Eco-friendly Synthesis of Silver Nanoparticles and its Application in Hydrogen Photogeneration and Nanoplasmonic Biosensing.

Environmentally friendly methods for silver nanoparticles (AgNPs) synthesis without the use of hazardous chemicals have recently drawn attention. In this work, AgNPs have been synthesized by microwave irradiation using only honey solutions or aqueous fresh pink radish extracts. The concentrations of honey, radish extract, AgNO3 and pH were varied. AgNPs presented mean sizes between 7.0 and 12.8 nm and were stable up to 120 days. The AgNPs were employed as co-catalyst (TiO2 @AgNPs) to increase the hydrogen photogeneration under UV-vis and only visible light irradiation, when compared to pristine TiO2 NPs. The prepared photocatalyst also showed hydrogen generation under visible light. Additionally, AgNPs were used to assemble a nanoplasmonic biosensor for the biodetection of extremely low concentrations of streptavidin, owing to its specific binding to biotin. It is shown here that green AgNPs are versatile nanomaterials, thus being potential candidates for hydrogen photogeneration and biosensing applications.

Impact of different assumptions on estimates of childhood diseases obtained from health care data: A retrospective cohort study.

PURPOSE: Accurate estimates of disease incidence in children are required to support pediatric drug development. Analysis of electronic health care records (EHR) may yield such estimates but pediatric-specific methods are lacking. We aimed to understand the impact of assumptions regarding duration of disease episode and length of run-in period on incidence estimates from EHRs. METHODS: Children aged 0 to 17 years (5-17 years for asthma) registered in the Integrated Primary Care Information database between 2002 and 2014 were studied. We tested the impact of the following: maximum duration of disease episode (0, 14, 30, 60, and 90 days) on recurrent diseases (acute otitis media [common] and acute pyelonephritis [rare]); and database run-in period on chronic diseases-asthma (common) and type 1 diabetes (DM) (rare). We calculated incidence rate ratios with 95% confidence intervals and stratified using 1-year age categories. RESULTS: Altogether, 503 495 children were registered. The incidence of acute otitis media was highest in <2-year-old children; using 30 days disease duration as reference, the rate increased with 8% if the duration was 14 days and decreased with 8% when extended to 60 days. Disease duration did not impact acute pyelonephritis (rare). No run-in (to exclude prevalent cases) versus 24-month run-in period overestimated the incidence rate for asthma and DM by a factor of 2. CONCLUSIONS: Analysis of EHR allows for estimation of disease incidence in children, but assumptions regarding episode length and run-in period impact the incidence estimates. Such assumptions may be routinely explored.

Masking by vaccines in pediatric drug safety signal detection in the EudraVigilance database.

PURPOSE: Postmarketing drug safety surveillance relies upon measures of disproportionate reporting in spontaneous reporting systems. It has been hypothesized that products or events reported frequently may "mask" signals. METHODS: We analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures). We measured performance of the reporting odds ratio (ROR) in both data sets using a pediatric-specific drug reference set and in the absence of a reference set. We assessed masking effects across age groups and conducted a classification tree (CART) analysis. RESULTS: Removal of vaccines decreased the ROR values both in negative and positive controls. Exceptions were drug-event combinations including outcomes frequent in vaccine reports. When restricted to positive control associations, removal of vaccine-related events resulted in increased ROR values for events commonly reported following vaccination. For events rarely associated with vaccination, ROR values decreased for all age groups, especially infants. Analysis in the absence of a reference set showed decrease in ROR following vaccine removal and CART revealed that change in ROR with vaccine removal depended upon age and proportion of reports including a vaccine. CONCLUSIONS: Removal of vaccines for signal detection in a pediatric population has an impact on ROR, dependent upon the reporting frequency of the event of interest in combination with vaccines. We recommend stratification by age and removal of vaccine exposures if the investigated adverse drug reactions include those typically reported in association with vaccines for the age strata.

CodeMapper: semiautomatic coding of case definitions. A contribution from the ADVANCE project.

BACKGROUND: Assessment of drug and vaccine effects by combining information from different healthcare databases in the European Union requires extensive efforts in the harmonization of codes as different vocabularies are being used across countries. In this paper, we present a web application called CodeMapper, which assists in the mapping of case definitions to codes from different vocabularies, while keeping a transparent record of the complete mapping process. METHODS: CodeMapper builds upon coding vocabularies contained in the Metathesaurus of the Unified Medical Language System. The mapping approach consists of three phases. First, medical concepts are automatically identified in a free-text case definition. Second, the user revises the set of medical concepts by adding or removing concepts, or expanding them to related concepts that are more general or more specific. Finally, the selected concepts are projected to codes from the targeted coding vocabularies. We evaluated the application by comparing codes that were automatically generated from case definitions by applying CodeMapper's concept identification and successive concept expansion, with reference codes that were manually created in a previous epidemiological study. RESULTS: Automated concept identification alone had a sensitivity of 0.246 and positive predictive value (PPV) of 0.420 for reproducing the reference codes. Three successive steps of concept expansion increased sensitivity to 0.953 and PPV to 0.616. CONCLUSIONS: Automatic concept identification in the case definition alone was insufficient to reproduce the reference codes, but CodeMapper's operations for concept expansion provide an effective, efficient, and transparent way for reproducing the reference codes.

Baseline incidence of intussusception in early childhood before rotavirus vaccine introduction, the Netherlands, January 2008 to December 2012.

Intussusception is a rare, potentially life-threatening condition in early childhood. It gained attention due to an unexpected association with the first rotavirus vaccine, RotaShield, which was subsequently withdrawn from the market. Across Europe, broad variations in intussusception incidence rates have been reported. This study provides a first estimate of intussusception incidence in young children in the Netherlands from 1 January 2008 to 31 December 2012, which could be used for future rotavirus safety monitoring. Our estimates are based on two different sources: electronic medical records from the primary healthcare database (IPCI), as well as administrative data from the Dutch hospital register (LBZ). The results from our study indicate a low rate of intussusception. Overall incidence rate in children < 36 months of age was 21.2 per 100,000 person-years (95% confidence interval (CI): 12.5-34.3) based on primary healthcare data and 22.6 per 100,000 person-years (95% CI: 20.9-24.4) based on hospital administrative data. The estimates suggest the upper and lower bound of the expected number of cases.

UV-Surface Treatment of Fungal Resistant Polyether Polyurethane Film-Induced Growth of Entomopathogenic Fungi.

Synthetic polymers are the cause of some major environmental impacts due to their low degradation rates. Polyurethanes (PU) are widely used synthetic polymers, and their growing use in industry has produced an increase in plastic waste. A commercial polyether-based thermoplastic PU with hydrolytic stability and fungus resistance was only attacked by an entomopathogenic fungus, Metarhiziumanisopliae, when the films were pre-treated with Ultraviolet (UV) irradiation in the presence of reactive atmospheres. Water contact angle, Fourier transform infrared spectroscopy in attenuated total reflection mode (FTIR-ATR), scanning electron microscopy (SEM), and profilometer measurements were mainly used for analysis. Permanent hydrophilic PU films were produced by the UV-assisted treatments. Pristine polyether PU films incubated for 10, 30, and 60 days did not show any indication of fungal growth. On the contrary, when using oxygen in the UV pre-treatment a layer of fungi spores covered the sample, indicating a great adherence of the microorganisms to the polymer. However, if acrylic acid vapors were used during the UV pre-treatment, a visible attack by the entomopathogenic fungi was observed. SEM and FTIR-ATR data showed clear evidence of fungal development: growth and ramifications of hyphae on the polymer surface with the increase in UV pre-treatment time and fungus incubation time. The results indicated that the simple UV surface activation process has proven to be a promising alternative for polyether PU waste management.

Pharmacoepidemiological safety studies in children: a systematic review.

PURPOSE: In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies. METHODS: Relevant articles from inception to 2013 were retrieved from Embase and Medline. We sequentially screened titles, abstracts and full texts with independent validation. We systematically collected data regarding general information, study methods and results. RESULTS: Out of 4825 unique articles, 268 full texts (5.6%) were retained; 147 (54.9%) pertained to drugs rather than vaccines. Considering the 268 studies, 202 (75.4%) concerned children and adolescents (2 to 11 years) and 14 (5.3%) included preterm newborns. Most studies originated from North America (154 [57.5%]) or Europe (92 [34.3%]). Only 47 studies (17.5%) were privately funded. The majority (174 [64.9%]) were cohort studies. Out of 268 studies, 196 (73.1%) collected data retrospectively; paper medical charts were the most common data source for the exposures (85 [31.7%]) and outcomes (122 [45.5%]). Only 3 (2.0%) drug-only studies investigated rarely used drugs. Considering all 268 studies, only 27 (10.1%) reported sample size or power calculation. Most (75 [51.0%]) drug-only studies corrected confounding by multivariate modeling unlike stratification in 66 (55.9%) vaccine-only studies. Considering 75 child-only studies without any statistically significant result, 41 (54.7%) did not discuss lack of power. CONCLUSIONS: Although the field of pediatric pharmacoepidemiology is steadily developing evaluation seldom includes neonates, is mainly focused on few drug classes and safety outcomes and concerns mainly drug use in developed countries. Small study size is a specific challenge in pediatrics. Reporting should be improved. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Superomniphobic and easily repairable coatings on copper substrates based on simple immersion or spray processes.

Textures that resemble typical fern or bracken plant species (dendrite structures) were fabricated for liquid repellency by dipping copper substrates in a single-step process in solutions containing AgNO3 or by a simple spray liquid application. Superhydrophobic surfaces were produced using a solution containing AgNO3 and trimethoxypropylsilane (TMPSi), and superomniphobic surfaces were produced by a two-step procedure, immersing the copper substrate in a AgNO3 solution and, after that, in a solution containing 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PFDTES). The simple functionalization processes can also be used when the superomniphobic surfaces were destroyed by mechanical stress. By immersion of the wrecked surfaces in the above solutions or by the spray method and soft heating, the copper substrates could be easily repaired, regenerating the surfaces' superrepellency to liquids. The micro- and nanoroughness structures generated on copper surfaces by the deposition of silver dendrites functionalized with TMPSi presented apparent contact angles greater than 150° with a contact angle hysteresis lower than 10° when water was used as the test liquid. To avoid total wettability with very low surface tension liquids, such as rapeseed oil and hexadecane, a thin perfluorinated coating of poly(tetrafluoroethylene) (PTFE), produced by physical vapor deposition, was used. A more efficient perfluorinated coating was obtained when PFDTES was used. The superomniphobic surfaces produced apparent contact angles above 150° with all of the tested liquids, including hexadecane, although the contact angle hysteresis with this liquid was above 10°. The coupling of dendritic structures with TMPSi/PTFE or directly by PFDTES coatings was responsible for the superrepellency of the as-prepared surfaces. These simple, fast, and reliable procedures allow the large area, and cost-effective scale fabrication of superrepellent surfaces on copper substrates for various industrial applications with the advantage of easy recovery of the surface repellency after damage.

COVID-19 Vaccine Safety Monitoring Studies in Low- and Middle-Income Countries (LMICs)-A Systematic Review of Study Designs and Methods.

BACKGROUND: Post-marketing vaccine safety surveillance aims to monitor and quantify adverse events following immunization in a population, but little is known about their implementation in low- and middle-income countries (LMICs). We aimed to synthesize methodological approaches used to assess adverse events following COVID-19 vaccination in LMICs. METHODS: For this systematic review, we searched articles published from 1 December 2019 to 18 February 2022 in main databases, including MEDLINE and Embase. We included all peer-reviewed observational COVID-19 vaccine safety monitoring studies. We excluded randomized controlled trials and case reports. We extracted data using a standardized extraction form. Two authors assessed study quality using the modified Newcastle-Ottawa Quality Assessment Scale. All findings were summarized narratively using frequency tables and figures. RESULTS: Our search found 4254 studies, of which 58 were eligible for analysis. Many of the studies included in this review were conducted in middle-income countries, with 26 studies (45%) in lower-middle-income and 28 (48%) in upper-middle-income countries. More specifically, 14 studies were conducted in the Middle East region, 16 in South Asia, 8 in Latin America, 8 in Europe and Central Asia, and 4 in Africa. Only 3% scored 7-8 points (good quality) on the Newcastle-Ottawa Scale methodological quality assessment, while 10% got 5-6 points (medium). About 15 studies (25.9%) used a cohort study design and the rest were cross-sectional. In half of them (50%), vaccination data were gathered from the participants' self-reporting methods. Seventeen studies (29.3%) used multivariable binary logistic regression and three (5.2%) used survival analyses. Only 12 studies (20.7%) performed model diagnostics and validity checks (e.g., the goodness of fit, identification of outliers, and co-linearity). CONCLUSIONS: Published studies on COVID-19 vaccine safety surveillance in LMICs are limited in number and the methods used do not often address potential confounders. Active surveillance of vaccines in LMICs are needed to advocate vaccination programs. Implementing training programs in pharmacoepidemiology in LMICs is essential.

Random demographic household surveys in highly mobile pastoral communities in Chad.

PROBLEM: Reliable demographic data is a central requirement for health planning and management, and for the implementation of adequate interventions. This study addresses the lack of demographic data on mobile pastoral communities in the Sahel. APPROACH: A total of 1081 Arab, Fulani and Gorane women and 2541 children (1336 boys and 1205 girls) were interviewed and registered by a biometric fingerprint scanner in five repeated random transect demographic and health surveys conducted from March 2007 to January 2008 in the Lake Chad region in Chad. LOCAL SETTING: Important determinants for the planning and implementation of household surveys among mobile pastoral communities include: environmental factors; availability of women for interviews; difficulties in defining "own" children; the need for information-education-communication campaigns; and informed consent of husbands in typically patriarchal societies. RELEVANT CHANGES: Due to their high mobility, only 5% (56/1081) of registered women were encountered twice. Therefore, it was not possible to establish a demographic and health cohort. LESSONS LEARNT: Prospective demographic and health cohorts are the most accurate method to assess child mortality and other demographic indices. However, their feasibility in a highly mobile pastoral setting remains to be shown. Future interdisciplinary scientific efforts need to target innovative methods, tools and approaches to include marginalized communities in operational health and demographic surveillance systems.

Diurnal variations in multi-sensor wearable-derived sleep characteristics in morning- and evening-type shift workers under naturalistic conditions.

Consumer-grade, multi-sensor, rest-activity trackers may be powerful tools, to help optimize rest-activity management in shiftwork populations undergoing circadian misalignment. Nevertheless, performance testing of such devices under field conditions is scarce. We previously validated Fitbit Charge 2TM against home polysomnography and now evaluated the potential of this device to document differences in rest-activity behavior, including sleep macrostructure, in first-responder shift workers in an operational setting. We continuously monitored 89 individuals (54% females; mean age: 33.9 ± 7.7 years) for 32.5 ± 9.3 days and collected 2,974 individual sleep episodes scattered around the clock. We stratified the study participants according to their self-reported circadian preference on the reduced Horne-Östberg Morningness-Evening Questionnaire (rMEQ; the scores from 4 participants were missing). Fitbit estimates of sleep duration, wakefulness after sleep onset (WASO), REM sleep percentage in the first NREM-REM sleep cycle, and REM sleep latency formed approximately sinusoidal oscillations across 24 hours. Generalized additive mixed model analyses revealed that the phase position of sleep duration minimum was delayed by 2.8 h in evening types (ET; rMEQ ≤ 11; n = 20) and by 2.6 h in intermediate types (IT; 11 < rMEQ < 18; n = 45) when compared to morning types (MT; rMEQ ≥ 18; n = 20). Similarly, the phase position of WASO was delayed by 2.7 h in ET compared to MT. While nocturnal sleep duration did not differ among the three groups, sleep episodes during the biological day decreased in duration from ET to IT to MT. Together, the findings support the notion that a consumer-grade, rest-activity tracker allows estimation of behavioral sleep/wake cycles and sleep macrostructure in shift workers under naturalistic conditions that are consistent with their self-reported chronotype.

Highly Water-Stable Polymer-Perovskite Nanocomposites.

The excellent performance of hybrid metal-halide perovskite nanocrystals (NCs) contrasts with their unsatisfactory stability in a high-humidity environment or water. Herein, polymer composite lead-halide perovskites (LHPs) NCs were prepared by casting or spin-coating to produce a high fluorescence yield and a fully water-resistant material. Poly(l-lactide) (PLla), polypropylene glycol (PPGly), and polysulfone (PSU) commercial polymers were used to prepare suspensions of MAPbBr3-HDA NCs (MA: CH3NH3; HDA: hexadecylamine). The MAPbBr3-HDA@PLla suspension exhibited a maximum fluorescence quantum yield of 93% compared to 43% for the pristine MAPbBr3-HDA NCs. Strong emissions around 528 nm were also observed, with the same full width at half maximum value of 20 nm, demonstrating the successful fabrication of brightly luminescent LHP NCs@polymer combinations. Time-resolved photoluminescence measurements directly observed the enhanced spontaneous emission of the NCs induced by the polymeric environment. However, the cast films of MAPbBr3-HDA NCs mixed with PLla or PPGly did not resist water immersion. On the contrary, MAPbBr3-HDA@PPGly/PSU films containing well-dispersed ∼10 nm LHP NCs retained a bright green fluorescence emission even after 18 months under air conditions or water immersion up to 45 °C. From water contact angle measurements, profilometry, and X-ray photoelectron spectroscopy data, it could be assumed that the slightly hydrophobic PSU polymer is responsible for the high water stability of the fluorescent films, which avoids MAPbBr3-HDA NC degradation. This work shows that the LHP NC dispersion in dissolved commodity polymers holds great promise toward the long-term stability of LHP NC composites for the future development of wearable electronic devices and other waterproof applications.

Incidence Rates of Autoimmune Diseases in European Healthcare Databases: A Contribution of the ADVANCE Project.

INTRODUCTION: The public-private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. METHODS: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. RESULTS: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell's palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6-24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6-0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. CONCLUSION: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data.

Systematic Review and Meta-analysis of Postlicensure Observational Studies on Human Papillomavirus Vaccination and Autoimmune and Other Rare Adverse Events.

BACKGROUND: Because of the limited number of subjects in prelicensure studies, autoimmune diseases and other rare adverse effects of vaccines may go undetected. Since 2006, millions of human papillomavirus (HPV) vaccine doses have been distributed and a considerable amount of postlicensure safety data has been generated. The objective of this study was to review available HPV postlicensure safety studies and to summarize risk estimates of autoimmune and other rare diseases. METHODS: For this systematic review and meta-analysis, we searched literature databases to identify any postlicensure safety studies related to HPV vaccination and autoimmune adverse events from inception to April 16, 2019. Pooled risk estimates were computed using fixed- or random-effects models if at least 2 estimates per disease and per HPV vaccine were available. RESULTS: Twenty-two studies met our inclusion criteria. The studies applied various methodologies and used different types of data sources and outcome definitions. Quadrivalent HPV vaccine (4vHPV) was most commonly assessed. Type 1 diabetes mellitus, immune thrombocytopenia purpura and thyroiditis diseases were most frequently reported. The meta-analysis was conducted on 35 diseases corresponding to 48 pooled risk estimates. Majority of the pooled estimates showed no significant effect (n = 43). Three negative (paralysis, immune thrombocytopenia purpura and chronic fatigue syndrome) and 2 positive (Hashimoto and Raynaud diseases) associations were detected. CONCLUSION: Our study demonstrated an absence of clear association between HPV vaccines and autoimmune and other rare diseases. The review also highlights the need for more systematic collaborations to monitor rare safety adverse events.

Vaccines safety and maternal knowledge for enhanced maternal immunization acceptability in rural Uganda: A qualitative study approach.

BACKGROUND: Maternal immunization is a successful and cost-effective public health strategy. It protects pregnant women and their infants from vaccine-preventable diseases. Uganda is exploring new vaccines for pregnant women like replacing Tetanus Toxoid (TT) with Tetanus-Diphtheria (Td). Research on knowledge, attitudes, beliefs, and willingness among pregnant women is needed before the introduction of vaccines for pregnant women. This study was aimed at exploring maternal knowledge, attitudes, willingness, and beliefs towards maternal immunization among pregnant women in rural Uganda. METHODS: This was a qualitative descriptive study. Ten focus group discussions (FGDs) were conducted at antenatal care (ANC) clinics and in a rural community of Uganda. Five key informant interviews (KIIs) were done with health workers, for triangulation. Considering context and research characteristics, data were collected and thematically analyzed. RESULTS: Women were familiar with the importance of maternal vaccines, had positive attitudes, and expressed willingness to take them. Acceptance of a new vaccine could be affected by worries of pregnant women and that of their partners, who influence health seeking decisions in a home concerning adverse events, following the maternal immunization (AEFI). There were misconceptions about introduction of vaccines such as the belief that vaccines treat malaria and general body weakness, and being used as guinea pigs to test for the vaccine before its introduction to the larger population. CONCLUSION: A range of diverse sentiments and beliefs may affect uptake and acceptability of vaccines that are introduced in communities. For instance, ignoring vaccine safety concerns may impede maternal immunization acceptability, because pregnant women and their husbands are concerned about AEFI. Moreover, husbands make all health-seeking decisions at home, and their opinion is key, when considering such interventions.

Bridging research integrity and global health epidemiology (BRIDGE) statement: guidelines for good epidemiological practice.

BACKGROUND: Research integrity and research fairness have gained considerable momentum in the past decade and have direct implications for global health epidemiology. Research integrity and research fairness principles should be equally nurtured to produce high-quality impactful research-but bridging the two can lead to practical and ethical dilemmas. In order to provide practical guidance to researchers and epidemiologist, we set out to develop good epidemiological practice guidelines specifically for global health epidemiology, targeted at stakeholders involved in the commissioning, conduct, appraisal and publication of global health research. METHODS: We developed preliminary guidelines based on targeted online searches on existing best practices for epidemiological studies and sought to align these with key elements of global health research and research fairness. We validated these guidelines through a Delphi consultation study, to reach a consensus among a wide representation of stakeholders. RESULTS: A total of 45 experts provided input on the first round of e-Delphi consultation and 40 in the second. Respondents covered a range of organisations (including for example academia, ministries, NGOs, research funders, technical agencies) involved in epidemiological studies from countries around the world (Europe: 19; Africa: 10; North America: 7; Asia: 5; South-America: 3 Australia: 1). A selection of eight experts were invited for a face-to-face meeting. The final guidelines consist of a set of 6 standards and 42 accompanying criteria including study preparation, protocol development, data collection, data management, data analysis, dissemination and communication. CONCLUSION: While guidelines will not by themselves guard global health from questionable and unfair research practices, they are certainly part of a concerted effort to ensure not only mutual accountability between individual researchers, their institutions and their funders but most importantly their joint accountability towards the communities they study and society at large.

ADVANCE system testing: Benefit-risk analysis of a marketed vaccine using multi-criteria decision analysis and individual-level state transition modelling.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example. METHODS: We used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts. RESULTS: Using state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores. CONCLUSION: Existing B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines.

ADVANCE system testing: Estimating the incidence of adverse events following pertussis vaccination in healthcare databases with incomplete exposure data.

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0-5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results.

Age-specific vaccination coverage estimates for influenza, human papillomavirus and measles containing vaccines from seven population-based healthcare databases from four EU countries - The ADVANCE project.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies. METHODS: A retrospective dynamic cohort study was conducted through a distributed network approach. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990-2000 and influenza-vaccine for birth years 1920-1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server. RESULTS: The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997-2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain). CONCLUSIONS: We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates.

ADVANCE system testing: Can safety studies be conducted using electronic healthcare data? An example using pertussis vaccination.

INTRODUCTION: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster. METHODS: The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses. RESULTS: The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP. CONCLUSIONS: The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination.