy exposures and health outcomes, the extent to which the different aspects of political economy influence health, and through which mechanisms and in what contexts, is only partially understood. The areas in which there are few high-quality studies are also unclear. Objectives. To systematically review the literature describing the impact of political economy on population health. Search Methods. We undertook a systematic review of reviews, searching MEDLINE, Embase, International Bibliography of the Social Sciences, ProQuest Public Health, Sociological Abstracts, Applied Social Sciences Index and Abstracts, EconLit, SocINDEX, Web of Science, and the gray literature via Google Scholar. Selection Criteria. We included studies that were a review of the literature. Relevant exposures were differences or changes in policy, law, or rules; economic conditions; institutions or social structures; or politics, power, or conflict. Relevant outcomes were any overall measure of population health such as self-assessed health, mortality, life expectancy, survival, morbidity, well-being, illness, ill health, and life span. Two authors independently reviewed all citations for relevance. Data Collection and Analysis. We undertook critical appraisal of all included reviews by using modified Assessing the Methodological Quality of Systematic Reviews (AMSTAR) criteria and then synthesized narratively giving greater weight to the higher-quality reviews. Main Results. From 4912 citations, we included 58 reviews. Both the quality of the reviews and the underlying studies within the reviews were variable. Social democratic welfare states, higher public spending, fair trade policies, extensions to compulsory education provision, microfinance initiatives in low-income countries, health and safety policy, improved access to health care, and high-quality affordable housing have positive impacts on population health. Neoliberal restructuring seems to be associated with increased health inequalities and higher income inequality with lower self-rated health and higher mortality. Authors' Conclusions. Politics, economics, and public policy are important determinants of population health. Countries with social democratic regimes, higher public spending, and lower income inequalities have populations with better health. There are substantial gaps in the synthesized evidence on the relationship between political economy and health, and there is a need for higher-quality reviews and empirical studies in this area. However, there is sufficient evidence in this review, if applied through policy and practice, to have marked beneficial health impacts. Public Health Implications. Policymakers should be aware that social democratic welfare state types, countries that spend more on public services, and countries with lower income inequalities have better self-rated health and lower mortality. Research funders and researchers should be aware that there remain substantial gaps in the available evidence base. One such area concerns the interrelationship between governance, polities, power, macroeconomic policy, public policy, and population health, including how these aspects of political economy generate social class processes and forms of discrimination that have a differential impact across social groups. This includes the influence of patterns of ownership (of land and capital) and tax policies. For some areas, there are many lower-quality reviews, which leave uncertainties in the relationship between political economy and population health, and a high-quality review is needed. There are also areas in which the available reviews have identified primary research gaps such as the impact of changes to housing policy, availability, and tenure.

Addressing the Mental Health Needs of Inmates Through Education for Correctional Officers-A Narrative Review.

INTRODUCTION: People with mental illness are overrepresented in correctional facilities. Correctional officers (COs) lack education to respond to inmates with mental illness. A review was conducted of mental health education programs for COs to identify factors related to effectiveness. METHODS: Medical and criminal justice databases were searched for articles describing mental health education for COs. Studies including measurable outcomes were analyzed using an inductive analytic approach. The review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for scoping reviews. Data were synthesized using Moore seven levels of outcomes for continuing professional development education. Findings were grouped by curriculum content and described according to levels of outcome. RESULTS: Of 1492 articles, 11 were included in the analysis. Six described mental health programs, two described skill-specific programs, and three described suicide prevention programs. Programs reviewed content about mental illness, practical skills, included didactic and experiential teaching. The programs achieved level 5 on Moore taxonomy. Programs led to improvements in knowledge, skills, and attitudes among officers; however, improvements declined post-training. Officers were receptive to facilitators with correctional or lived mental health experience. Experiential teaching was preferred. Common themes related to programs' effectiveness included applicability to COs, information retention, program facilitators, and teaching methods. DISCUSSION: There is limited, but positive literature suggesting that education programs are beneficial. The decline in improvements suggests need to ensure sustainability of improvements. This review can guide the planning of future education programs for COs based on continuing professional development best practices.

Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63.

Leishmania parasites have evolved sophisticated mechanisms to subvert macrophage immune responses by altering the host cell signal transduction machinery, including inhibition of JAK/STAT signalling and other transcription factors such as AP-1, CREB and NF-κB. AP-1 regulates pro-inflammatory cytokines, chemokines and nitric oxide production. Herein we show that upon Leishmania infection, AP-1 activity within host cells is abolished and correlates with lower expression of 5 of the 7 AP-1 subunits. Of interest, c-Jun, the central component of AP-1, is cleaved by Leishmania. Furthermore, the cleavage of c-Jun is dependent on the expression and activity of the major Leishmania surface protease GP63. Immunoprecipitation of c-Jun from nuclear extracts showed that GP63 interacts, and cleaves c-Jun at the perinuclear area shortly after infection. Phagocytosis inhibition by cytochalasin D did not block c-Jun down-regulation, suggesting that internalization of the parasite might not be necessary to deliver GP63 molecules inside the host cell. This observation was corroborated by the maintenance of c-Jun cleavage upon incubation with L. mexicana culture supernatant, suggesting that secreted, soluble GP63 could use a phagocytosis-independent mechanism to enter the host cell. In support of this, disruption of macrophage lipid raft microdomains by Methyl ß-Cyclodextrin (MßCD) partially inhibits the degradation of full length c-Jun. Together our results indicate a novel role of the surface protease GP63 in the Leishmania-mediated subversion of host AP-1 activity.

Systematic review of intervention practices for depression in the workplace.

DESIGN: Systematic Review. OBJECTIVE: To determine which intervention approaches to manage depression in the workplace have been successful and yielded value for employers in developed economies. DATA SOURCES: We searched MEDLINE, EMBASE, CINAHL, Central, PsycINFO, and Business Source Premier up to June 2010 using search terms in four broad areas: work setting, depression, intervention, and work outcomes. STUDY SELECTION: Two independent reviewers selected potential articles that met the following criteria: working age individuals with mild or moderate depression; interventions or programs that were workplace-based or could be implemented and/or facilitated by the employer; inclusion of a comparator group in the analysis; outcomes of prevention, management, and recurrences of work disability or sickness absence, and work functioning. METHODS: Two reviewers independently reviewed each article for quality and extracted data using standardised forms. Following guidelines from the GRADE Working Group, the quality of evidence addressing each outcome was graded as high, moderate, low, or very low on the basis of six criteria: study design, risk of bias, consistency, generalisability, data precision, and economic benefit. Using this information and following Cochrane Collaboration guidelines, the findings for each intervention were summarised and key messages were developed. RESULTS: We identified ten randomised trials and two non-randomised studies from various countries and jurisdictions that evaluated a wide range of intervention practices. The evidence was graded as "very low" for all outcomes identified. Therefore, no intervention could be recommended. CONCLUSIONS: To date, there is insufficient quality of evidence to determine which interventions are effective and yield value to manage depression in the workplace.

Is austerity a cause of slower improvements in mortality in high-income countries? A panel analysis.

BACKGROUND: The rate of improvement in mortality slowed across many high-income countries after 2010. Following the 2007-08 financial crisis, macroeconomic policy was dominated by austerity as countries attempted to address perceived problems of growing state debt and government budget deficits. This study estimates the impact of austerity on mortality trends for 37 high-income countries between 2000 and 2019. METHODS: We fitted a suite of fixed-effects panel regression models to mortality data (period life expectancy, age-standardised mortality rates (ASMRs), age-stratified mortality rates and lifespan variation). Austerity was measured using the Alesina-Ardagna Fiscal Index (AAFI), Cyclically-Adjusted Primary Balance (CAPB), real indexed Government Expenditure, and Public Social Spending as a % of GDP. Sensitivity analyses varied the lag times, and confined the panel to economic downturns and to non-oil-dominated economies. RESULTS: Slower improvements, or deteriorations, in life expectancy and mortality trends were seen in the majority of countries, with the worst trends in England & Wales, Estonia, Iceland, Scotland, Slovenia, and the USA, with generally worse trends for females than males. Austerity was implemented across all countries for at least some time when measured by AAFI and CAPB, and for many countries across all four measures (and particularly after 2010). Austerity adversely impacted life expectancy, ASMR, age-specific mortality and lifespan variation trends when measured with Government Expenditure, Public Social Spending and CAPB, but not with AAFI. However, when the dataset was restricted to periods of economic downturn and in economies not dominated hydrocarbon production, all measures of austerity were found to reduce the rate of mortality improvement. INTERPRETATION: Stalled mortality trends and austerity are widespread phenomena across high-income countries. Austerity is likely to be a cause of stalled mortality trends. Governments should consider alternative economic policy approaches if these harmful population health impacts are to be avoided.

Glossary: economics and health.

As we emerge from the COVID-19 pandemic, there is an increasing focus on how the economy is rebuilt and the impact this will have on population health. Many of the economic policy proposals being discussed have their own vocabulary, which is not always understood in the same way within or between disciplines. This glossary seeks to provide a common language and concise summary of the key economic terminology relevant for policymakers and public health at this time.

Molecular signatures of end-stage heart failure.

BACKGROUND: To date, gene expression studies related to chronic heart failure (CHF) have mainly involved microarray analysis of myocardial tissues. The potential utility of blood to infer the etiology, pathogenesis, and course of CHF remains unclear. Further, the use of proteomic and metabolomic platforms for molecular profiling of CHF is relatively unexplored. METHODS: Microarray genomic, iTRAQ proteomic, and nuclear magnetic resonance metabolomic analyses were carried out on blood samples from 29 end-stage CHF patients (16 ischemic heart disease [IHD], 13 nonischemic cardiomyopathy [NICM]), and 20 normal cardiac function (NCF) controls. Robust statistical tests and bioinformatical tools were applied to identify and compare the molecular signatures among these subject groups. RESULTS: No genes or proteins, and only two metabolites, were differentially expressed between IHD and NICM patients at end stage. However, CHF versus NCF comparison revealed differential expression of 7,426 probe sets, 71 proteins, and 8 metabolites. Functional enrichment analyses of the CHF versus NCF results revealed several in-common biological themes and potential mechanisms underlying advanced heart failure. CONCLUSION: Multiple "-omic" analyses support the convergence of dramatic changes in molecular processes underlying IHD and NICM at end stage.

Population health post-pandemic: critiquing the economic approach to recovery.

The COVID-19 pandemic has exposed that the economic crisis is inseparable from the health and inequalities crisis. This commentary identifies the key overarching economic decisions that governments will make that are likely have a larger impact on the health of nations than the direct impact of COVID-19 itself. We present these economic decisions to a health audience. The public health profession will need to develop opinions on these key economic decisions if we are to shape the environment that has such a large impact on the work we do.

Delineating West Nile Virus Transmission Cycles at Various Scales: The Nearest Neighbor Distance-Time Model.

Various approaches are used to identify West Nile virus (WNV) exposure areas, including unusual sightings of infected dead birds, mosquito pools or human cases both prospectively and retrospectively. A significant and largely unmet need in WNV research is to incorporate the temporal characterization of virus spread and locational information of the three components of transmission cycle-i.e., birds (reservoir), mosquitoes (vector), and humans (host)-on a localized scale. Exposure areas containing all three components of the WNV cycle in close proximity have higher potential to amplify an outbreak as compared to exposure areas delineated by a single component. In this paper, we introduce a novel approach, termed 'Nearest Neighbor Distance Time' or NNDT, to identify and retrospectively monitor WNV transmission cycles on various scales in the Twin Cities Metropolitan area of Minnesota. The NNDT model was implemented in a geographic information system using data from the period 2002 to 2006. The results indicated that 2002 and 2003 had three such WNV cycles, followed by one, two, and four respectively in 2004, 2005, and 2006. The NNDT method can be useful in locating chronically exposed areas and generating hypotheses about the transmission of WNV.

Is austerity responsible for the recent change in mortality trends across high-income nations? A protocol for an observational study.

INTRODUCTION: Mortality rates in many high-income countries have changed from their long-term trends since around 2011. This paper sets out a protocol for testing the extent to which economic austerity can explain the variance in recent mortality trends across high-income countries. METHODS AND ANALYSIS: This is an ecological natural experiment study, which will use regression adjustment to account for differences in exposure, outcomes and confounding. All high-income countries with available data will be included in the sample. The timing of any changes in the trends for four measures of austerity (the Alesina-Ardagna Fiscal Index, real per capita government expenditure, public social spending and the cyclically adjusted primary balance) will be identified and the cumulative difference in exposure to these measures thereafter will be calculated. These will be regressed against the difference in the mean annual change in life expectancy, mortality rates and lifespan variation compared with the previous trends, with an initial lag of 2 years after the identified change point in the exposure measure. The role of underemployment and individual incomes as outcomes in their own right and as mediating any relationship between austerity and mortality will also be considered. Sensitivity analyses varying the lag period to 0 and 5 years, and adjusting for recession, will be undertaken. ETHICS AND DISSEMINATION: All of the data used for this study are publicly available, aggregated datasets with no individuals identifiable. There is, therefore, no requirement for ethical committee approval for the study. The study will be lodged within the National Health Service research governance system. All results of the study will be published following sharing with partner agencies. No new datasets will be created as part of this work for deposition or curation.

Adaptation of the Clinical Global Impression for Use in Correctional Settings: The CGI-C.

Background: Provision of mental health care in correctional settings presents unique challenges. There is a need for a simple-to-use tool to measure severity of mental illness in correctional settings that can be used by mental health staff from different disciplines. We adapted the severity scale of the Clinical Global Impression for use in correctional settings, which we have called CGI-C, and carried out a reliability study. Method: Clinical descriptions of typical inmate presentations were developed to benchmark each of the seven possible ratings of the CGI. Twenty-one case vignettes were then developed for study of inter-rater reliability, which were then rated using the CGI-C by five forensic psychiatrists (on three occasions) and 11 multidisciplinary health care clinicians (twice). The tool was introduced into clinical practice, and the first 57 joint assessments carried out by both a psychiatrist and a clinician in which a CGI-C was rated were compared to measure inter-rater reliability. Results: We found very good inter-rater and test-retest reliability in all analyses. Gwet's AC, calculated on initial ratings of the vignettes by the psychiatrists, was 0.85 (95% CI 0.81-0.90, p < 0.001) and 0.87 (95% CI 0.83-0.91, p < 0.001) for clinician ratings. Inter-rater reliability based on 57 joint face-to-face assessments of inmates showed Gwet's AC coefficient of 0.93 (95% CI 0.88-0.97). Conclusion: The CGI-C is simple to use, can be used by members of the multidisciplinary team, and shows high reliability. The advantage in correctional settings is that it can be used even with the most severely ill and behaviorally disturbed, based on observation and collateral information.

Rehabilitation service models for people with physical and/or mental disability living in low- and middle-income countries: A systematic review.

OBJECTIVE: To compare models of rehabilitation services for people with mental and/or physical disability in order to determine optimal models for therapy and interventions in low- to middle-income countries. DATA SOURCES: CINAHL, EMBASE, MEDLINE, CENTRAL, PsycINFO, Business Source Premier, HINARI, CEBHA and PubMed. STUDY SELECTION: Systematic reviews, randomized control trials and observational studies comparing >2 models of rehabilitation care in any language. Date extraction: Standardized forms were used. Methodological quality was assessed using AMSTAR and quality of evidence was assessed using GRADE. DATA SYNTHESIS: Twenty-four systematic reviews which included 578 studies and 202,307 participants were selected. In addition, four primary studies were included to complement the gaps in the systematic reviews. The studies were all done at various countries. Moderate- to high-quality evidence supports the following models of rehabilitation services: psychological intervention in primary care settings for people with major depression, admission into an inpatient, multidisciplinary, specialized rehabilitation unit for those with recent onset of a severe disabling condition; outpatient rehabilitation with multidisciplinary care in the community, hospital or home is recommended for less severe conditions; However, a model of rehabilitation service that includes early discharge is not recommended for elderly patients with severe stroke, chronic obstructive pulmonary disease, hip fracture and total joints. CONCLUSION: Models of rehabilitation care in inpatient, multidisciplinary and specialized rehabilitation units are recommended for the treatment of severe conditions with recent onset, as they reduce mortality and the need for institutionalized care, especially among elderly patients, stroke patients, or those with chronic back pain. Results are expected to be generalizable for brain/spinal cord injury and complex fractures.

Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression.

AIMS: Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular cardiac rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular rejection in heart transplantation. METHODS AND RESULTS: Exosomes isolated from serum samples of heart transplant patients with and without acute cardiac allograft rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability. CONCLUSION: We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection.

Association of Serum MiR-142-3p and MiR-101-3p Levels with Acute Cellular Rejection after Heart Transplantation.

BACKGROUND: Identifying non-invasive and reliable blood-derived biomarkers for early detection of acute cellular rejection in heart transplant recipients is of great importance in clinical practice. MicroRNAs are small molecules found to be stable in serum and their expression patterns reflect both physiological and underlying pathological conditions in human. METHODS: We compared a group of heart transplant recipients with histologically-verified acute cellular rejection (ACR, n = 26) with a control group of heart transplant recipients without allograft rejection (NR, n = 37) by assessing the levels of a select set of microRNAs in serum specimens. RESULTS: The levels of seven microRNAs, miR-142-3p, miR-101-3p, miR-424-5p, miR-27a-3p, miR-144-3p, miR-339-3p and miR-326 were significantly higher in ACR group compared to the control group and could discriminate between patients with and without allograft rejection. MiR-142-3p and miR-101-3p had the best diagnostic test performance among the microRNAs tested. Serum levels of miR-142-3p and miR-101-3p were independent of calcineurin inhibitor levels, as measured by tacrolimus and cyclosporin; kidney function, as measured by creatinine level, and general inflammation state, as measured by CRP level. CONCLUSION: This study demonstrated two microRNAs, miR-142-3p and miR-101-3p, that could be relevant as non-invasive diagnostic tools for identifying heart transplant patients with acute cellular rejection.

A role for matrix metalloproteinases and tumor host interaction in hepatocellular carcinomas.

BACKGROUND: Hepatocellular carcinoma (HCC) occur in livers with injury-remodeling, accomplished by enzymes called matrix metalloproteinases (MMP). Metastasis involves basement membrane invasion also caused by MMP activity. Alterations in MMP expression and their endogenous inhibitor (TIMP) may factor in HCC metastasis. METHODS: HCC specimens and lymph nodes (n = 7), and normal lymph tissue from organ donors (n = 8), were snap-frozen in liquid nitrogen and the mRNA precipitated. A series of reverse transcription-polymerase chain reactions (RT-PCR) were performed using MMP (MMP2, MMP7, MMP9) primers and TIMP (TIMP1, TIMP2) primers. These were semiquantitatively analyzed by comparing concentration with constitutive GADPH expression. RESULTS: There is an increase in MMP2:TIMP2 mRNA expression ratio in the normal and tumor margin tissue compared to the tumor. There are increases in all MMP and TIMP mRNA expression (except TIMP1) and alterations in all of the MMP:TIMP expression ratios in the draining lymph node. CONCLUSIONS: Alterations exist in MMP2:TIMP2: expression at the margin, and all of the MMPs in the draining lymph nodes. This likely reflects a host-tumor interaction that regulates tumor metastasis.

Multirater reliability of the historical, clinical, and risk management-20.

The assessment and management of risk for future violence is a core requirement of mental health professionals in many settings. Despite an increasing need for violence risk assessments across diverse contexts, little is known regarding the ecological validity of many widely used risk assessment schemes or the level of reliability with which actual practicing clinicians score these instruments. The current study investigated the interrater reliability of the Historical, Clinical, and Risk Management-20 (HCR-20), a widely used structured professional tool to assess violence risk, among 21 practicing clinicians in a forensic psychiatric program in Ontario, Canada. Results suggest that clinicians with varying professional training backgrounds and experience were able to rate the HCR-20 with good to excellent levels of reliability across three patients who varied in risk level. Consistent with studies investigating rater reliability for research purposes, we found that the risk management scale of the HCR-20 was the most challenging for clinicians to rate reliably. Importantly, results from generalizability theory analyses revealed that less than 3% of the variance in HCR-20 total scores and summary risk ratings is attributable to rater effects, whereas the majority of variance is attributable to differences among patients.

Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.

In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.

Two-stage, in silico deconvolution of the lymphocyte compartment of the peripheral whole blood transcriptome in the context of acute kidney allograft rejection.

Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially expressed probe-set lists is consistent with the originating tissue and their functional enrichment consistent with allograft rejection. Finally, we demonstrate that the strategy described here can be used to derive useful hypotheses by validating a cell type-specific ratio in an independent cohort using the nanoString nCounter assay.

Proteomic biomarkers of recovered heart function.

AIMS: Chronic heart failure is a costly epidemic that affects up to 2% of people in developed countries. The purpose of this study was to discover novel blood proteomic biomarker signatures of recovered heart function that could lead to more effective heart failure patient management by both primary care and specialty physicians. METHODS AND RESULTS: The discovery cohort included 41 heart transplant patients and 20 healthy individuals. Plasma levels of 138 proteins were detected in at least 75% of these subjects by iTRAQ mass spectrometry. Eighteen proteins were identified that had (i) differential levels between pre-transplant patients with end-stage heart failure and healthy individuals; and (ii) levels that returned to normal by 1 month post-transplant in patients with stable heart function after transplantation. Seventeen of the 18 markers were validated by multiple reaction monitoring mass spectrometry in a cohort of 39 heart failure patients treated with drug therapy, of which 30 had recovered heart function and 9 had not. This 17-protein biomarker panel had 93% sensitivity and 89% specificity, while the RAMP® NT-proBNP assay had the same specificity but 80% sensitivity. Performance further improved when the panel was combined with NT-proBNP, yielding a net reclassification index relative to NT-proBNP of 0.28. CONCLUSIONS: We have identified potential blood biomarkers of recovered heart function by harnessing data from transplant patients. These biomarkers can lead to the development of an inexpensive protein-based blood test that could be used by physicians to monitor response to therapy in heart failure, resulting in more personalized, front-line heart failure patient management.