Using big data and Population Health Management to assess care and costs for patients with severe mental disorders and move toward a value-based payment system.

BACKGROUND: Mental health (MH) care often exhibits uneven quality and poor coordination of physical and MH needs, especially for patients with severe mental disorders. This study tests a Population Health Management (PHM) approach to identify patients with severe mental disorders using administrative health databases in Italy and evaluate, manage and monitor care pathways and costs. A second objective explores the feasibility of changing the payment system from fee-for-service to a value-based system (e.g., increased care integration, bundled payments) to introduce performance measures and guide improvement in outcomes. METHODS: Since diagnosis alone may poorly predict condition severity and needs, we conducted a retrospective observational study on a 9,019-patient cohort assessed in 2018 (30.5% of 29,570 patients with SMDs from three Italian regions) using the Mental Health Clustering Tool (MHCT), developed in the United Kingdom, to stratify patients according to severity and needs, providing a basis for payment for episode of care. Patients were linked (blinded) with retrospective (2014-2017) physical and MH databases to map resource use, care pathways, and assess costs globally and by cluster. Two regions (3,525 patients) provided data for generalized linear model regression to explore determinants of cost variation among clusters and regions. RESULTS: Substantial heterogeneity was observed in care organization, resource use and costs across and within 3 Italian regions and 20 clusters. Annual mean costs per patient across regions was €3,925, ranging from €3,101 to €6,501 in the three regions. Some 70% of total costs were for MH services and medications, 37% incurred in dedicated mental health facilities, 33% for MH services and medications noted in physical healthcare databases, and 30% for other conditions. Regression analysis showed comorbidities, resident psychiatric services, and consumption noted in physical health databases have considerable impact on total costs. CONCLUSIONS: The current MH care system in Italy lacks evidence of coordination of physical and mental health and matching services to patient needs, with high variation between regions. Using available assessment tools and administrative data, implementation of an episodic approach to funding MH could account for differences in disease phase and physical health for patients with SMDs and introduce performance measurement to improve outcomes and provide oversight.

An accelerated access pathway for innovative high-risk medical devices under the new European Union Medical Devices and health technology assessment regulations? Analysis and recommendations.

INTRODUCTION: The new European Union (EU) Regulations for medical devices (MDs) and health technology assessment (HTA) are welcome developments that should increase the quality of clinical evidence for MDs and reduce fragmentation in the EU market access process. To fully exploit anticipated benefits, their respective assessment processes should be closely coordinated, particularly for promising, highly innovative MDs. Accelerated approval is worth exploring for certain categories of high-risk MDs to keep the EU regulatory process competitive compared to accelerated MD approval programs elsewhere (e.g. US). AREAS COVERED: Problems observed in worldwide accelerated drug and MD regulatory approval programs are reviewed, including greater uncertainty in premarket clinical evidence generation and lack of oversight for post approval evidence requirements. Implications for MD approval, HTA and coverage are explored. EXPERT OPINION: Through analysis of two decades of drug and MD accelerated approval programs worldwide, recommendations for an Accelerated Access Pathway for select innovative, high-risk MDs are proposed to fit the EU context, leverage the two new regulations, increase opportunities for Expert Panels to provide timely advice regarding manufacturers' evidence generation plans along the MD lifecycle (pre, postmarket), and safely speed patient access while promoting increased collaboration among Member States on coverage decisions.

DM management in HIV patients: the adoption of population health management to transform the chronic management of HIV.

BACKGROUND: The success of antiretroviral therapies has made human immunodeficiency virus (HIV) a chronic disease, changing the care scenario dramatically. This study aimed to measure adherence to diabetes mellitus standards of care provided for people living with HIV (PLWH). Diabetes represents a paradigmatic case for tackling chronic care management in this target group. METHODS: This retrospective observational study was performed on administrative health data retrieved from 2014 to 2016, with a validated algorithm to identify patients with HIV using: (i) hospital discharge records (ICD9-CM codes); (ii) drug dispensing records (with ATC codes); and (iii) disease-specific exemptions from co-payments for healthcare services. HIV-related treatments, comorbidities and health service utilization were measured, as was adherence to clinical guidelines-recommended standards of care for diabetes. RESULTS: A population of 738 cases were identified in two Local Health Authorities in Italy, representing a prevalence of 0.14% of the general population, in line with the expected prevalence. Thirty-one cases of HIV patients diagnosed with diabetes were identified, a prevalence ratio of 4.2% compared to the 8% in the overall population. Adherence to diabetes standards of care tested within the same population was low, with the exception of those tests commonly administered for standard HIV follow-up care. CONCLUSIONS: The use of administrative data, combined with a Population Health Management approach represents a powerful tool for evaluating system capacity to manage HIV comorbidities. Study findings prove that it is time to design new care models for PLWH, affected by one or more chronic conditions, both to prevent their onset and to manage their comorbidities.

Avoidable hospitalizations and access to primary care: comparisons among Italians, resident immigrants and undocumented immigrants in administrative hospital discharge records.

Background: Immigrants face multiple barriers in accessing healthcare; however, empirical assessment of access presents serious methodological issues, and evidence on undocumented immigrants is scant and based mainly on non-representative samples. We examine avoidable hospitalization (AH) as an indicator of poor access to primary care (PC) in Italy, where a universal healthcare system guarantees access but fails to assign general practitioners to undocumented immigrants. Methods: Using anonymized national hospital discharge records in 2019, undocumented immigrants were identified through an administrative financing code. Potential effects of poor access to PC were measured by focusing on the incidence of AH, differentiated among chronic, acute and vaccine-preventable conditions, comparing Italian citizens, documented (foreign nationals with residence permits) and undocumented immigrants. We estimated odd ratios (ORs) through logistic regression models, controlling for individual and contextual confounders. Findings: Compared with Italians, undocumented and documented immigrants adjusted odd ratios (OR) for the risk of AH were 1·422 (95% CI 1·322-1·528) and 1·243 (95% CI 1·201-1·287), respectively. Documented immigrants showed ORs not significantly greater than 1 for AH due to chronic diseases compared with Italians, while undocumented immigrants registered higher adjusted OR for all AH categories - chronic (OR 1·187; 95% CI 1·064-1·325), acute (OR 1·645; 95% CI 1·500-1·803) and vaccine-preventable (OR 2·170; 95% CI 1·285-3·664). Interpretation: Documented and undocumented immigrants face considerably higher risk of AH compared to Italians. Considering the burden of AHs, access to PC (including preventive and ambulatory care) should be provided to undocumented immigrants, and additional barriers to care for all immigrants should be further explored. Funding: None.

Establishing a national HTA program for medical devices in Italy: Overhauling a fragmented system to ensure value and equal access to new medical technologies.

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.

Factors influencing adherence to adjuvant endocrine therapy in breast cancer-treated women: using real-world data to inform a switch from acute to chronic disease management.

PURPOSE: Adjuvant endocrine therapy (AET) for ≥ 5 years is generally recommended for women with hormone receptor-positive breast cancer to reduce cancer recurrence/mortality; however, adherence can be suboptimal. We tested determinants of AET adherence using patient characteristics, treatment pathways, AET initiation timing, and multiple healthcare facility use. An underlying objective was to explore how oncological pathways mirror chronic disease management to monitor adherence and target improvement interventions using administrative datasets. METHODS: Using patient-linked administrative health data from the Italian Lombardy Region, we identified 33.291 surviving patients starting AET in 2010-2016, with two (22.939 patients) or five years (8400 patients) follow-up, using a ≥ 80% prescription refill approach to measure adherence and logistic regression to test determinants of adherence. RESULTS: AET crude adherence falls significantly during follow-up, from 94% at 1 Year to 58% at 5 Years. At 5 Years, patients who were older (>70), prescribed tamoxifen-only (OR 0.69; 95% CI 0.57-0.83; p = 0.0001) vs. aromatase inhibitors-only or therapy switches, treated for depression (OR 0.68; 95% CI 0.60-0.78; p < 0.0001), with surgery performed in high-volume hospitals (OR 0.85; 95% CI 0.75-0.97; p = 0.0116) showed lower adherence. Loyalty, or continued care in the surgical hospital (OR 1.73; 95% CI 1.51-2.00; p < 0.0001), undergoing chemotherapy before AET (OR 2.65; 95% CI 2.02-3.48; p < 0.0001), and earlier AET initiation, positively influenced adherence. CONCLUSIONS: Chronic disease monitoring using administrative data can help oncologists focus efforts to ensure AET adherence. Results suggest addressing mental health, age, disease severity patient perceptions, timely AET initiation and therapy switches, and encouraging continued follow-up in the same hospital or better care coordination with outside follow-up specialists.

Leishmania infantum infection reduces the amyloid ß42-stimulated NLRP3 inflammasome activation.

Activation of the NLRP3 inflammasome has been shown to play a major role in the neuroinflammation that accompanies Alzheimer's disease (AD); interventions that down regulate the NLRP3 inflammasome could thus be beneficial in AD. Parasite infections were recently shown to be associated with improved cognitive functions in Apolipoprotein E4 (ApoE4)-expressing members of an Amazonian tribe. We verified in an in vitro model whether Leishmania infantum infection could reduce NLRP3. Results obtained in an initial experimental model in which PBMC were LPS primed and nigericin-stimulated showed that L. infantum infection significantly reduced ASC-speck formation (i.e. intracellular inflammasome proteins assembly), as well as the production of activated caspase 5 and IL-1ß, but increased that of activated caspase 1 and IL-18. Moreover, L. infantum infection induced the generation of an anti-inflammatory milieu by suppressing the production of TNFα and increasing that of IL-10. These results were replicated when cells that had been LPS-primed were stimulated with Aß42 and infected with L. infantum. Results herein indicate that Leishmania infection favors an anti-inflammatory milieu, which includes the down-regulation of NLRP3 inflammasome activation, possibly to facilitate its survival inside host cells. A side effect of Leishmaniasis would be the hampering of neuroinflammation; this could play a protective role against AD development.

A scoping review of core outcome sets and their 'mapping' onto real-world data using prostate cancer as a case study.

BACKGROUND: A Core Outcomes Set (COS) is an agreed minimum set of outcomes that should be reported in all clinical studies related to a specific condition. Using prostate cancer as a case study, we identified, summarized, and critically appraised published COS development studies and assessed the degree of overlap between them and selected real-world data (RWD) sources. METHODS: We conducted a scoping review of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database to identify all COS studies developed for prostate cancer. Several characteristics (i.e., study type, methods for consensus, type of participants, outcomes included in COS and corresponding measurement instruments, timing, and sources) were extracted from the studies; outcomes were classified according to a predefined 38-item taxonomy. The study methodology was assessed based on the recent COS-STAndards for Development (COS-STAD) recommendations. A 'mapping' exercise was conducted between the COS identified and RWD routinely collected in selected European countries. RESULTS: Eleven COS development studies published between 1995 and 2017 were retrieved, of which 8 were classified as 'COS for clinical trials and clinical research', 2 as 'COS for practice' and 1 as 'COS patient reported outcomes'. Recommended outcomes were mainly categorized into 'mortality and survival' (17%), 'outcomes related to neoplasm' (18%), and 'renal and urinary outcomes' (13%) with no relevant differences among COS study types. The studies generally fulfilled the criteria for the COS-STAD 'scope specification' domain but not the 'stakeholders involved' and 'consensus process' domains. About 72% overlap existed between COS and linked administrative data sources, with important gaps. Linking with patient registries improved coverage (85%), but was sometimes limited to smaller follow-up patient groups. CONCLUSIONS: This scoping review identified few COS development studies in prostate cancer, some quite dated and with a growing level of methodological quality over time. This study revealed promising overlap between COS and RWD sources, though with important limitations; linking established, national patient registries to administrative data provide the best means to additionally capture patient-reported and some clinical outcomes over time. Thus, increasing the combination of different data sources and the interoperability of systems to follow larger patient groups in RWD is required.

Patient access to oral nutritional supplements: Which policies count?

OBJECTIVES: Oral nutritional supplements (ONS) represent a cost-effective method for treating malnutrition. The aim of this study was to investigate the effects of public policies on patient access to ONS, using the Italian regionalized health care system as a case study, subsequently compared with the centralized British National Health Service. METHODS: Regional policies in the nine largest Italian regions and British policies were gathered through a literature review; interviews with officers responsible for clinical nutrition policies at the regional level in Italy were also conducted. Total ONS regional sales in Italy were gathered from industry sources. RESULTS: Regulation by Italian regions focused on patient access and local prescribing issues (facilities and specialists allowed to prescribe reimbursed ONS, clinical pathways for malnutrition or disease-related malnutrition, length of prescriptions, and distribution of ONS). British policies focused on organizational issues (clinical governance through multidisciplinary Nutrition Support Teams, Nutrition Steering Committees and Clinical Commissioning Groups), education and referral by health care professionals. Neither per capita reimbursed ONS expenditure nor the proportion covered by public funds seem dependent on policies implemented at the regional level in Italy. There is no cutting-edge evidence that British policies produced broader diffusion of ONS, but they appear to have standardized their use within a more homogenous framework. CONCLUSION: As no clear relation between regional policies and variation in patient access to ONS emerges in Italy, national policies should be encouraged to enhance awareness of malnutrition among health care professionals and encourage the diffusion of multidisciplinary nutrition teams in health care organizations.

Opportunities and challenges of a novel cardiac output response to stress (CORS) test to enhance diagnosis of heart failure in primary care: qualitative study.

OBJECTIVE: To explore the role of the novel cardiac output response to stress (CORS), test in the current diagnostic pathway for heart failure and the opportunities and challenges to potential implementation in primary care. DESIGN: Qualitative study using semistructured in-depth interviews which were audio recorded and transcribed verbatim. Data from the interviews were analysed thematically using an inductive approach. SETTING: Newcastle upon Tyne, UK. PARTICIPANTS: Fourteen healthcare professionals (six males, eight females) from primary (general practitioners (GPs), nurses, healthcare assistant, practice managers) and secondary care (consultant cardiologists). RESULTS: Four themes relating to opportunities and challenges surrounding the implementation of the new diagnostic technology were identified. These reflected that the adoption of CORS test would be an advantage to primary care but the test had barriers to implementation which include: establishment of clinical utility, suitability for immobile patients and cost implication to GP practices. CONCLUSION: The development of a simple non-invasive clinical test to accelerate the diagnosis of heart failure in primary care maybe helpful to reduce unnecessary referrals to secondary care. The CORS test has the potential to serve this purpose; however, factors such as cost effectiveness, diagnostic accuracy and seamless implementation in primary care have to be fully explored.

The short-term economic burden of gestational diabetes mellitus in Italy.

BACKGROUND: The incidence of Gestational Diabetes Mellitus (GDM) is rising in all developed countries. This study aimed at assessing the short-term economic burden of GDM from the Italian healthcare system perspective. METHODS: A model was built over the last pregnancy trimester (i.e., from the 28th gestational week until childbirth included). The National Hospital Discharge Database (2014) was accessed to estimate delivery outcome probabilities and inpatient costs in GDM and normal pregnancies (i.e., euglycemia). International Classification of Disease-9th Revision-Clinical Modification (ICD9-CM) diagnostic codes and Diagnosis-Related Group (DRG) codes were used to identify GDM cases and different types of delivery (i.e., vaginal or cesarean) within the database. Neonatal outcomes probabilities were estimated from the literature and included macrosomia, hypoglycemia, hyperbilirubinemia, shoulder dystocia, respiratory distress, and brachial plexus injury. Additional data sources such as regional documents, official price and tariff lists, national statistics and expert opinion were used to populate the model. The average cost per case was calculated at national level to estimate the annual economic burden of GDM. One-way sensitivity analyses and Monte Carlo simulations were performed to quantify the uncertainty around base case results. RESULTS: The amount of pregnancies complicated by GDM in Italy was assessed at 54,783 in 2014 using a prevalence rate of 10.9%. The antenatal outpatient cost per case was estimated at €43.7 in normal pregnancies compared to €370.6 in GDM patients, which is equivalent to a weighted sum of insulin- (14%; €1034.6) and diet- (86%; €262.5) treated women's costs. Inpatient delivery costs were assessed at €1601.6 and €1150.3 for euglycemic women and their infants, and at €1835.0 and €1407.7 for GDM women and their infants, respectively. Thus, the overall cost per case difference between GDM and normal pregnancies was equal to €817.8 (+ 29.2%), resulting in an economic burden of about €44.8 million in 2014 at national level. Probabilistic sensitivity analysis yielded a cost per case difference ranging between €464.9 and €1164.8 in 80% of simulations. CONCLUSIONS: The economic burden of GDM in Italy is substantial even accounting for short-term medical costs only. Future research also addressing long-term consequences from a broader societal perspective is recommended.

Five year trends (2008-2012) in cardiac implantable electrical device utilization in five European nations: a case study in cross-country comparisons using administrative databases.

Aims: Common methodologies for analysis of analogous data sets are needed for international comparisons of treatment and outcomes. This study tests using administrative hospital discharge (HD) databases in five European countries to investigate variation/trends in pacemaker (PM) and implantable cardioverter defibrillator (ICD) implant rates in terms of patient characteristics/management, device subtype, and initial implantation vs. replacement, and compares findings with existing literature and European Heart Rhythm Association (EHRA) reports. Methods and results: HD databases from 2008 to 2012 in Austria, England, Germany, Italy and Slovenia were interrogated to extract admissions (without patient identification) associated with PM and ICD implants and replacements, using direct cross-referencing of procedure codes and common methodology to compare aggregate data. 1 338 199 records revealed 212 952 PM and 62 567 ICD procedures/year on average for a 204.4 million combined population, a crude implant rate of about 104/100 000 inhabitants for PMs and 30.6 for ICDs. The first implant/replacement rate ratios were 81/24 (PMs) and 25/7 (ICDs). Rates have increased, with cardiac resynchronization therapy (CRT) subtypes for both devices rising dramatically. Significant between- and within-country variation persists in lengths of stay and rates (Germany highest, Slovenia lowest). Adjusting for age lessened differences for PM rates, scarcely affected ICDs. Male/female ratios remained stable at 56/44% (PMs) and 79/21% (ICDs). About 90% of patients were discharged to home; 85-100% were inpatient admissions. Conclusion: To aid in policymaking and track outcomes, HD administrative data provides a reliable, relatively cheap, methodology for tracking implant rates for PMs and ICDs across countries, as comparisons to EHRA data and the literature indicated.

Correction: Mortality and Length of Stay of Very Low Birth Weight and Very Preterm Infants: A EuroHOPE Study.

[This corrects the article DOI: 10.1371/journal.pone.0131685.].

Investigating Regional Variation of Cardiac Implantable Electrical Device Implant Rates in European Healthcare Systems: What Drives Differences?

Despite established efficacy for cardiac implantable electrical devices (CIEDs), large differences in CIED implant rates have been documented across and within countries. The aim of this paper is to investigate the influence of socio-economic, epidemiological and supply side factors on CIED implant rates across 57 Regions in 5 EU countries and to assess the feasibility of using administrative data for this purpose. A total of 1 330 098 hospitalizations for CIED procedures extracted from hospital discharge databases in Austria, England, Germany, Italy and Slovenia from 2008 to 2012 was used in the analysis. Higher levels of tertiary education among the labour force and percent of aged population are positively associated with implant rates of CIED. Regional per capita GDP and number of implanting centres appear to have no significant effect. Institutional factors are shown to be important for the diffusion of CIED. Wide variation in CIED implant rates across and within five EU countries is undeniable. However, regional factors play a limited part in explaining these differences with few exceptions. Administrative databases are a valuable source of data for investigating the diffusion of medical technologies, while the choice of appropriate modelling strategy is crucial in identifying the drivers for variation across countries. © 2017 The Authors. Health Economics published by John Wiley & Sons, Ltd.

Parameter Heterogeneity In Breast Cancer Cost Regressions - Evidence From Five European Countries.

We investigate parameter heterogeneity in breast cancer 1-year cumulative hospital costs across five European countries as part of the EuroHOPE project. The paper aims to explore whether conditional mean effects provide a suitable representation of the national variation in hospital costs. A cohort of patients with a primary diagnosis of invasive breast cancer (ICD-9 codes 174 and ICD-10 C50 codes) is derived using routinely collected individual breast cancer data from Finland, the metropolitan area of Turin (Italy), Norway, Scotland and Sweden. Conditional mean effects are estimated by ordinary least squares for each country, and quantile regressions are used to explore heterogeneity across the conditional quantile distribution. Point estimates based on conditional mean effects provide a good approximation of treatment response for some key demographic and diagnostic specific variables (e.g. age and ICD-10 diagnosis) across the conditional quantile distribution. For many policy variables of interest, however, there is considerable evidence of parameter heterogeneity that is concealed if decisions are based solely on conditional mean results. The use of quantile regression methods reinforce the need to consider beyond an average effect given the greater recognition that breast cancer is a complex disease reflecting patient heterogeneity.

Variations and Determinants of Mortality and Length of Stay of Very Low Birth Weight and Very Low for Gestational Age Infants in Seven European Countries.

The EuroHOPE very low birth weight and very low for gestational age infants study aimed to measure and explain variation in mortality and length of stay (LoS) in the populations of seven European nations (Finland, Hungary, Italy (only the province of Rome), the Netherlands, Norway, Scotland and Sweden). Data were linked from birth, hospital discharge and mortality registries. For each infant basic clinical and demographic information, infant mortality and LoS at 1 year were retrieved. In addition, socio-economic variables at the regional level were used. Results based on 16,087 infants confirm that gestational age and Apgar score at 5 min are important determinants of both mortality and LoS. In most countries, infants admitted or transferred to third-level hospitals showed lower probability of death and longer LoS. In the meta-analyses, the combined estimates show that being male, multiple births, presence of malformations, per capita income and low population density are significant risk factors for death. It is essential that national policies improve the quality of administrative datasets and address systemic problems in assigning identification numbers at birth. European policy should aim at improving the comparability of data across jurisdictions.

Hospital Burden and Gastrointestinal Surgery in Inflammatory Bowel Disease Patients in Italy: A Retrospective Observational Study.

BACKGROUNDS AND AIMS: Despite recent advances in medical therapies for inflammatory bowel disease [IBD], little is known about their impact on inpatient management. Our objectives were to explore hospitalisation and surgery trends for all IBD patients in Italy at three time points over 7 years. METHODS: National hospital discharge records were retrospectively reviewed for all admissions with a Crohn's disease [CD, 555*] or ulcerative colitis [UC, 556*] diagnosis in 2005, 2008, and 2011. Quantitative variables [mean, standard deviation] and categorical variables [frequencies] were described; comparison among admission-years was made by analysis of variance and chi-square tests. A multivariate logistic regression analysis was performed to identify predictors of surgery risk regarding demographics, inpatient management, and clinical features; p-values ≤ 0.05 were considered statistically significant. RESULTS: Overall, 109657 hospitalisations occurred over the 3 years, with a decreasing trend observed in UC admissions. Mean age was higher in UC [50.1±19.7] than in CD [43.2±21.9]. The number of paediatric admissions rose from 3637 to 4372 between 2005 and 2011. An increasing proportion of CD [from 12.4% to 14.6%] and UC [from 5.8% to 8.0%] admissions reported a digestive system-related, surgical diagnosis-related group in the same period; overall, gastrointestinal surgical admissions increased from 3299 to 3964. In regression analysis, male gender, age, admission year, northern university hospital, disease localisation, and cancer as independent factors significantly affected the likelihood of surgery. CONCLUSIONS: Despite a reduction in total IBD hospitalisations, surgical and paediatric admissions rose over time. Further study is needed to clarify benefits associated with new drugs in terms of inpatient management.

Mortality and Length of Stay of Very Low Birth Weight and Very Preterm Infants: A EuroHOPE Study.

The objective of this paper was to compare health outcomes and hospital care use of very low birth weight (VLBW), and very preterm (VLGA) infants in seven European countries. Analysis was performed on linkable patient-level registry data from seven European countries between 2006 and 2008 (Finland, Hungary, Italy (the Province of Rome), the Netherlands, Norway, Scotland, and Sweden). Mortality and length of stay (LoS) were adjusted for differences in gestational age (GA), sex, intrauterine growth, Apgar score at five minutes, parity and multiple births. The analysis included 16,087 infants. Both the 30-day and one-year adjusted mortality rates were lowest in the Nordic countries (Finland, Sweden and Norway) and Scotland and highest in Hungary and the Netherlands. For survivors, the adjusted average LoS during the first year of life ranged from 56 days in the Netherlands and Scotland to 81 days in Hungary. There were large differences between European countries in mortality rates and LoS in VLBW and VLGA infants. Substantial data linkage problems were observed in most countries due to inadequate identification procedures at birth, which limit data validity and should be addressed by policy makers across Europe.

The role of transposable elements in the regulation of IFN-lambda1 gene expression.

IFNs lambda1, lambda2, and lambda3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-lambda1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-kappaB binding sites. Remarkably, these sites, which bind efficiently to NF-kappaB and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-kappaB RelA protein significantly reduces the level of the IFN-lambda1 gene expression. We conclude that IFN-lambda1 gene expression requires NF-kappaB, and we propose a model for IFN-lambda1 gene regulation, in which IRF and NF-kappaB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-lambda1 and IFN-beta promoters and directly implicate transposable elements in the regulation of the IFN-lambda1 gene by NF-kappaB.

Detecting and modulating the NF-kB activity in human immune cells: generation of human cell lines with altered levels of NF-kappaB.

NF-kappaB plays a pivotal role in immunity and inflammation and is considered to be a promising candidate for drug development. However, global suppression of NF-kappaB may have undesirable side-effects. Our data and the results of others suggest that each of the five NF-kappaB subunits may have a specific function in controlling the expression of inflammatory mediators in immune cells. Identifying the role for each NF-kappaB subunit in primary human immune cells will allow a more targeted approach to inhibiting NF-kappaB subunit-specific cellular functions. However, results obtained with primary human cells can often be inconsistent due to donor heterogeneity. Therefore one possible approach could be to generate human immune cell lines with stably inhibited expression of specific NF-kappaB subunit(s) as described in this chapter.