Differential Globalization of Industry- and Non-Industry–Sponsored Clinical Trials

Background

Mapping the international landscape of clinical trials may inform global health research governance, but no large-scale data are available. Industry or non-industry sponsorship may have a major influence in this mapping. We aimed to map the global landscape of industry- and non-industry–sponsored clinical trials and its evolution over time.

Methods

We analyzed clinical trials initiated between 2006 and 2013 and registered in the WHO International Clinical Trials Registry Platform (ICTRP). We mapped single-country and international trials by World Bank''s income groups and by sponsorship (industry- vs. non- industry), including its evolution over time from 2006 to 2012. We identified clusters of countries that collaborated significantly more than expected in industry- and non-industry–sponsored international trials.

Results

119,679 clinical trials conducted in 177 countries were analysed. The median number of trials per million inhabitants in high-income countries was 100 times that in low-income countries (116.0 vs. 1.1). Industry sponsors were involved in three times more trials per million inhabitants than non-industry sponsors in high-income countries (75.0 vs. 24.5) and in ten times fewer trials in low- income countries (0.08 vs. 1.08). Among industry- and non-industry–sponsored trials, 30.3% and 3.2% were international, respectively. In the industry-sponsored network of collaboration, Eastern European and South American countries collaborated more than expected; in the non-industry–sponsored network, collaboration among Scandinavian countries was overrepresented. Industry-sponsored international trials became more inter-continental with time between 2006 and 2012 (from 54.8% to 67.3%) as compared with non-industry–sponsored trials (from 42.4% to 37.2%).

Conclusions

Based on trials registered in the WHO ICTRP we documented a substantial gap between the globalization of industry- and non-industry–sponsored clinical research. Only 3% of academic trials but 30% of industry trials are international. The latter appeared to be conducted in preferentially selected countries.     

The census of heronries, 1960–61

Capsule Eleonora's Falcons wintering in Madagascar selected degraded humid forests and cultivated areas close to pristine humid forest.

Aims To identify the habitat preferences of Eleonora's Falcon Falco eleonorae on their wintering grounds in Madagascar, and to use this information to gain insights into the conservation priorities of this species.

Methods A total of 11 Eleonora's Falcons were captured in Spain in 2007 and 2008 and equipped with solar-powered satellite transmitters. We obtained information on five complete wintering events for three birds, two of them tracked for two consecutive years. Data were analyzed using geographic information system-based cartography.

Results The analyses showed a preference for degraded humid forests and cultivated lands within areas where pristine humid forests were the most abundant habitat type.

Conclusions Eleonora's Falcons could be taking advantage from a spill-over edge effect of their insect prey into cultivated and more open areas close to humid forests. However, the importance of humid forests for Eleonora's Falcons seems to be high. The current loss of this habitat in Madagascar is a cause for concern with respect to the conservation of this long-distance migratory falcon species.     

2011–12 Seasonal Influenza Vaccines Effectiveness against Confirmed A(H3N2) Influenza Hospitalisation: Pooled Analysis from a European Network of Hospitals. A Pilot Study

Background

Influenza vaccination strategies aim at protecting high-risk population from severe outcomes. Estimating the effectiveness of seasonal vaccines against influenza related hospitalisation is important to guide these strategies. Large sample size is needed to have precise estimate of influenza vaccine effectiveness (IVE) against severe outcomes. We assessed the feasibility of measuring seasonal IVE against hospitalisation with laboratory confirmed influenza through a network of 21 hospitals in the European Union.

Methods

We conducted a multicentre study in France (seven hospitals), Italy (one hospital), and Navarra (four hospitals) and Valencia (nine hospitals) regions in Spain. All ≥18 years hospitalised patients presenting an influenza-like illness within seven days were swabbed. Cases were patients RT-PCR positive for influenza A (H3N2); controls were patients negative for any influenza virus. Using logistic regression with study site as a fixed effect we calculated IVE adjusted for potential confounders. We restricted the analyses to those swabbed within four days.

Results

We included, 375 A(H3N2) cases and 770 controls. The overall adjusted IVE was 24.9% (95%CI–1.8;44.6). Among the target group for vaccination (N = 1058) the adjusted IVE was 28.8% (95%CI:2.8;47.9); it was respectively 36.8% (95%CI:−48.8; 73.1), 42.6% (95%CI:−16.5;71.7), 17.8%(95%CI:−40.8; 52.1) and 37.5% (95%CI:−22.8;68.2) in the age groups 18–64, 65–74, 75–84 and more than 84 years.

Discussion

Estimation of IVE based on the pooling of data obtained through a European network of hospitals was feasible. Our results suggest a low IVE against hospitalised confirmed influenza in 2011–12. The low IVE may be explained by a poor immune response in the high-risk population, imperfect match between vaccine and circulating strain or waning immunity due to a late season. Increased sample size within this network would allow more precise estimates and stratification of the IVE by time since vaccination and vaccine types or brands.     

Efficient Estimation of Mann–Whitney-Type Effect Measures for Right-Censored Survival Outcomes in Randomized Clinical Trials

Statistics in Biosciences - Mann–Whitney-type effect measures are clinically relevant, easy to interpret, and readily applicable to a wide range of study settings. This article considers...     

Memories of The New York Botanical Garden, 1960–1980

Memories of employment at The New York Botanical Garden between 1960 and 1980 are given.     

Epidemiological Characteristics of Influenza A and B in Macau, 2010–2018

Virologica Sinica - Influenza is one of the major respiratory diseases in humans. Macau is a tourist city with high density of population and special population mobility. The study on the...     

Improving the Clinical Diagnosis of Influenza—a Comparative Analysis of New Influenza A (H1N1) Cases

Background

The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting.

Methodology/Principal Findings

Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5–17.5) and 9.2 (95%CI 4.1–20.3) respectively).

Conclusions/Significance

The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38°C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.     

Estimating Influenza Deaths in Canada, 1992–2009

Background

Poisson regression modelling has been widely used to estimate the disease burden attributable to influenza, though not without concerns that some of the excess burden could be due to other causes. This study aims to provide annual estimates of the mortality and hospitalization burden attributable to both seasonal influenza and the 2009 A/H1N1 pandemic influenza for Canada, and to discuss issues related to the reliability of these estimates.

Methods

Weekly time-series for all-cause mortality and regression models were used to estimate the number of deaths in Canada attributable to influenza from September 1992 to December 2009. To assess their robustness, the annual estimates derived from different parameterizations of the regression model for all-cause mortality were compared. In addition, the association between the annual estimates for mortality and hospitalization by age group, underlying cause of death or primary reason for admission and discharge status is discussed.

Results

The crude influenza-attributed mortality rate based on all-cause mortality and averaged over 17 influenza seasons prior to the 2009 A/H1N1 pandemic was 11.3 (95%CI, 10.5 - 12.1) deaths per 100 000 population per year, or an average of 3,500 (95%CI, 3,200 - 3,700) deaths per year attributable to seasonal influenza. The estimated annual rates ranged from undetectable at the ecological level to more than 6000 deaths per year over the three A/Sydney seasons. In comparison, we attributed an estimated 740 deaths (95%CI, 350–1500) to A(H1N1)pdm09. Annual estimates from different model parameterizations were strongly correlated, as were estimates for mortality and morbidity; the higher A(H1N1)pdm09 burden in younger age groups was the most notable exception.

Interpretation

With the exception of some of the Serfling models, differences in the ecological estimates of the disease burden attributable to influenza were small in comparison to the variation in disease burden from one season to another.     

Clinical Efficacy and Tolerability of Praziquantel for Intestinal and Urinary Schistosomiasis—A Meta-analysis of Comparative and Non-comparative Clinical Trials

Background

Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.

Methodology/Principal Findings

A systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n = 17,017) and egg reduction rate (ERR, n = 13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2–98.0) for S. japonicum, 77.1% (68.4–85.1) for S. haematobium, 76.7% (95%CI 71.9–81.2) for S. mansoni, and 63.5% (95%CI 48.2–77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4–67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.

Conclusions/Significance

The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.     

The Lapwing habitat enquiry, 1960–61

More time is available for foraging by Cinereous Vultures Aegypius monachus in summer, but in winter they maximize flight time by starting close to sunrise. Vultures nesting in mountains begin to fly earlier than those in plains because of wind producing ‘slope-lift’. Rain impedes flight for whole days in winter. In general, time devoted to foraging may depend upon both food availability and soaring conditions.     

Influenza Illness and Hospitalizations Averted by Influenza Vaccination in the United States, 2005–2011

Context

The goal of influenza vaccination programs is to reduce influenza-associated disease outcomes. Therefore, estimating the reduced burden of influenza as a result of vaccination over time and by age group would allow for a clear understanding of the value of influenza vaccines in the US, and of areas where improvements could lead to greatest benefits.

Objective

To estimate the direct effect of influenza vaccination in the US in terms of averted number of cases, medically-attended cases, and hospitalizations over six recent influenza seasons.

Design

Using existing surveillance data, we present a method for assessing the impact of influenza vaccination where impact is defined as either the number of averted outcomes or as the prevented disease fraction (the number of cases estimated to have been averted relative to the number of cases that would have occurred in the absence of vaccination).

Results

We estimated that during our 6-year study period, the number of influenza illnesses averted by vaccination ranged from a low of approximately 1.1 million (95% confidence interval (CI) 0.6–1.7 million) during the 2006–2007 season to a high of 5 million (CI 2.9–8.6 million) during the 2010–2011 season while the number of averted hospitalizations ranged from a low of 7,700 (CI 3,700–14,100) in 2009–2010 to a high of 40,400 (CI 20,800–73,000) in 2010–2011. Prevented fractions varied across age groups and over time. The highest prevented fraction in the study period was observed in 2010–2011, reflecting the post-pandemic expansion of vaccination coverage.

Conclusions

Influenza vaccination programs in the US produce a substantial health benefit in terms of averted cases, clinic visits and hospitalizations. Our results underscore the potential for additional disease prevention through increased vaccination coverage, particularly among nonelderly adults, and increased vaccine effectiveness, particularly among the elderly.     

Spatial,Temporal and Genetic Dynamics Characteristics of Influenza B Viruses in China, 1973–2018

Annual influenza B virus epidemics and outbreaks cause severe influenza diseases in humans and pose a threat to public health. China is an important epidemic area of influenza B viruses. However, the spatial, temporal transmission pathways and the demography history of influenza B viruses in China remain unknown. We collected the haemagglutinin gene sequences sampled of influenza B virus in China between 1973 and 2018. A Bayesian Markov chain Monte Carlo phylogeographic discrete approach was used to infer the spatial and temporal phylodynamics of influenza B virus. The Bayesian phylogeographic analysis of influenza B viruses showed that the North subtropical and South subtropical zones are the origins of the Victoria and Yamagata lineage viruses, respectively. Furthermore, the South temperate and North subtropical zones acted as transition nodes in the Victoria lineage virus dispersion network and that the North subtropical and Mid subtropical zones acted as transition nodes in the Yamagata lineage virus dispersion network. Our findings contribute to the knowledge regarding the spatial and temporal patterns of influenza B virus outbreaks in China.     

The Association of Meningococcal Disease with Influenza in the United States, 1989–2009

Importance and Objective

Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fraction of meningococcal disease attributable to influenza could improve understanding of viral-bacterial interaction and indicate additional health benefits to influenza immunization.

Design, Setting and Participants

A time series analysis of the association of influenza and meningococcal disease using hospitalizations in 9 states from 1989–2009 included in the State Inpatient Databases from the Agency for Healthcare Research and Quality and the proportion of positive influenza tests by subtype reported to the Centers for Disease Control. The model accounts for the autocorrelation of meningococcal disease and influenza between weeks, temporal trends, co-circulating respiratory syncytial virus, and seasonality. The influenza-subtype-attributable fraction was estimated using the model coefficients. We analyzed the synchrony of seasonal peaks in hospitalizations for influenza, respiratory syncytial virus, and meningococcal disease.

Results and Conclusions

In 19 of 20 seasons, influenza peaked≤2 weeks before meningococcal disease, and peaks were highly correlated in time (ρ = 0.95; P <.001). H3N2 and H1N1 peaks were highly synchronized with meningococcal disease while pandemic H1N1, B, and respiratory syncytial virus were not. Over 20 years, 12.8% (95% CI, 9.1–15.0) of meningococcal disease can be attributable to influenza in the preceding weeks with H3N2 accounting for 5.2% (95% CI, 3.0–6.5), H1N1 4.3% (95% CI, 2.6–5.6), B 3.0% (95% CI, 0.8–4.9) and pH1N1 0.2% (95% CI, 0–0.4). During the height of influenza season, weekly attributable fractions reach 59%. While vaccination against meningococcal disease is the most important prevention strategy, influenza vaccination could provide further protection, particularly in young children where the meningococcal disease vaccine is not recommended or protective against the most common serogroup.     

Ten Years after the International Committee of Medical Journal Editors’ Clinical Trial Registration Initiative,One Quarter of Phase 3 Pediatric Epilepsy Clinical Trials Still Remain Unpublished: A Cross Sectional Analysis

Introduction

Although selective reporting of clinical trial results introduces bias into evidence based clinical decision making, publication bias in pediatric epilepsy is unknown today. Since there is a considerable ambiguity in the treatment of an important and common clinical problem, pediatric seizures, we assessed the public availability of results of phase 3 clinical trials that evaluated treatments of seizures in children and adolescents as a surrogate for the extent of publication bias in pediatric epilepsy.

Methods

We determined the proportion of published and unpublished study results of phase 3 clinical trials that were registered as completed on ClinicalTrials.gov. We searched ClinicalTrials.gov, PubMed, and Google Scholar for publications and contacted principal investigators or sponsors. The analysis was performed according to STROBE criteria.

Results

Considering studies that were completed before 2014 (N = 99), 75 (76%) pediatric phase 3 clinical trials were published but 24 (24%) remained unpublished. The unpublished studies concealed evidence from 4,437 patients. Mean time-to-publication was 25 SD ± 15.6 months, more than twice as long as mandated.

Conclusion

Ten years after the ICMJE’s clinical trials registration initiative there is still a considerable amount of selective reporting and delay of publication that potentially distorts the body of evidence in the treatment of pediatric seizures.