Whatever can go wrong, need not go wrong: Open Quality approach for epidemiology.

Quality assurance is one of the most important aspects of an epidemiological study, as its validity is largely determined by data quality. The mounting success of quality management in the industrial sector caused a rapid spread throughout manufacturing industries and beyond. Yet, little has been published so far on quality assurance in epidemiology. In this article we review three models for quality assurance (Juran, Donabedian and ISO 9000) and showcase how these can be brought together in one intuitive, systematic and flexible approach to quality assurance in epidemiology. The resulting Open Quality approach refers back to the three processes identified by Juran (planning, control and verification). During the planning stage, we propose a subdivision of the study process in a set of steps and a definition of quality attributes corresponding to activities in that step as suggested by the ISO approach. We refer to the Donabedian model to determine the level at which the control/monitoring should take place-structure, processes or outcomes. Along with an overview of the Open Quality approach we propose an Open Quality tool to support the definition of quality attributes, failure modes, preventive strategies, verification activities, and corrective actions, which form the backbone of the Open Quality approach.

Completeness of tuberculosis (TB) notification: inventory studies and capture-recapture analyses, six European Union countries, 2014 to 2016.

BackgroundProgress towards the World Health Organization's End TB Strategy is monitored by assessing tuberculosis (TB) incidence, often derived from TB notification, assuming complete case detection and reporting. This assumption is unlikely to hold in many settings, including European Union (EU) countries.AimWe aimed to assess observed and estimated completeness of TB notification through inventory studies and capture-recapture (CRC) methodology in six EU countries: Croatia, Denmark, Finland, the Netherlands, Portugal Slovenia.MethodsWe performed record linkage, case ascertainment and CRC analyses of data collected retrospectively from at least three national TB-related registers in each country between 2014 and 2016.ResultsObserved completeness of TB notification by inventory studies was 73.9% in Croatia, 98.7% in Denmark, 83.6% in Finland, 81.6% in the Netherlands, 85.8% in Portugal and 100% in Slovenia. Subsequent CRC analysis estimated completeness of TB notification to be 98.4% in Denmark, 76.5% in Finland and 77.0% in Portugal. In Croatia, CRC analyses produced implausible results while in the Netherlands and Slovenia, it was methodologically considered not meaningful.ConclusionInventory studies and CRC methodology suggest a TB notification completeness between 73.9% and 100% in the six EU countries. Mandatory reporting by clinicians and laboratories, and cross-checking of registers, strongly contributes to accurate notification rates, but hospital episode registers likely contain a considerable proportion of false-positive TB records and are thus less useful. Further strengthening routine surveillance to count TB cases, i.e. incidence, accurately by employing record-linkage of high-quality TB registers should make CRC studies obsolete in EU countries.

Cytokine profiles amongst Sudanese patients with visceral leishmaniasis and malaria co-infections.

BACKGROUND: The immune system plays a critical role in the development of co-infections, promoting or preventing establishment of multiple infections and shaping the outcome of pathogen-host interactions. Its ability to mediate the interplay between visceral leishmaniasis (VL) and malaria has been suggested, but poorly documented. The present study investigated whether concomitant infection with Leishmania donovani complex and Plasmodium falciparum in naturally co-infected patients altered the immunological response elicited by the two pathogens individually. RESULTS: Circulating levels of interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-17A and tumor necrosis factor (TNF) were assessed in sera of patients infected with active VL and/or malaria and healthy individuals from Gedarif State, Sudan. Comparative analysis of cytokine profiles from co- and mono-infected patients highlighted significant differences in the immune response mounted upon co-infection, confirming the ability of L. donovani and P. falciparum to mutually interact at the immunological level. Progressive polarization towards type-1 and pro-inflammatory cytokine patterns characterized the co-infected patients, whose response partly reflected the effect elicited by VL (IFN-γ, TNF) and malaria (IL-2, IL-13), and partly resulted from a synergistic interaction of the two diseases upon each other (IL-17A). Significantly reduced levels of P. falciparum parasitaemia (P <0.01) were detected in the co-infected group as opposed to the malaria-only patients, suggesting either a protective or a non-detrimental effect of the co-infection against P. falciparum infection. CONCLUSIONS: These findings suggest that a new immunological scenario may occur when L. donovani and P. falciparum co-infect the same patient, with potential implications on the course and resolution of these diseases.

Aligning the principles and practice of research integrity and research fairness in global health: a mixed-methods study.

INTRODUCTION: In the past decade, global health research has seen a growing emphasis on research integrity and fairness. The concept of research integrity emerged in response to the reproducibility crisis in science during the late 2000s. Research fairness initiatives aim to enhance ownership and inclusivity in research involving partners with varying powers, decision-making roles and resource capacities, ultimately prioritising local health research needs. Despite extensive academic discussions, empirical data on these aspects, especially in the context of global health, remain limited. METHODS: To address this gap, we conducted a mixed-methods study focusing on research integrity and fairness. The study included an online frequency survey and in-depth key informant interviews with researchers from international research networks. The dual objectives were to quantify the frequency of practices related to research integrity and fairness and explore the determinants influencing these practices in global health. RESULTS: Out of 145 participants in the quantitative survey (8.4% response rate), findings indicate that global health researchers generally adhere to principles of research integrity and fairness, with variations in reported behaviours. The study identified structural, institutional and individual factors influencing these patterns, including donor landscape rigidity, institutional investments in relationship building, guidelines, mentoring and power differentials among researchers. CONCLUSION: This research highlights that, despite some variations, there is a substantial alignment between research integrity and fairness, with both sharing similar determinants and the overarching goal of enhancing research quality and societal benefits. The study emphasises the potential to explicitly recognise and leverage these synergies, aligning both agendas to further advance global health research.

Tuberculosis treatment outcome monitoring in European Union countries: systematic review.

Treatment success measured by treatment outcome monitoring (TOM) is a key programmatic output of tuberculosis (TB) control programmes. We performed a systematic literature review on national-level TOM in the 30 European Union (EU)/European Economic Areas (EEA) countries to summarise methods used to collect and report data on TOM. Online reference bibliographic databases PubMed/MEDLINE and EMBASE were searched to identify relevant indexed and non-indexed literature published between January 2000 and August 2010. The search strategy resulted in 615 potentially relevant indexed citations, of which 27 full-text national studies (79 data sets) were included for final analysis. The selected studies were performed in 10 EU/EEA countries and gave a fragmented impression of TOM in the EU/EEA. Publication year, study period, sample size, databases, definitions, variables, patient and outcome categories, and population subgroups varied widely, portraying a very heterogeneous picture. This review confirmed previous reports of considerable heterogeneity in publications of TOM results across EU/EEA countries. PubMed/MEDLINE and EMBASE indexed studies are not a suitable instrument to measure representative TOM results for the 30 EU/EEA countries. Uniform and complete reporting to the centralised European Surveillance System will produce the most timely and reliable results of TB treatment outcomes in the EU/EEA.

Time Trend Analysis of Tuberculosis Treatment While Using Digital Adherence Technologies-An Individual Patient Data Meta-Analysis of Eleven Projects across Ten High Tuberculosis-Burden Countries.

Worldwide, non-adherence to tuberculosis (TB) treatment is problematic. Digital adherence technologies (DATs) offer a person-centered approach to support and monitor treatment. We explored adherence over time while using DATs. We conducted a meta-analysis on anonymized longitudinal adherence data for drug-susceptible (DS) TB (n = 4515) and drug-resistant (DR) TB (n = 473) populations from 11 DAT projects. Using Tobit regression, we assessed adherence for six months of treatment across sex, age, project enrolment phase, DAT-type, health care facility (HCF), and project. We found that DATs recorded high levels of adherence throughout treatment: 80% to 71% of DS-TB patients had ≥90% adherence in month 1 and 6, respectively, and 73% to 75% for DR-TB patients. Adherence increased between month 1 and 2 (DS-TB and DR-TB populations), then decreased (DS-TB). Males displayed lower adherence and steeper decreases than females (DS-TB). DS-TB patients aged 15−34 years compared to those >50 years displayed steeper decreases. Adherence was correlated within HCFs and differed between projects. TB treatment adherence decreased over time and differed between subgroups, suggesting that over time, some patients are at risk for non-adherence. The real-time monitoring of medication adherence using DATs provides opportunities for health care workers to identify patients who need greater levels of adherence support.

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.

Automatic outbreak detection algorithm versus electronic reporting system.

To determine efficacy of automatic outbreak detection algorithms (AODAs), we analyzed 3,582 AODA signals and 4,427 reports of outbreaks caused by Campylobacter spp. or norovirus during 2005-2006 in Germany. Local health departments reported local outbreaks with higher sensitivity and positive predictive value than did AODAs.

Risk factors for elevated blood lead levels among African refugee children in New Hampshire, 2004.

OBJECTIVES: Surveillance blood lead screening of refugee children resettled in Manchester, NH, in 2004 revealed that 39 (42%) of 92 children had elevated levels (>or=10 microg/dL) after resettlement. Furthermore, 27/92 children (29%) had nonelevated screening blood lead levels on arrival (BLL1) but had elevated follow-up blood lead levels 3-6 months after settlement (BLL2). The main objective was to identify risk factors for increasing lead levels among refugee children after resettlement in Manchester in 2004. PATIENTS AND METHODS: We conducted a cohort study, with completion of household interviews and home assessments for refugee families who had resettled in 2004 in Manchester, NH. Blood lead level (BLL) data were abstracted from the New Hampshire (NH) Childhood Lead Poisoning Prevention Program. To assess acute and chronic malnutrition among refugees, we used anthropometric data from International Organization of Migration documents to calculate nutritional indices. RESULTS AND DISCUSSION: Of the 93 African refugee children in 42 families who participated, 60 (65%) had been born in a refugee camp. Median age was 5.5 years at the time of BLL2 measurement. Thirty-six (39%) of the refugee children had BLL2 >or= 10 microg/dL. Liberians and those born in refugee camps had higher geometric mean BLL2 than those not Liberian or not born in camps. Younger children and children with nutritional wasting before immigrating to the United States had a greater increase in geometric mean from BLL1 to BLL2, compared to older children and those without nutritional wasting. Follow-up blood lead testing of refugee children, particularly those resettled in areas with older housing stock, as in Manchester, is important for identifying lead exposure occurring after resettlement. Increased attention to improve nutritional status of children in refugee camps and after arrival in the United States and awareness of children who were born in refugee camps should be incorporated into lead-poisoning prevention strategies.

Development and validation of a predictive ecological model for TB prevalence.

Background: Nationally representative tuberculosis (TB) prevalence surveys provide invaluable empirical measurements of TB burden but are a massive and complex undertaking. Therefore, methods that capitalize on data from these surveys are both attractive and imperative. The aim of this study was to use existing TB prevalence estimates to develop and validate an ecological predictive statistical model to indirectly estimate TB prevalence in low- and middle-income countries without survey data. Methods: We included national and subnational estimates from 30 nationally representative surveys and 2 district-level surveys in India, resulting in 50 data points for model development (training set). Ecological predictors included TB notification and programmatic data, co-morbidities and socio-environmental factors extracted from online data repositories. A random-effects multivariable binomial regression model was developed using the training set and was used to predict bacteriologically confirmed TB prevalence in 63 low- and middle-income countries across Africa and Asia in 2015. Results: Out of the 111 ecological predictors considered, 14 were retained for model building (due to incompleteness or collinearity). The final model retained for predictions included five predictors: continent, percentage retreated cases out of all notified, all forms TB notification rates per 100 000 population, population density and proportion of the population under the age of 15. Cross-fold validations in the training set showed very good average fit (R-sq = 0.92). Conclusion: Predictive ecological modelling is a useful complementary approach to indirectly estimating TB burden and can be considered alongside other methods in countries with limited robust empirical measurements of TB among the general population.

Prioritization strategies for pandemic influenza vaccine in 27 countries of the European Union and the Global Health Security Action Group: a review.

BACKGROUND: Although there is rapid progress in vaccine research regarding influenza pandemic vaccines it is expected that pandemic influenza vaccine production can only start once the pandemic virus has been recognized. Therefore, pandemic vaccine capacity will be limited at least during the first phase of an influenza pandemic, requiring vaccine prioritization strategies. WHO recommends developing preliminary priorities for pandemic vaccine use. The goal of this review is to provide a thorough overview of pandemic vaccine prioritization concepts in the 27 European Union (EU) member states and the four non-EU countries of the Global Health Security Action Group. METHODS: Between September and December 2006 data was collected for each country through two data sources: (i) the national influenza pandemic plan; (ii) contacting key persons involved in pandemic planning by email and/or phone and/or fax. RESULTS: Twenty-six (84%) countries had established at least one vaccine priority group. Most common reported vaccine priority groups were health care workers (HCW) (100%), essential service providers (ESP) (92%) and high risk individuals (HRI) (92%). Ranking of at least one vaccine priority group was done by 17 (65%) of 26 countries. Fifteen (88%) of these 17 countries including a ranking strategy, decided that HCW with close contact to influenza patients should be vaccinated first; in most countries followed and/or ranked equally by ESP and subsequently HRI. Rationales for prioritization were provided by 22 (85%) of 26 countries that established vaccine priority groups. There was large variation in the phrasing and level of detailed specification of rationales. Seven (32%) of 22 countries providing rationales clearly associated each vaccine priority group with the specific rationale. Ten (32% of the 31 countries studied) countries have consulted and involved ethical experts to guide decisions related to vaccine prioritization. CONCLUSION: In the majority of the countries the establishment of vaccine priority groups, ranking and underlying rationales are in line with WHO recommendations. In most public plans the criteria by which prioritized groups are identified are not easily recognizable. Clarity however, may be necessary to assure public acceptability of the prioritization. Ethical experts, results of modelling exercises could play an increasing role in the future decision making process.

Population Based National Tuberculosis Prevalence Survey among Adults (>15 Years) in Pakistan, 2010-2011.

BACKGROUND: We aimed to determine the prevalence of pulmonary tuberculosis (TB) amongst the adult population in 2010-2011 in Pakistan. METHOD: A nationwide cross-sectional survey with multistage cluster sampling was conducted among adults (≥15 years) in 95 clusters in 2010-2011. All consenting participants were screened for cough and by chest X-ray. Participants with presumptive TB submitted two sputum samples for smear microscopy, culture, and molecular testing if needed. The TB prevalence estimates were adjusted for missing data and the cluster design. RESULT: Of 131,329 eligible individuals, 105,913 (81%) participated in the survey, of whom 10,471 (9.9%) were eligible for sputum examination. We found 341 bacteriologically positive TB cases of whom 233 had sputum smear-positive TB. The adjusted prevalence estimates for smear and bacteriologically positive TB were 270/100,000 (95% confidence interval (CI) 217-323), and 398/100,000 (95% CI 333-463), respectively. Only 61% of the diagnosed TB cases screened positive on symptoms (cough >2wks), whereas the other TB cases were detected based on X-ray abnormalities. The TB prevalence increased with age and was 1.8 times higher among men than women. The prevalence-to-notification ratio of smear-positive TB was 3.1 (95% CI 2.5-3.7), was higher among men than women, and increased with age. CONCLUSION: Our data suggest that there is under-detection and/or -notification of TB, especially among men and elderly. TB control should be strengthened specifically in these risk groups. X-ray examination should be combined with symptom screening to enhance case detection.

Eustachian tube function before recurrence of otitis media with effusion.

OBJECTIVE: To study the role of eustachian tube function in the development of recurrent otitis media with effusion (OME) in children treated with tympanostomy tubes for OME. DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received tympanostomy tubes for bilateral OME at study entry. MAIN OUTCOME MEASURE: Recurrence of OME within 6 months of tube extrusion. RESULTS: No statistically significant differences were present in eustachian tube function test results between ears that developed recurrent OME and those that did not. The difference in passive ventilatory function between ears with and without OME recurrence was 10 daPa (95% confidence interval, -24 to 43 daPa) for opening pressure and -3 daPa (95% confidence interval, -18 to 11 daPa) for closing pressure. The overall difference in the proportion of ears with and without OME recurrence that could not equilibrate positive and negative applied pressures was 12% (95% confidence interval, -2% to 26%). The proportions of ears with and without OME recurrence that induced negative pressure in the middle ear by forcefully sniffing were 22% and 31%, respectively (P = .75). CONCLUSION: Measurement of ventilatory and protective eustachian tube function using the forced response test, the pressure equilibration test, and the sniff test has no value in predicting whether children have an increased risk of OME recurrence.

Immune status and eustachian tube function in recurrence of otitis media with effusion.

OBJECTIVE: To study the combined role of immune status and eustachian tube function in the development of recurrent bilateral otitis media with effusion (OME). DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of bilateral OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received bilateral tympanostomy tubes at study entry. MAIN OUTCOME MEASURE: Recurrence of bilateral OME within 6 months after tube extrusion. RESULTS: Univariate analyses of various immunologic factors (IgA, IgG1, IgG2, IgG3, IgG4, mannose-binding lectin, and the FcgammaRIIa-H/R131 genotype) and eustachian tube function (forced response test) did not show any significant associations with bilateral OME recurrence. Multivariate analyses showed that children with closing pressures higher than the 75th percentile and IgA or IgG2 levels below the 50th percentile of the cohort were more likely to develop recurrent OME than children with closing pressures higher than the 75th percentile and IgA or IgG2 levels above the 50th percentile. The corresponding risk ratios were 6.3 (95% confidence interval [CI], 1.0-40.1) for IgA level and 3.0 (95% CI, 1.1-8.2) for IgG2 level. The multivariate analyses also revealed that increasing serum levels of functional mannose-binding lectin were associated with decreasing probabilities of developing recurrent OME (odds ratio, 0.7; 95% CI, 0.6-1.0). CONCLUSION: Recurrence of bilateral OME after tympanostomy tube placement is more likely in children with a combination of low IgA or low IgG2 levels with poor eustachian tube function and decreased levels of mannose-binding lectin.

Birth characteristics and recurrent otitis media with effusion in young children.

OBJECTIVE: To study the association between birth characteristics and the recurrence of otitis media with effusion (OME). METHODS: Prospective cohort study on 136 children aged 2-7 years, who received tympanostomy tubes for bilateral otitis media with effusion. Checkups were planned 1 week after tube insertion and once every 3 months thereafter. An otologist examined the ear status to assess tube extrusion and otitis media with effusion recurrence. Outcome measure was the recurrence of otitis media with effusion within 6 months after documentation of spontaneous tube extrusion. Birth characteristics were investigated in relation with the recurrence of otitis media with effusion in 90 children with known clinical outcome. RESULTS: No statistically significant associations were found between various birth characteristics and the recurrence of otitis media with effusion. Multivariate analyses showed positive but fairly weak associations between recurrence of otitis media with effusion and low birth weight (<2500 g) and/or low gestational age (<37 weeks) and/or a history of incubator care (odds ratio (OR) 1.95, 95% confidence interval (CI): 0.21-18.2), male sex (OR 1.85, 95% CI: 0.56-6.13) and maternal medication use during pregnancy (OR 4.80, 95% CI: 0.57-40.72). A remarkable finding was the asymmetrical distribution of certain birth characteristics within the group of children with recurrence of otitis media with effusion: children with unilateral recurrence had a relatively lower gestational age, lower birth weight, lower 'birth length to birth weight' ratio than the children with bilateral recurrence. CONCLUSION: These findings suggest that determination of birth characteristics cannot help us in the treatment strategy for recurrent otitis media with effusion in childhood.

Randomized single-blinded non-inferiority trial of 7 mg/kg pentamidine isethionate versus 4 mg/kg pentamidine isethionate for cutaneous leishmaniaisis in Suriname.

BACKGROUND: Standard treatment of cutaneous leishmaniasis (CL) in Suriname entails three injections of pentamidine isethionate (PI) 4 mg/kg per injection in 7 days (7 day regimen). Compliance to treatment is low and may contribute to increasing therapy failure. A 3 day regimen, including 2 injections of 7 mg/kg in 3 days may increase compliance. METHODS: In a randomized, single-blinded non-inferiority trial conducted in Suriname, 84 CL patients received the 7 day regimen and 79 CL patients received the 3 day regimen. Primary objective was the proportion of patients clinically cured at 6 weeks follow-up. Secondary objectives were clinical cure at 12 weeks follow-up; parasitological cure at 6 and 12 weeks; adverse and drug related toxicity events recorded one week after the end of treatment and health related quality of life. The non-inferiority margin was set at 15%, 1 sided test, α = 0.1. RESULTS: At 6 weeks follow-up 31 (39%) patients in the 3 day regimen and 41 (49%) patients in the 7 day regimen were clinically cured. Intention to treat (ITT) analyses showed that the difference in proportion clinically cured was -9.6% (90% Confidence Interval (CI): -22.3% to 3.2%). Per protocol (PP) analysis showed that the difference in proportion clinically cured was 0.2% (90% CI: -14.6% to 15.2%). ITT analysis showed that the difference in proportion parasitological cured at 6 weeks was -15.2% (90% CI:-28.0% to -2.5%). PP analyses showed similar results. Non-inferiority could not be concluded for all adverse and toxicological events. CONCLUSION: We cannot conclude that the 3 day regimen is non-inferior to the 7 day regimen regarding proportion clinically and parasitological cured. Therefore there is no evidence to change the current standard practice of the 7 day regimen for the treatment of CL in Suriname.

Review of randomized controlled trials on pneumococcal vaccination for prevention of otitis media.

BACKGROUND: Increasing resistance to antibiotics of the pathogens causing acute otitis media (AOM) emphasize the need for effective methods to prevent episodes of otitis media in young children. OBJECTIVE: To assess the effectiveness of pneumococcal vaccination for prevention of AOM in children age 12 years and younger. METHODS: Systematic review of 11 randomized controlled trials including 46 074 children in whom pneumococcal vaccination against AOM was compared with a control treatment. Vaccine effect was estimated as a rate ratio (RR): AOM episodes per child month in pneumococcal vaccination group divided by the AOM episodes per child-month in control group. RESULTS: A moderate effect of pneumococcal polysaccharide vaccination was found in children 24 months of age and older [RR 0.78; 95% confidence interval (CI) 0.63 to 0.97]. Pneumococcal polysaccharide vaccine had little effect on prevention of AOM in children without previous documented episodes before vaccination (RR 0.92; 95% CI 0.85 to 0.99). Better efficacy was seen in those children with documented prior AOM before vaccination (RR 0.81; 95% CI 0.72 to 0.91). Pooled results of pneumococcal conjugate vaccine trials in infants vaccinated as early as 2 months of age and in toddlers attending day care showed only a small effect on prevention of AOM (RR 0.92; 95% CI 0.85 to 0.99). CONCLUSION: Based on these results, a large scale pneumococcal vaccination program for a primary indication of preventing AOM in infancy is not indicated. The results of ongoing trials should provide more information whether the conjugate vaccine is effective in high risk (otitis-prone) children after 1 year of age.

Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005-May 2006).

BACKGROUND: During the summer of 2005, multiple cities in the United States began to report outbreaks of fentanyl-associated fatalities among illicit drug users. The objectives of this study were to (1) determine if an outbreak of fentanyl-associated fatalities occurred in mid-2005 to mid-2006 and (2) to examine trends and compare features of fentanyl-contaminated heroin-associated fatalities (FHFs) with non-fentanyl, heroin-associated fatalities (NFHFs) among illicit drug users. METHODS: Baseline prevalence of fentanyl- and heroin-associated deaths was estimated from January to May 2005 based on recorded cause of death (determined by the medical examiner (ME)) using the Wayne County, MI, USA toxicology database. The database was then queried for both FHFs and NFHFs between July 1, 2005 and May 12, 2006. A FHF was defined as having fentanyl or norfentanyl (metabolite) detected in any postmortem biological sample and either (1) detection of heroin or its metabolite (6-acetylmorphine) and/or cocaine or its metabolite (benzoylecgonine) in a postmortem biological specimen or (2) confirmation of fentanyl abuse as the cause of death by the ME or a medical history available sufficient enough to exclude prescription fentanyl or other therapeutic opioid use. A NFHF was defined as detection of heroin, 6-acetylmorphine (heroin metabolite) or morphine in any postmortem biological specimen, heroin overdose listed as the cause of death by the ME, and absence of fentanyl detection on postmortem laboratory testing. Information was systematically collected, trended for each group and then compared between the two groups with regard to demographic, exposure, autopsy, and toxicology data. Logistic regression was performed using SAS v 9.1 examining the effects of age, gender, and marital status with fentanyl group status. RESULTS: Monthly prevalence of fentanyl-associated fatalities among illicit drug users increased from an average of two in early 2005 to a peak of 24 in May, 2006. In total, 101 FHFs and 90 NFHFs were analyzed. The median age of decedents was 46 and 45 years for the fentanyl and non-fentanyl groups, respectively. Fentanyl-contaminated heroin-associated fatalities (FHFs) were more likely to be female (p = 0.003). Women aged over 44 years (OR = 4.67;95 % CI = 1.29-16.96) and divorced/widowed women (OR = 14.18;95 % CI = 1.59-127.01) were more likely to be FHFs when compared to women aged less than 44 years and single, respectively. A significant interaction occurred between gender and age, and gender and marital status. Most FHFs had central (heart) blood samples available for fentanyl testing (n = 96; 95 %): fentanyl was detected in most (n = 91; 95 %). Of these, close to half had no detectable heroin (or 6-acetylmorphine) concentrations (n = 37; 40.7 %). About half of these samples had detectable cocaine concentrations (n = 20; 54 %). Median fentanyl concentration in central blood samples was 0.02 µg/ml (n = 91, range <0.002-0.051 µg/ml) and 0.02 µg/ml (n = 32, range <0.004-0.069 µg/ml) in peripheral blood samples. The geometric mean of the ratio of central to peripheral values was 2.10 (median C/P = 1.75). At autopsy, pulmonary edema was the most frequently encountered finding for both groups (77 %). CONCLUSION: Illicit drugs may contain undeclared ingredients that may increase the likelihood of fatality in users. Gender differences in fentanyl-related mortality may be modified by age and/or marital status. These findings may help inform public health and prevention activities if fatalities associated with fentanyl-contaminated illicit drugs reoccur.

Towards the burden of human leptospirosis: duration of acute illness and occurrence of post-leptospirosis symptoms of patients in the Netherlands.

BACKGROUND: Leptospirosis is a global zoonotic disease. Although important for the assessment of the burden of leptospirosis, data on the duration of the illness and the occurrence of post-leptospirosis complaints are not well documented. Hence the main objective of this study was to estimate the occurrence of persistent complaints and duration of hospital stay in laboratory confirmed leptospirosis patients in the Netherlands during 1985 to 2010. Additionally, several risk factors potentially impacting on the occurrence of post-leptospirosis complaints were investigated. METHODS/PRINCIPAL FINDINGS: The duration of the acute phase of leptospirosis was 16 days (IQR 12-23); 10 days (IQR 7-16) were spent hospitalized. Eighteen fatal cases were excluded from this analysis. Complaints of leptospirosis patients by passive case investigations (CPC) derived from files on ambulant consultations occurring one month after hospital discharge, revealed persistent complaints in 108 of 236 (45.8%) laboratory confirmed cases. Data on persistent complaints after acute leptospirosis (PCAC), assessed in 225 laboratory confirmed leptospirosis cases collected through questionnaires during 1985-1993, indicated 68 (30.2%) PCAC cases. Frequently reported complaints included (extreme) fatigue, myalgia, malaise, headache, and a weak physical condition. These complaints prolonged in 21.1% of the cases beyond 24 months after onset of disease. There was no association between post-leptospirosis complaints and hospitalization. However, individuals admitted at the intensive care unit (ICU) were twice as likely to have continuing complaints after discharge adjusting for age and dialysis (OR 2.0 95% CI 0.8-4.8). No significant association could be found between prolongation of complaints and infecting serogroup, although subgroup analysis suggest that infection with serogroups Sejroe (OR 4.8, 95%CI 0.9-27.0) and icterohaemorrhagiae (OR 2.0, 95%CI 0.9-4.3 CI) are more likely to result in CPC than infections with serogroup Grippotyphosa. CONCLUSION/SIGNIFICANCE: In addition to the acute disease, persistent complaints have an impact on the burden of leptospirosis.