A new method to predict the epidemiology of fungal keratitis by monitoring the sales distribution of antifungal eye drops in Brazil

Purpose

Fungi are a major cause of keratitis, although few medications are licensed for their treatment. The aim of this study is to observe the variation in commercialisation of antifungal eye drops, and to predict the seasonal distribution of fungal keratitis in Brazil.

Methods

Data from a retrospective study of antifungal eye drops sales from the only pharmaceutical ophthalmologic laboratory, authorized to dispense them in Brazil (Opthalmos) were gathered. These data were correlated with geographic and seasonal distribution of fungal keratitis in Brazil between July 2002 and June 2008.

Results

A total of 26,087 antifungal eye drop units were sold, with a mean of 2.3 per patient. There was significant variation in antifungal sales during the year (p<0.01). A linear regression model displayed a significant association between reduced relative humidity and antifungal drug sales (R2 = 0.17,p<0.01).

Conclusions

Antifungal eye drops sales suggest that there is a seasonal distribution of fungal keratitis. A possible interpretation is that the third quarter of the year (a period when the climate is drier), when agricultural activity is more intense in Brazil, suggests a correlation with a higher incidence of fungal keratitis. A similar model could be applied to other diseases, that are managed with unique, or few, and monitorable medications to predict epidemiological aspects.     

Suicide seasonality: complex demodulation as a novel approach in epidemiologic analysis

Background

Seasonality of suicides is well-known and nearly ubiquitous, but recent evidence showed inconsistent patterns of decreasing or increasing seasonality in different countries. Furthermore, strength of seasonality was hypothesized to be associated with suicide prevalence. This study aimed at pointing out methodological difficulties in examining changes in suicide seasonality.

Methododology/Principal Findings

The present study examines the hypothesis of decreasing seasonality with a superior method that allows continuous modeling of seasonality. Suicides in Austria (1970–2008, N = 67,741) were analyzed with complex demodulation, a local (point-in-time specific) version of harmonic analysis. This avoids the need to arbitrarily split the time series, as is common practice in the field of suicide seasonality research, and facilitates incorporating the association with suicide prevalence. Regression models were used to assess time trends and association of amplitude and absolute suicide numbers. Results showed that strength of seasonality was associated with absolute suicide numbers, and that strength of seasonality was stable during the study period when this association was taken into account.

Conclusion/Significance

Continuous modeling of suicide seasonality with complex demodulation avoids spurious findings that can result when time series are segmented and analyzed piecewise or when the association with suicide prevalence is disregarded.     

Vitamin D (25OHD) Serum Seasonality in the United States

Background

Vitamin D is an important micronutrient for health. Hypovitaminosis D is thought to play a role in the seasonality of a number of diseases and adverse health conditions. To refine hypotheses about the links between vitamin D and seasonal diseases, good estimates of the cyclicality of serum vitamin D are necessary.

Objectives

The objective of this study is to describe quantitatively the cyclicality of 25-hydroxyvitamin D (25OHD) in the United States. We provide a statistical analysis with weekly time resolution, in comparison to the quarterly (winter/spring/summer/fall) estimates already in the literature.

Methods

We analyzed time series data on 25OHD, spanning 287 consecutive weeks. The pooled data set comes from 3.44 million serum samples from the United States. We statistically analyzed the proportion of sera that were vitamin D sufficient, defined as 25OHD ng/mL, as a function of date.

Results

In the United States, serum 25OHD follows a lagged pattern relative to the astronomical seasons, peaking in late summer (August) and troughing in late winter (February). Airmass, which is a function of solar altitude, fits the 25OHD data very well when lagged by 8 weeks.

Conclusions

Serum vitamin D levels can be modeled as a function of date, working through a double-log transformation of minimal solar airmass (easily calculated from solar altitude, retrievable from an online solar altitude/azimuth table).     

A Standardized Vascular Disease Health Check in Europe: A Cost-Effectiveness Analysis

Background

No clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries.

Methods

We used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40–75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY).

Results

Compared with current care, health checks reduced the incidence of MACE (6–17 events prevented per 1000 people screened) and diabetes related microvasular complications (5–11 events prevented per 1000 people screened), and increased QALYs (31–59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from €14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of €10200 (France) or less, and pre-screening with a non-invasive risk score was similar.

Conclusions

A vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom.     

Tuberculosis Incidence Correlates with Sunshine: An Ecological 28-Year Time Series Study

Background

Birmingham is the largest UK city after London, and central Birmingham has an annual tuberculosis incidence of 80 per 100,000. We examined seasonality and sunlight as drivers of tuberculosis incidence. Hours of sunshine are seasonal, sunshine exposure is necessary for the production of vitamin D by the body and vitamin D plays a role in the host response to tuberculosis.

Methods

We performed an ecological study that examined tuberculosis incidence in Birmingham from Dec 1981 to Nov 2009, using publicly-available data from statutory tuberculosis notifications, and related this to the seasons and hours of sunshine (UK Meteorological Office data) using unmeasured component models.

Results

There were 9,739 tuberculosis cases over the study period. There was strong evidence for seasonality, with notifications being 24.1% higher in summer than winter (p<0.001). Winter dips in sunshine correlated with peaks in tuberculosis incidence six months later (4.7% increase in incidence for each 100 hours decrease in sunshine, p<0.001).

Discussion and Conclusion

A potential mechanism for these associations includes decreased vitamin D levels with consequent impaired host defence arising from reduced sunshine exposure in winter. This is the longest time series of any published study and our use of statutory notifications means this data is essentially complete. We cannot, however, exclude the possibility that another factor closely correlated with the seasons, other than sunshine, is responsible. Furthermore, exposure to sunlight depends not only on total hours of sunshine but also on multiple individual factors. Our results should therefore be considered hypothesis-generating. Confirmation of a potential causal relationship between winter vitamin D deficiency and summer peaks in tuberculosis incidence would require a randomized-controlled trial of the effect of vitamin D supplementation on future tuberculosis incidence.     

Influenza Vaccination Guidelines and Vaccine Sales in Southeast Asia: 2008–2011

Background

Southeast Asia is a region with great potential for the emergence of a pandemic influenza virus. Global efforts to improve influenza surveillance in this region have documented the burden and seasonality of influenza viruses and have informed influenza prevention strategies, but little information exists about influenza vaccination guidelines and vaccine sales.

Methods

To ascertain the existence of influenza vaccine guidelines and define the scope of vaccine sales, we sent a standard three-page questionnaire to the ten member nations of the Association of Southeast Asian Nations. We also surveyed three multinational manufacturers who supply influenza vaccines in the region.

Results

Vaccine sales in the private sector were <1000 per 100,000 population in the 10 countries. Five countries reported purchasing vaccine for use in the public sector. In 2011, Thailand had the highest combined reported rate of vaccine sales (10,333 per 100,000). In the 10 countries combined, the rate of private sector sales during 2010–2011 (after the A(H1N1)2009pdm pandemic) exceeded 2008 pre-pandemic levels. Five countries (Indonesia, Malaysia, Singapore, Thailand and Vietnam) had guidelines for influenza vaccination but only two were consistent with global guidelines. Four recommended vaccination for health care workers, four for elderly persons, three for young children, three for persons with underlying disease, and two for pregnant women.

Conclusions

The rate of vaccine sales in Southeast Asia remains low, but there was a positive impact in sales after the A(H1N1)2009pdm pandemic. Low adherence to global vaccine guidelines suggests that more work is needed in the policy arena.     

Spatiotemporal Pattern of Bacillary Dysentery in China from 1990 to 2009: What Is the Driver Behind?

Background

Little is known about the spatiotemporal pattern of bacillary dysentery (BD) in China. This study assessed the geographic distribution and seasonality of BD in China over the past two decades.

Methods

Data on monthly BD cases in 31 provinces of China from January 1990 to December 2009 obtained from Chinese Center for Disease Control and Prevention, and data on demographic and geographic factors, as well as climatic factors, were compiled. The spatial distributions of BD in the four periods across different provinces were mapped, and heat maps were created to present the seasonality of BD by geography. A cosinor function combined with Poisson regression was used to quantify the seasonal parameters of BD, and a regression analysis was conducted to identify the potential drivers of morbidity and seasonality of BD.

Results

Although most regions of China have experienced considerable declines in BD morbidity over the past two decades, Beijing and Ningxia still had high BD morbidity in 2009. BD morbidity decreased more slowly in North-west China than other regions. BD in China mainly peaked from July to September, with heterogeneity in peak time between regions. Relative humidity was associated with BD morbidity and peak time, and latitude was the major predictor of BD amplitude.

Conclusions

The transmission of BD was heterogeneous in China. Improved sanitation and hygiene in North-west China, and better access to clean water and food in the big floating population in some metropolises could be the focus of future preventive interventions against BD. BD control efforts should put more emphasis on those dry areas in summer.     

Rotavirus Seasonality and Age Effects in a Birth Cohort Study of Southern India

Introduction

Understanding the temporal patterns in disease occurrence is valuable for formulating effective disease preventive programs. Cohort studies present a unique opportunity to explore complex interactions associated with emergence of seasonal patterns of infectious diseases.

Methods

We used data from 452 children participating in a birth cohort study to assess the seasonal patterns of rotavirus diarrhea by creating a weekly time series of rotavirus incidence and fitting a Poisson harmonic regression with biannual peaks. Age and cohort effects were adjusted for by including the weekly counts of number of children in the study and the median age of cohort in a given week. Weekly average temperature, humidity and an interaction term to reflect the joint effect of temperature and humidity were included to consider the effects of meteorological variables.

Results

In the overall rotavirus time series, two significant peaks within a single year were observed – one in winter and the other in summer. The effect of age was found to be the most significant contributor for rotavirus incidence, showing a strong negative association. Seasonality remained a significant factor, even after adjusting for meteorological parameters, and the age and cohort effects.

Conclusions

The methodology for assessing seasonality in cohort studies is not yet developed. This is the first attempt to explore seasonal patterns in a cohort study with a dynamic denominator and rapidly changing immune response on individual and group levels, and provides a highly promising approach for a better understanding of the seasonal patterns of infectious diseases, tracking emergence of pathogenic strains and evaluating the efficacy of intervention programs.     

A Meta-Analysis of the Impacts of Genetically Modified Crops

Background

Despite the rapid adoption of genetically modified (GM) crops by farmers in many countries, controversies about this technology continue. Uncertainty about GM crop impacts is one reason for widespread public suspicion.

Objective

We carry out a meta-analysis of the agronomic and economic impacts of GM crops to consolidate the evidence.

Data Sources

Original studies for inclusion were identified through keyword searches in ISI Web of Knowledge, Google Scholar, EconLit, and AgEcon Search.

Study Eligibility Criteria

Studies were included when they build on primary data from farm surveys or field trials anywhere in the world, and when they report impacts of GM soybean, maize, or cotton on crop yields, pesticide use, and/or farmer profits. In total, 147 original studies were included.

Synthesis Methods

Analysis of mean impacts and meta-regressions to examine factors that influence outcomes.

Results

On average, GM technology adoption has reduced chemical pesticide use by 37%, increased crop yields by 22%, and increased farmer profits by 68%. Yield gains and pesticide reductions are larger for insect-resistant crops than for herbicide-tolerant crops. Yield and profit gains are higher in developing countries than in developed countries.

Limitations

Several of the original studies did not report sample sizes and measures of variance.

Conclusion

The meta-analysis reveals robust evidence of GM crop benefits for farmers in developed and developing countries. Such evidence may help to gradually increase public trust in this technology.     

Rapid qualitative urinary tract infection pathogen identification by SeptiFast real-time PCR

Background

Urinary tract infections (UTI) are frequent in outpatients. Fast pathogen identification is mandatory for shortening the time of discomfort and preventing serious complications. Urine culture needs up to 48 hours until pathogen identification. Consequently, the initial antibiotic regimen is empirical.

Aim

To evaluate the feasibility of qualitative urine pathogen identification by a commercially available real-time PCR blood pathogen test (SeptiFast^®) and to compare the results with dipslide and microbiological culture.

Design of study

Pilot study with prospectively collected urine samples.

Setting

University hospital.

Methods

82 prospectively collected urine samples from 81 patients with suspected UTI were included. Dipslide urine culture was followed by microbiological pathogen identification in dipslide positive samples. In parallel, qualitative DNA based pathogen identification (SeptiFast^®) was performed in all samples.

Results

61 samples were SeptiFast^® positive, whereas 67 samples were dipslide culture positive. The inter-methodological concordance of positive and negative findings in the gram+, gram- and fungi sector was 371/410 (90%), 477/492 (97%) and 238/246 (97%), respectively. Sensitivity and specificity of the SeptiFast^® test for the detection of an infection was 0.82 and 0.60, respectively. SeptiFast^® pathogen identifications were available at least 43 hours prior to culture results.

Conclusion

The SeptiFast^® platform identified bacterial DNA in urine specimens considerably faster compared to conventional culture. For UTI diagnosis sensitivity and specificity is limited by its present qualitative setup which does not allow pathogen quantification. Future quantitative assays may hold promise for PCR based UTI pathogen identification as a supplementation of conventional culture methods.     

Microbiology of Urinary Tract Infections in Gaborone,Botswana

Objective

The microbiology and epidemiology of UTI pathogens are largely unknown in Botswana, a high prevalence HIV setting. Using laboratory data from the largest referral hospital and a private hospital, we describe the major pathogens causing UTI and their antimicrobial resistance patterns.

Methods

This retrospective study examined antimicrobial susceptibility data for urine samples collected at Princess Marina Hospital (PMH), Bokamoso Private Hospital (BPH), or one of their affiliated outpatient clinics. A urine sample was included in our dataset if it demonstrated pure growth of a single organism and accompanying antimicrobial susceptibility and subject demographic data were available.

Results

A total of 744 samples were included. Greater than 10% resistance was observed for amoxicillin, co-trimoxazole, amoxicillin-clavulanate, and ciprofloxacin. Resistance of E. coli isolates to ampicillin and co-trimoxazole was greater than 60% in all settings. HIV status did not significantly impact the microbiology of UTIs, but did impact antimicrobial resistance to co-trimoxazole.

Conclusions

Data suggests that antimicrobial resistance has already emerged to most oral antibiotics, making empiric management of outpatient UTIs challenging. Ampicillin, co-trimoxazole, and ciprofloxacin should not be used as empiric treatment for UTI in this context. Nitrofurantoin could be used for simple cystitis; aminoglycosides for uncomplicated UTI in inpatients.     

The disappearing seasonality of autism conceptions in california

Background

Autism incidence and prevalence have increased dramatically in the last two decades. The autism caseload in California increased 600% between 1992 and 2006, yet there is little consensus as to the cause. Studying the seasonality of conceptions of children later diagnosed with autism may yield clues to potential etiological drivers.

Objective

To assess if the conceptions of children later diagnosed with autism cluster temporally in a systematic manner and whether any pattern of temporal clustering persists over time.

Method

We searched for seasonality in conceptions of children later diagnosed with autism by applying a one-dimensional scan statistic with adaptive temporal windows on case and control population data from California for 1992 through 2000. We tested for potential confounding effects from known risk factors using logistic regression models.

Results

There is a consistent but decreasing seasonal pattern in the risk of conceiving a child later diagnosed with autism in November for the first half of the study period. Temporal clustering of autism conceptions is not an artifact of composition with respect to known risk factors for autism such as socio-economic status.

Conclusion

There is some evidence of seasonality in the risk of conceiving a child later diagnosed with autism. Searches for environmental factors related to autism should allow for the possibility of risk factors or etiological drivers that are seasonally patterned and that appear and remain salient for a discrete number of years.     

Seasonality in human zoonotic enteric diseases: a systematic review

Background

Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour.

Methodology/Principal Findings

We systematically reviewed published literature from 1960–2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini = 0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18).

Conclusions/Significance

Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries.     

Present,past and future of the European rock fern Asplenium fontanum: combining distribution modelling and population genetics to study the effect of climate change on geographic range and genetic diversity

Background and Aims

Climate change is expected to alter the geographic range of many plant species dramatically. Predicting this response will be critical to managing the conservation of plant resources and the effects of invasive species. The aim of this study was to predict the response of temperate homosporous ferns to climate change.

Methods

Genetic diversity and changes in distribution range were inferred for the diploid rock fern Asplenium fontanum along a South–North transect, extending from its putative last glacial maximum (LGM) refugia in southern France towards southern Germany and eastern-central France. This study reconciles observations from distribution models and phylogeographic analyses derived from plastid and nuclear diversity.

Key Results

Genetic diversity distribution and niche modelling propose that genetic diversity accumulates in the LGM climate refugium in southern France with the formation of a diversity gradient reflecting a slow, post-LGM range expansion towards the current distribution range. Evidence supports the fern''s preference for outcrossing, contradicting the expectation that homosporous ferns would populate new sites by single-spore colonization. Prediction of climate and distribution range change suggests that a dramatic loss of range and genetic diversity in this fern is possible. The observed migration is best described by the phalanx expansion model.

Conclusions

The results suggest that homosporous ferns reproducing preferentially by outcrossing accumulate genetic diversity primarily in LGM climate refugia and may be threatened if these areas disappear due to global climate change.     

Using web search query data to monitor dengue epidemics: a new model for neglected tropical disease surveillance

Background

A variety of obstacles including bureaucracy and lack of resources have interfered with timely detection and reporting of dengue cases in many endemic countries. Surveillance efforts have turned to modern data sources, such as Internet search queries, which have been shown to be effective for monitoring influenza-like illnesses. However, few have evaluated the utility of web search query data for other diseases, especially those of high morbidity and mortality or where a vaccine may not exist. In this study, we aimed to assess whether web search queries are a viable data source for the early detection and monitoring of dengue epidemics.

Methodology/Principal Findings

Bolivia, Brazil, India, Indonesia and Singapore were chosen for analysis based on available data and adequate search volume. For each country, a univariate linear model was then built by fitting a time series of the fraction of Google search query volume for specific dengue-related queries from that country against a time series of official dengue case counts for a time-frame within 2003–2010. The specific combination of queries used was chosen to maximize model fit. Spurious spikes in the data were also removed prior to model fitting. The final models, fit using a training subset of the data, were cross-validated against both the overall dataset and a holdout subset of the data. All models were found to fit the data quite well, with validation correlations ranging from 0.82 to 0.99.

Conclusions/Significance

Web search query data were found to be capable of tracking dengue activity in Bolivia, Brazil, India, Indonesia and Singapore. Whereas traditional dengue data from official sources are often not available until after some substantial delay, web search query data are available in near real-time. These data represent valuable complement to assist with traditional dengue surveillance.     

Association of Toll-like receptor 4 gene polymorphism and expression with urinary tract infection types in adults

Background

Innate immunity of which Toll-like receptor (TLR) 4 and CXCR1 are key elements plays a central role in the development of urinary tract infection (UTI). Although the relation between the genetics of TLR4 and CXCR1 and UTI is investigated partly, the polymorphisms and expression of TLR4 and CXCR1 in different types of UTI in adults are not extremely clear.

Methodology/Principal Findings

This study investigates the presence of TLR4 A (896) G and CXCR1 G (2608) C polymorphisms in 129 UTI patients using RFLP-PCR. Gene and allelic prevalence were compared with 248 healthy controls. Flow cytometry was used to detect TLR4 and CXCR1 expression in the monocytes of UTI patients and healthy controls. TLR4 (896) AG genotype and TLR4 (896) G allele had higher prevalence in UTI (especially in acute cystitis and urethritis) patients, whereas CXCR1 (2608) GC genotype and CXCR1 (2608) C allele had lower prevalence in UTI patients than controls. TLR4 expression was significantly lower in chronic UTI patients than in acute pyelonephritis or healthy controls. CXCR1 expression was similar in both controls and patients. TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment.

Conclusions

The results indicate the relationship between the carrier status of TLR4 (896) G alleles and the development of UTI, especially acute cystitis and urethritis, in adults. TLR4 expression levels are correlated with chronic UTI.     

Copeptin,Procalcitonin and Routine Inflammatory Markers–Predictors of Infection after Stroke

Background

Early predictors for the development of stroke-associated infection may identify patients at high risk and reduce post-stroke infection and mortality.

Methods

In 383 prospectively enrolled acute stroke patients we assessed time point and type of post-stroke infections (i.e. pneumonia, urinary tract infection (UTI) other infection (OI)). Blood samples were collected on admission, and days 1, and 3 to assess white blood cells (WBC), monocytes, C-reactive protein (CRP), procalcitonin (PCT), and copeptin. To determine the magnitude of association with the development of infections, odds ratios (OR) were calculated for each prognostic blood marker. The discriminatory ability of different predictors was assessed, by calculating area under the receiver operating characteristic curves (AUC). Prognostic models including the three parameters with the best performance were identified.

Results

Of 383 patients, 66 (17.2%) developed an infection after onset of stroke. WBC, CRP, copeptin and PCT were all independent predictors of any infection, pneumonia and UTI developed at least 24 hours after measurements. The combination of the biomarkers WBC, CRP and copeptin (AUC: 0.92) and WBC, CRP and PCT (AUC: 0.90) showed a better predictive accuracy concerning the development of pneumonia during hospitalization compared to each marker by itself (p-Wald <0.0001).

Conclusion

Among ischemic stroke patients, copeptin, PCT, WBC and CRP measured on admission were predictors of infection in general, and specifically for pneumonia and UTI within 5 days after stroke. The combination of these biomarkers improved the prediction of patients who developed an infection.     

Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study

Background

The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy.

Methodology/Principal Findings

The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined.

Conclusions

The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age.