Correction: Siegel et al. PEN-13: A New Generic 13-Item Questionnaire for Measuring Patient Enablement (German Version). Int. J. Environ. Res. Public Health 2019, 16, 4867.

In the original publication [...].

Prescribing of valproate and oral antiepileptics for women of childbearing age and during pregnancy in Germany between 2010 and 2020.

PURPOSE: To examine prescriptions of valproate and oral antiepileptic drugs (OAED) in Germany irrespective of the indication in women in general and particularly in women of childbearing age (13-49 years) and during pregnancy between 2010 and 2020, that is, before, during and after the implementation of the EU risk minimization measures (RMMs). METHODS: Analysis of claims data. STUDY POPULATION: all women continuously insured with the AOK health insurance fund in the respective observation year (2010-2020) and the previous year. OAED were identified by ATC code N03. Period of pregnancy was calculated based on birth information in claims data. MAIN OUTCOMES MEASURES: (i) prevalent use of valproate/OAED: number of women with at least one prescription of valproate/OAED per year divided by all women of the study population (rate per 1000 women); (ii) percentage of OAED recipients with at least one valproate prescription during pregnancy (13-49 years) in the respective observation year. RESULTS: Prevalence rate/1000 women for valproate use decreased by -31.33% across all age groups (2010-2014: -7.48%; 2014-2018: -16.47%; 2018-2020: -11,17%) with a strong reduction in women 13-49 years between 2014 and 2018 (-28.74%). The rate for OAED across all age groups rose from 33.43/1000 women in 2010 to 41.03/1000 (+22,73%). Valproate use during pregnancy of women with OAED declined from 1.29% in 2010 to 0.59% in 2020 (-54,26%) (2010-2014: -5.14%; 2014-2018: -42.31%; 2018-2020: -16.69%). CONCLUSION: Even if, due to the descriptive nature of the study, no causal relationship can be postulated between the RMMs and the strong decrease in valproate prescriptions, our results are compatible with the hypothesis that the measures have improved drug therapy safety.

Claims data analysis of the health care utilization for patients with coronary heart disease and mental comorbidity.

OBJECTIVE: Mental disorders (MD) are a common comorbidity in patients with coronary heart disease (CHD) and have a significant impact on morbidity and mortality. The aim of this study was to determine to what extent mental disorders are diagnosed as comorbidity in patients with CHD and whether adequate therapeutic measures are taken. METHODS: Claims data from 4435 Cologne citizens with diagnosed CHD and a hospital stay due to CHD in 2015 were examined through a longitudinal analysis. The data were analyzed descriptively with regard to mental disorders, investigating diagnostic examinations performed, prescriptions for psychotropic drugs, and utilization of psychotherapy. We differentiated between pre-existing MD, existing in the year before the CHD-related hospital stay, and incident MD with new onset during or within six months after hospitalization. RESULTS: Psychodiagnostic examinations for mental disorders occurred very rarely during cardiological hospitalization (0.04%) and psychiatric/psychosomatic consultation sessions rarely (5%). The longitudinal analysis showed a high rate of pre-existing MDs (56%, n = 2490) and a new diagnosis of mental disorders in 7% (n = 302) of the patients. Within one year after inpatient treatment for CHD, psychotropic medication was prescribed in 64-67% of patients with newly diagnosed affective or neurotic, adjustment/somatoform disorder and 10-13% received outpatient psychotherapy. CONCLUSION: The results indicate low rates of inpatient diagnostic examinations and low rates of adequate treatment of mental disorders in patients from Cologne with CHD and new onset mental disorders. The rate of prescriptions of psychopharmacotherapy after hospitalization due to CHD exceeds that of the utilization of outpatient psychotherapy.

Effects of a Primary Care-Based Intervention on the Identification and Management of Patients with Coronary Heart Disease and Mental or Cognitive Comorbidity-A Study Protocol.

Mental and cognitive disorders (MCD) negatively affect the incidence and prognosis of coronary heart disease (CHD). Medical guidelines recommend the appropriate management of comorbid MCD in patients with CHD, yet there is evidence that the implementation in primary care is not always adequate. We present the protocol for a pilot study that aims to develop a minimally invasive intervention and evaluate its feasibility in the primary care setting to improve the identification and management of comorbid MCD in patients with CHD. The study consists of two consecutive parts and will be carried out in Cologne, Germany. Part 1 comprises the development and tailoring of the intervention, which is guided by qualitative interviews with primary care physicians (PCPs, n = 10), patients with CHD and MCD and patient representatives (n = 10). Part II focuses on the implementation and evaluation of the intervention in n = 10 PCP offices. Changes in PCP behaviour will be analysed by comparing routine data in the practice management system six months before and six months after study participation. In addition, we will explore the influence of organisational characteristics and perform a socio-economic impact assessment. The outcomes of this mixed-method study will inform the feasibility of a PCP-based intervention to improve quality of care in patients with CHD and comorbid MCD.

[Development and Internal Validation of Case Definitions for Prevalence Estimation of Microvascular Complications of Diabetes in Routine Data]. / Entwicklung und interne Validierung von Falldefinitionen für die Prävalenzschätzung mikrovaskulärer Komplikationen des Diabetes in Routinedaten.

BACKGROUND: Surveillance of diabetes requires up-to-date information on the prevalence of diabetes and its complications over time. For this purpose, statutory health insurance (SHI) data is being increasingly used, as the data is available in a timely fashion and case numbers enable detailed estimates also of diabetes complications. The aim of the present study was the development and internal validation of case definitions for the prevalence estimation of diabetic retinopathy (DRP), diabetic polyneuropathy (DPN) and diabetic foot syndrome (DFS). METHODS: Persons with diabetes differentiated by type 1, type 2, and other diabetes in an age- and sex-stratified sample of persons insured by Barmer SHI in 2018 (n=72,744) comprised the study popuation. Based on the central ICD codes for microvascular complications (DRP: H36.0; DPN: G63.2; DFS: E1X.74/.75), case definitions were developed including additional ICD codes for complications without direct diabetes reference. Subsequently, the case definitions were internally validated. For the validation, coding in the inpatient setting (m1S) or repeatedly in the outpatient setting (m2Q) as well as coding of specific procedures (EBM, OPS) and drug prescriptions or by relevant specialists were considered. Additionally, we analysed the documentation of the diagnoses in the previous years. RESULTS: In 2018, the prevalence of the central ICD codes was 8.4% for DRP (H36.0), 18.9% for DPN (G63.2) and 13.4% for DFS (E1X.74/.75). After inclusion of additional ICD codes in the case definition, prevalence increased significantly for DRP (9.6%) and DPN (20.7%), and barely for DFS (13.5%). Internal validation confirmed the majority of diagnoses (DRP: 96.7%; DPN: 96.5% DFS: 95.8%) and m2Q represented the most relevant criterion. When up to four previous years were considered, prevalences were up to 30% higher for DPN and DFS and up to 64% higher for DRP. CONCLUSION: The inclusion of additional ICD codes in the case definition of microvascular complications of diabetes appears meaningful, as this increases the sensitivity of the prevalence estimate. Internal validation suggests that the documented diagnoses are plausible. However, not all diagnoses are documented annually, leading to an underestimation of the prevalence using a cross-sectional study design of one year.

Drilling for 'New Oil' in Care Integration - Co-Production of the Concept and Specification of an Integrated Data Centre for Policy Decision Making, Care Planning, and Research in Estonia.

Introduction: Care integration needs to take place on different levels, including that of infrastructure and especially data infrastructure. Only integrated data allow for policy making, care planning, research, and evaluation that spans across different sectors of care and support. Methods: In the course of an EU-funded reform initiative on integrated care, the Estonian government and various agencies have developed a concept for an integrated data centre, bringing together information from social, medical, and vocational support services. The concept was developed in co-production with many stakeholders. A test data set from all covered sectors, including the pseudonymised data of 17,945 citizens of an Estonian municipality, was created and analysed as a proof-of-concept exercise. Results: The co-production approach resulted in a set of requirements and use cases as well as a specification of premises, processes, and data flows for the data centre. The analysis of the test dataset showed the principal feasibility of the dataset for the intended purposes. Conclusion: The concept development phase showed that an integrated data centre for Estonia is feasible per se and helped to specify concrete actions required for its realisation. Strategic and financial decisions from the Estonian Reform Steering Committee are now needed to create the data centre.

[Research Data Center on Health - Vision for Further Development from the Research Perspective]. / Forschungsdatenzentrum Gesundheit ­ Vision für eine Weiterentwicklung aus Sicht der Forschung.

The German research data center for health will provide claims data of statutory health insurances. The data center was set up at the medical regulatory body BfArM pursuant to the German data transparency regulation (DaTraV). The data provided by the center will cover about 90% of the German population, supporting research on healthcare issues, including questions of care supply, demand and the (mis-)match of both. These data support the development of recommendations for evidence-based healthcare. The legal framework for the center (including §§ 303a-f of Book V of the Social Security Code and two subsequent ordinances) leaves a considerable degree of freedom when it comes to organisational and procedural aspects of the center's operation. The present paper addresses these degrees of freedom. From the point of view of researchers, ten statements show the potential of the data center and provide ideas for its further and sustainable development.

Effectiveness of the application of an electronic medication management support system in patients with polypharmacy in general practice: a study protocol of cluster-randomised controlled trial (AdAM).

INTRODUCTION: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. METHODS AND ANALYSIS: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. SCOPE: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. POPULATION: patients (≥18 years) with polypharmacy (≥5 prescriptions). SAMPLE SIZE: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. INTERVENTION: complex intervention eMMa. FOLLOW-UP: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. OUTCOMES: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. STATISTICAL ANALYSIS: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints. ETHICS AND DISSEMINATION: Trial approved by Ethics Commission of North-Rhine Medical Association. Results will be disseminated through workshops, peer-reviewed publications, local and international conferences. TRIAL REGISTRATION: NCT03430336. ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03430336).

Last Year of Life Study-Cologne (LYOL-C) (Part II): study protocol of a prospective interventional mixed-methods study in acute hospitals to analyse the implementation of a trigger question and patient question prompt sheets to optimise patient-centred care.

INTRODUCTION: The Last Year of Life Study-Cologne Part I (LYOL-C I) has identified general hospital units as the most important checkpoints for transitions in the last year of life of patients. Yet, satisfaction with hospitals, as reported by bereaved relatives, is the lowest of all health service providers. Thus, the LYOL-C Part II (LYOL-C II) focuses on optimising patient-centred care in acute hospitals for patients identified to be in their last year of life. LYOL-C II aims to test an intervention for hospitals by using a two-sided (healthcare professionals (HCPs) and patients) trigger question-based intervention to 'shake' the system in a minimally invasive manner. METHODS AND ANALYSIS: Prospective interventional mixed-methods study following a two-phase approach: phase I, individual interviews with HCPs and patient representatives to design the intervention to maximise ease of implementation and phase II, exploratory study with two arms and a prepost design with patients in their last year of life. The intervention will consist of the Surprise Question and the German version of the Supportive and Palliative Care Indicators Tool (SPICT-DE) for HCPs to identify patients and provide patient-centred care, plus question prompt sheets for patients, encouraging them to initiate discussions with their HCPs. Data on transitions, changes in therapy, quality of care, palliative care integration and death of patients will be analysed. Furthermore, a staff survey (pre/post) and guided interviews with staff, patients and relatives (post) will be conducted. Finally, a formative socioeconomic impact assessment to provide evidence regarding the sustainability of the intervention will be performed. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of the Faculty of Medicine of the University of Cologne (#20-1431). Results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: DRKS00022378.

[The use of data for public health and healthcare-a shared goal of the EU member states]. / Die Nutzbarmachung von Daten für Public Health und Gesundheitsversorgung ­ ein gemeinsames Ziel der EU-Mitgliedsstaaten.

Population health - understood both as prevention and healthcare - needs good data. Data can support decision making on the system level as well as the delivery of services for each individual. Furthermore, data are a prerequisite for research and innovation. At the same time, health data are hard to come by: coverage is spotty or - for certain parts of the system - lacking, available data only provides a proxy view of actual prevention or healthcare, or it exists in formats that hamper or prevent automated processing at scale. Furthermore, the high sensitivity of health data necessitates an equally high degree of protection, further complicating access.These challenges are not specific to Germany but are common in all member states of the European Union. However, up to now, German stakeholders tend to neglect the potential of a joint European approach to these challenges. The article provides an overview of different European initiatives in the domain of health data. The focus is on how German stakeholders can gain better access to these initiatives to benefit from the knowledge and experiences of neighbouring countries, but also to feed back their own knowledge into the European loop.

[Security and user acceptance of an intelligent home emergency call system for older people living at home with limited daily living skills and receiving home care]. / Sicherheit und Nutzerakzeptanz eines intelligenten Hausnotrufsystems im Einsatz bei älteren pflegebedürftigen zu Hause lebenden Menschen mit eingeschränkter Alltagskompetenz.

BACKGROUND: Technically based support measures are becoming increasingly more important in an aging society. Such support measures can provide a self-determined life in familiar surroundings despite the need for care. An example for such a support measure is an intelligent home emergency call system (iHNR system), which automatically detects critical situations (e.g. falling down), transmits this information to an emergency call center and therefore initiates assistance faster. OBJECTIVE: The aim of this uncontrolled, two center observational study was to evaluate the security and acceptance of an iHNR system used by older people receiving home care. MATERIAL AND METHODS: The study was carried out based on 51 subjects with at least a 6-month observation period using the iHNR system. The iHNR system was installed in all homes of the participants. Interviews about acceptance, perceived and objective security, impact on independence and usability of the new iHNR system were conducted. Analysis was performed with particular respect to depression, quality of life, frailty and self-estimated need for assistance. RESULTS: A total of 39 complete records were collected and evaluated. The participants represented a vulnerable group of people with rather depressive moods, negative quality of life and a high level of frailty without significant changes over the observation period. Positive results were found regarding subjective and objective security and acceptance as well as ease of operation of the iHNR system. The fear of falling was only marginally influenced. CONCLUSION: Acceptance regarding the new iHNR system was high. The system provoked a stronger sense of security while at the same time leading to a reduced sense of control. The system seems to be able to detect critical events and can automatically and quickly alert the necessary help services. Therefore, people in need of care can remain longer in their own homes.

BeyondSilos, a Telehealth-Enhanced Integrated Care Model in the Domiciliary Setting for Older Patients: Observational Prospective Cohort Study for Effectiveness and Cost-Effectiveness Assessments.

BACKGROUND: Information and communication technology may provide domiciliary care programs with continuity of care. However, evidence about the effectiveness and cost-effectiveness of information and communication technology in the context of integrated care models is relatively scarce. OBJECTIVE: The objective of our study was to provide evidence on the clinical effectiveness and cost-effectiveness of the BeyondSilos project for patients enrolled in the Badalona city pilot site in Spain. METHODS: A quasi-experimental study was used to assess the cost-effectiveness of information and communication technology-enhanced integration of health and social care, including the third sector (intervention), compared to basic health and social care coordination (comparator). The study was conducted in Badalona between 2015 and 2016. Participants were followed for 8 months. RESULTS: The study included 198 patients: 98 in the intervention group and 100 in the comparator group. The mean Barthel index remained unchanged in the intervention group (mean change 0.14, 95% CI -4.51 to 4.78; P=.95) but decreased in the comparator group (mean change -3.23, 95% CI -5.34 to -1.11; P=.003). Instrumental Activities of Daily Living significantly decreased in both groups: mean changes of -0.23 (95% CI -0.44 to -0.02; P=.03) and -0.33 (95% CI -0.46 to -0.20; P<.001) in the intervention and comparator groups, respectively. No differences were found in the Geriatric Depression Scale (intervention: mean change 0.28, 95% CI -0.44 to 1.01, P=.44; comparator: mean change -0.29, 95% CI -0.59 to 0.01, P=.06). The intervention showed cost-effectiveness (incremental cost-effectiveness ratio €6505.52, approximately US $7582). CONCLUSIONS: The information and communication technology-enhanced integrated domiciliary care program was cost-effective. The beneficial effects of this approach strongly rely upon the commitment of the professional staff involved. TRIAL REGISTRATION: ClinicalTrials.gov NCT03111004; http://clinicaltrials.gov/ct2/show/ NCT03111004.

Good Practice Data Linkage (GPD): A Translation of the German Version.

The data linkage of different data sources for research purposes is being increasingly used in recent years. However, generally accepted methodological guidance is missing. The aim of this article is to provide methodological guidelines and recommendations for research projects that have been consented to across different German research societies. Another aim is to endow readers with a checklist for the critical appraisal of research proposals and articles. This Good Practice Data Linkage (GPD) was already published in German in 2019, but the aspects mentioned can easily be transferred to an international context, especially for other European Union (EU) member states. Therefore, it is now also published in English. Since 2016, an expert panel of members of different German scientific societies have worked together and developed seven guidelines with a total of 27 practical recommendations. These recommendations include (1) the research objectives, research questions, data sources, and resources; (2) the data infrastructure and data flow; (3) data protection; (4) ethics; (5) the key variables and linkage methods; (6) data validation/quality assurance; and (7) the long-term use of data for questions still to be determined. The authors provide a rationale for each recommendation. Future revisions will include new developments in science and updates of data privacy regulations.

[Date of Service Provision and Date of Payment in Claims Data: Dealing with Time Differences]. / Leistungs- und Abrechnungsdatum in GKV-Routinedaten: Umgang mit zeitlichen Abweichungen.

AIM: The paper quantifies discrepancies between date of payment and date of service provision when doing analyses in relation to date of death and also in relation to the end of a calendar year. In analyses of this type, time differences between service provision and payment can lead to both under- and overestimation of service use. We aim to capture these phenomena in claims data from different sectors (primary care, medication prescription, prescription of remedies and medical aids, hospital care). METHOD: We have used pre-structured claims data from a scientific data warehouse of a large German statutory health insurance covering people that died in 2016. We investigated the discrepancies in time between date of service provision and date of payment for different outpatient and inpatient services based on data from 2015 to 2017. An exact date (dd/mm/yyyy) was only available for data covering prescriptions of remedies and medical aids. Data covering medication prescriptions were only exact to the month of payment (mm/yyyy), whereas data covering outpatient physician care were only exact to the quarter of payment (q/yyyy). RESULTS: For both outpatient physician care and hospital care, less than 1% had a payment date after the date of death. The share is considerably higher (28-31%) for prescriptions of remedies and medical aids. The majority of payments occurred within 3 months after death (93% for prescriptions of remedies and medical aids, 67% for primary care services). Less than 1% of outpatient physician care and about 18% of remedies had been paid after the end of the calender year 2015. Here too, the majority of payments were made within the first 3 months of 2016 (100% of prescriptions of remedies and medical aids, 65% of primary care services). CONCLUSIONS: Discrepancies in time between date of service provision and date of payment pose a challenge and are a potential source of under-/overestimation of health service utilization when doing analyses in relation to date of death or the end of a calendar year. This needs to be taken into account when requesting the data, but also in preparing and analysing them. The primary recommendation is to ensure that services with a payment date after death are included explicitly.

PEN-13: A New Generic 13-Item Questionnaire for Measuring Patient Enablement (German Version).

Background: The purpose of our study was to develop and psychometrically test a German-language survey instrument that measures patient enablement generically and in greater detail than previous instruments. Methods: A multidisciplinary team developed 13 items to capture individual aspects of patient enablement (PEN-13). A pre-test with 26 subjects was followed by a random sample survey of N = 1168 subjects. An exploratory factor analysis was conducted in a random split-half sample of the data to explore PEN-13's factor structure; a confirmatory factor analysis was conducted in the validation sample. The internal consistency of the factors was evaluated using Cronbach's alpha, PEN-13's construct validity was checked by means of additional hypothesis testing. Results: The two factors self-management and patient-practitioner interaction, detected in the exploratory analysis, were confirmed with a few modifications in the confirmatory factor analysis, with the comparative fit index (CFI) amounting to 0.903. The Cronbach's alpha values of those two factors amounted to α = 0.90 and α = 0.82, respectively. The correlations of the PEN-13 score with the 'general self-efficacy' and 'health literacy' (HLS-EU-Q16) scores further confirmed its construct validity; the respective correlation coefficients amounted to 0.57 and 0.60. Conclusion: The German version of the survey instrument Patient Enablement Scale-13 items (PEN-13) shows acceptable psychometric properties. Practical implications: PEN-13 seems particularly suitable for health services research purposes. We recommend checking the results in another sample as well as evaluating its responsiveness to enablement-enhancing interventions.

[Good Practice Data Linkage]. / Gute Praxis Datenlinkage (GPD).

Individual data linkage of different data sources for research purposes is being increasingly used in Germany in recent years. However, generally accepted methodological guidance is missing. The aim of this article is to define such methodological standards for research projects. Another aim is to provide readers with a checklist for critical appraisal of research proposals and articles. Since 2016, an expert panel of members of different German scientific societies have worked together and developed 7 guidelines with a total of 27 practical recommendations. These recommendations include (1) research aims, questions, data sources and resources, (2) infrastructure and data flow, (3) data privacy, (4) ethics, (5) key variables and type of linkage, (6) data validation/quality assurance and (7) long-term use for future research questions. The authors provide a rationale for each recommendation. Future revisions will include any new developments in science and data privacy.

RNA-based adjuvant CV8102 enhances the immunogenicity of a licensed rabies vaccine in a first-in-human trial.

BACKGROUND: We report the first-in-concept human trial of the safety, tolerability and immunogenicity when a novel TLR 7/8/RIG I agonist RNA-based adjuvant, CV8102, was administered alone or mixed with fractional doses of a licensed rabies vaccine (Rabipur®) as model antigen. METHODS: The primary objective was to assess the safety and reactogenicity of various dose levels of CV8102 alone or mixed with Rabipur® in healthy 18-40 year-old male volunteers. A secondary objective was to assess the immune-enhancing potential of bedside-mixes of CV8102 with fractional doses of Rabipur® by measuring induction of rabies virus neutralising titres (VNTs). RESULTS: Fifty-six volunteers received 50-100 µg CV8102 alone (n = 11), bedside-mixed CV8102 and Rabipur® (n = 20), or Rabipur® alone (n = 25; control). When given alone or mixed with Rabipur® CV8102 caused mostly Grade 1 or 2 local or systemic reactogenicity, but no related SAEs. As 100 µg CV8102 was associated with marked CRP increases further dose escalation was stopped. Combining 25-50 µg of CV8102 with fractional doses of Rabipur® significantly improved the kinetics of VNT responses; 50 µg CV8102 also improved the magnitude of VNT responses to 1/10 Rabipur® but caused severe but self-limiting influenza-like symptoms in 2 of 14 subjects. CONCLUSIONS: Doses of 25 and 50 µg CV8102 appeared safe and with an acceptable reactogenicity profile while significantly enhancing the immunogenicity of fractional doses of rabies vaccine. EudraCT No. 2013-004514-18.

Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: A phase III randomized, double-blind clinical trial.

Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes.

BACKGROUND: Development of cigarettes that reduce exposure to harmful smoke constituents is a suggested tobacco harm reduction strategy, but robust methods for measurement of change are required. We investigated whether changes in biomarkers of exposure (BoE), effective dose (BoED) and biological effect (BoBE) could be detected after switching from conventional cigarettes to a reduced-toxicant-prototype cigarette (RTP). METHODS: Regular smokers of 6-8mg ISO tar yield cigarettes were recruited in Hamburg, Germany, and supplied with a conventional 7mg ISO tar yield cigarette for 2weeks then switched to the same cigarette with a different tipping paper (control) or the RTP for 6months. Subjects smoked mostly at home and attended five residential clinic visits where urine and blood samples were collected for analysis. Primary endpoints were changes in specific biomarker levels compared with non-smoker background levels. Changes in daily cigarette consumption were also investigated. RESULTS: BoE levels in controls generally increased over the study period, whereas most BoE and all BoED significantly declined in RTP smokers. Most BoBE data were similar across groups and/or too variable within individuals to detect changes. Increased daily cigarette consumption was affected by supply of free cigarettes, perceived shorter smoking time per cigarette than usual brands, and perceived reduced harm. CONCLUSIONS: Despite increased cigarette consumption, reductions in BoE and BoED were detectable.