Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial.

INTRODUCTION: Complement C5 antibodies reduce brain injury after experimental subarachnoid hemorrhage. PATIENTS AND METHODS: In this randomized, controlled, open-label, phase 2a clinical trial with blinded-outcome assessment, we included adult aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to a tertiary referral center ⩽11 h after ictus. Patients were randomized (1:1) to eculizumab plus care as usual or to care as usual. Eculizumab (1200 mg) was administered <12 h, and on days 3 and 7 after ictus. In the intervention group, all patients received prophylactic antibiotics and, after a protocol amendment, fluconazole if indicated. Primary outcome was C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Safety was monitored during 4 weeks. In each group, 13 patients with CSF assessments were needed to detect a 55% reduction in CSF C5a concentration. RESULTS: From October 2018 to May 2021, we enrolled 31 patients of whom 26 with CSF samples, 13 per group. Median C5a concentration in CSF on day 3 was 251 pg/ml [IQR: 103-402] in the intervention group and 371 pg/ml [IQR: 131-534] in the control group (p = 0.29). Infections occurred in two patients in the intervention group and four patients in the control group. One patient in the intervention group developed a C. albicans meningitis prior to the protocol amendment. DISCUSSION AND CONCLUSION: One dose of eculizumab did not result in a ⩾ 55% decrease in C5a concentration in CSF on day 3 after aSAH. The study did not reveal new safety concerns, except for a C. albicans drain-related infection prior to antifungal monitoring and treatment. TRIAL REGISTRATION: EudraCT 2017-004307-51, https://www.clinicaltrialsregister.eu/.

Multi-part strategy for testing differential taxa abundance in sequencing data: A simulation study with an application to a microbiome study.

Comparing the microbiome across study arms is a recurrent goal in many studies. Standard statistical methods are often used for this purpose, however, they do not always represent the best choice in this context given the characteristics of microbiota sequencing data, e.g., non-negative, highly skewed counts with a large number of zeros. A multi-part strategy, that combines a two-part test (as described by Wagner et al., 2011), a Wilcoxon sum-rank test, a Chi-square and a Barnard's test was explored to compare the taxa abundance between study arms. The choice of the test is based on the data structure. The type I error of the multi-part strategy was evaluated by using a simulation study and the method was applied to real data. The script to perform the analysis with the multi-part approach is provided in the statistical software SAS. Several scenarios were simulated and in all of them the type I error was not inflated. Based on the statistical differences resulting from the two-part test (as described by Wagner et al., 2011) and the multi-part strategy (as proposed in this article), different biological implications can be extracted from the same comparison in the same data set. In the comparison of taxa abundance between study arms, we showed that careful attention needs to be paid on the data structure, in order to be able to choose an appropriate analysis method. Our approach selects the most suitable test according to the type of data observed, maintains a good type I error and is easily applicable by using the SAS macro provided.

Daily intranasal palivizumab to prevent respiratory syncytial virus infection in healthy preterm infants: a phase 1/2b randomized placebo-controlled trial.

Background: Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking. Methods: In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403). We randomized infants 1:1 to receive intranasal palivizumab (1 mg/mL) or placebo once daily during the RSV season. Any RSV infection was the primary outcome and RSV hospitalization was the key secondary outcome. The primary outcome was analyzed with a mixed effect logistic regression on the modified intention-to-treat population. Findings: We recruited 268 infants between Jan 14, 2019 and Jan 28, 2021, after which the trial was stopped for futility following the planned interim analysis. Adverse events were similar in both groups (22/134 (16.4%) palivizumab arm versus 26/134 (19.4%) placebo arm). There were 6 dropouts and 168 infants were excluded from the efficacy analyses due to absent RSV circulation during the SARS-CoV-2 pandemic. Any RSV infection was similar in infants in both groups (18/47 (38.3%) palivizumab arm versus 11/47 (23.4%) placebo arm; aOR 2.2, 95% CI 0.7-6.5). Interpretation: Daily intranasal palivizumab did not prevent RSV infection in late preterm infants. Our findings have important implications for the clinical development of mucosal mAbs, namely the necessity of timely interim analyses and further research to understand mucosal antibody half-life. Funding: Funded by the Department of Pediatrics, University Medical Centre Utrecht, the Netherlands.

Clinical outcomes of second relapsed and refractory first relapsed paediatric AML: A retrospective study within the NOPHO-DB SHIP consortium.

As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured.

Clinical presentation, microbiological aetiology and disease course in patients with flu-like illness: a post hoc analysis of randomised controlled trial data.

BACKGROUND: There is little evidence about the relationship between aetiology, illness severity, and clinical course of respiratory tract infections (RTIs) in primary care. Understanding these associations would aid in the development of effective management strategies for these infections. AIM: To investigate whether clinical presentation and illness course differ between RTIs where a viral pathogen was detected and those where a potential bacterial pathogen was found. DESIGN AND SETTING: Post hoc analysis of data from a pragmatic randomised trial on the effects of oseltamivir in patients with flu-like illness in primary care (n = 3266) in 15 European countries. METHOD: Patient characteristics and their signs and symptoms of disease were registered at baseline. Nasopharyngeal (adults) or nasal and pharyngeal (children) swabs were taken for polymerase chain reaction analysis. Patients were followed up until 28 days after inclusion. Regression models and Kaplan-Meier curves were used to analyse the relationship between aetiology, clinical presentation at baseline, and course of disease including complications. RESULTS: Except for a less prominent congested nose (odds ratio [OR] 0.55, 95% confidence interval [CI] = 0.35 to 0.86) and acute cough (OR 0.42, 95% CI = 0.27 to 0.65) in patients with flu-like illness in whom a possible bacterial pathogen was isolated, there were no clear clinical differences in presentations between those with a possible bacterial aetiology compared with those with a viral aetiology. Also, course of disease and complications were not related to aetiology. CONCLUSION: Given current available microbiological tests and antimicrobial treatments, and outside pandemics such as COVID-19, microbiological testing in primary care patients with flu-like illness seems to have limited value. A wait-and-see policy in most of these patients with flu-like illness seems the best option.

Point-of-care testing, antibiotic prescribing, and prescribing confidence for respiratory tract infections in primary care: a prospective audit in 18 European countries.

BACKGROUND: Between-country differences have been described in antibiotic prescribing for respiratory tract infection (RTI) in primary care, but not yet for diagnostic testing procedures and prescribing confidence. AIM: To describe between-country differences in RTI management, particularly diagnostic testing and antibiotic prescribing, and investigate which factors relate to antibiotic prescribing and GPs' prescribing confidence. DESIGN & SETTING: Prospective audit in 18 European countries. METHOD: An audit of GP-registered patient, clinical, and management characteristics for patients presenting with sore throat and/or lower RTI (n = 4982), and GPs' confidence in their antibiotic prescribing decision. Factors related to antibiotic prescribing and confidence were analysed using multi-level logistic regression. RESULTS: Antibiotic prescribing proportions varied considerably: <20% in four countries, and >40% in six countries. There was also considerable variation in point-of-care (POC) testing (0% in Croatia, Moldova, and Romania, and >65% in Denmark and Norway, mainly for C-reactive protein [CRP] and group A streptococcal [strep A] infection), and in laboratory or hospital-based testing (<3% in Hungary, the Netherlands, and Spain, and >30% in Croatia, Georgia, Greece, and Moldova, mainly chest X-ray and white blood cell counting). Antibiotic prescribing was related to illness severity, comorbidity, age, fever, and country, but not to having performed a POC test. In nearly 90% of consultations, GPs were confident in their antibiotic prescribing decision. CONCLUSION: Despite high confidence in decisions about antibiotic prescribing, there is considerable variation in the primary care of RTI in European countries, with GPs prescribing antibiotics overall more often than is considered appropriate. POC testing may enhance the quality of antibiotic prescribing decisions if it can safely reverse decisions confidently made on clinical grounds alone to prescribe antibiotics.

Oseltamivir for coronavirus illness: post-hoc exploratory analysis of an open-label, pragmatic, randomised controlled trial in European primary care from 2016 to 2018.

BACKGROUND: Patients infected with the novel coronavirus (SARS-CoV-2) are being treated empirically with oseltamivir, but there is little evidence from randomised controlled trials to support the treatment of coronavirus infections with oseltamivir. AIM: To determine whether adding oseltamivir to usual care reduces time to recovery in symptomatic patients who have tested positive for coronavirus (not including SARS-CoV-2). DESIGN AND SETTING: Exploratory analysis of data from an open-label, pragmatic, randomised controlled trial during three influenza seasons, from 2016 to 2018, in primary care research networks, in 15 European countries. METHOD: Patients aged ≥1 year presenting to primary care with influenza-like illness (ILI), and who tested positive for coronavirus (not including SARS-CoV-2), were randomised to usual care or usual care plus oseltamivir. The primary outcome was time to recovery defined as a return to usual activities, with minor or absent fever, headache, and muscle ache. RESULTS: Coronaviruses (CoV-229E, CoV-OC43, CoV-KU1 and CoV-NL63) were identified in 308 (9%) out of 3266 randomised participants in the trial; 153 of these were allocated to usual care and 155 to usual care plus oseltamivir; the primary outcome was ascertained in 136 and 147 participants, respectively. The median time to recovery was shorter in patients randomised to oseltamivir: 4 days (interquartile range [IQR] 3-6) versus 5 days (IQR 3-8; hazard ratio 1.31; 95% confidence interval = 1.03 to 1.66; P = 0.026). CONCLUSION: Primary care patients with ILI testing positive for coronavirus (not including SARS-CoV-2) recovered sooner when oseltamivir was added to usual care compared with usual care alone. This may be of relevance to the primary care management of COVID-19.

High Resolution Spatial Analysis of Habitat Preference of Aedes Albopictus (Diptera: Culicidae) in an Urban Environment.

Over the past decades, the Asian tiger mosquito (Aedes albopictus (Skuse, 1895)) has emerged in many countries, and it has colonized new environments, including urban areas. The species is a nuisance and a potential vector of several human pathogens, and a better understanding of the habitat preferences of the species is needed for help in successful prevention and control. So far, the habitat preference in urban environments has not been studied in Southern European cities. In this paper, spatial statistical models were used to evaluate the relationship between egg abundances and land cover types on the campus of Sapienza University in Rome, which is taken as an example of a European urban habitat. Predictor variables included land cover types, classified in detail on a high resolution image, as well as solar radiation and month of capture. The models account for repeated measures in the same trap and are adjusted for meteorological circumstances. Vegetation and solar radiation were found to be positively related to the number of eggs. More specifically, trees were positively related to the number of eggs and the relationship with grass was negative. These findings are consistent with the species' known preference for shaded areas. The unexpected positive relationship with solar radiation is amply discussed in the paper. This study represents a first step toward a better understanding of the spatial distribution of Ae. albopictus in urban environments.

Modelling the spatial distribution of the nuisance mosquito species Anopheles plumbeus (Diptera: Culicidae) in the Netherlands.

BACKGROUND: Landscape modifications, urbanization or changes of use of rural-agricultural areas can create more favourable conditions for certain mosquito species and therefore indirectly cause nuisance problems for humans. This could potentially result in mosquito-borne disease outbreaks when the nuisance is caused by mosquito species that can transmit pathogens. Anopheles plumbeus is a nuisance mosquito species and a potential malaria vector. It is one of the most frequently observed species in the Netherlands. Information on the distribution of this species is essential for risk assessments. The purpose of the study was to investigate the potential spatial distribution of An. plumbeus in the Netherlands. METHODS: Random forest models were used to link the occurrence and the abundance of An. plumbeus with environmental features and to produce distribution maps in the Netherlands. Mosquito data were collected using a cross-sectional study design in the Netherlands, from April to October 2010-2013. The environmental data were obtained from satellite imagery and weather stations. Statistical measures (accuracy for the occurrence model and mean squared error for the abundance model) were used to evaluate the models performance. The models were externally validated. RESULTS: The maps show that forested areas (centre of the Netherlands) and the east of the country were predicted as suitable for An. plumbeus. In particular high suitability and high abundance was predicted in the south-eastern provinces Limburg and North Brabant. Elevation, precipitation, day and night temperature and vegetation indices were important predictors for calculating the probability of occurrence for An. plumbeus. The probability of occurrence, vegetation indices and precipitation were important for predicting its abundance. The AUC value was 0.73 and the error in the validation was 0.29; the mean squared error value was 0.12. CONCLUSIONS: The areas identified by the model as suitable and with high abundance of An. plumbeus, are consistent with the areas from which nuisance was reported. Our results can be helpful in the assessment of vector-borne disease risk.

Modelling the potential spatial distribution of mosquito species using three different techniques.

BACKGROUND: Models for the spatial distribution of vector species are important tools in the assessment of the risk of establishment and subsequent spread of vector-borne diseases. The aims of this study are to define the environmental conditions suitable for several mosquito species through species distribution modelling techniques, and to compare the results produced with the different techniques. METHODS: Three different modelling techniques, i.e., non-linear discriminant analysis, random forest and generalised linear model, were used to investigate the environmental suitability in the Netherlands for three indigenous mosquito species (Culiseta annulata, Anopheles claviger and Ochlerotatus punctor). Results obtained with the three statistical models were compared with regard to: (i) environmental suitability maps, (ii) environmental variables associated with occurrence, (iii) model evaluation. RESULTS: The models indicated that precipitation, temperature and population density were associated with the occurrence of Cs. annulata and An. claviger, whereas land surface temperature and vegetation indices were associated with the presence of Oc. punctor. The maps produced with the three different modelling techniques showed consistent spatial patterns for each species, but differences in the ranges of the predictions. Non-linear discriminant analysis had lower predictions than other methods. The model with the best classification skills for all the species was the random forest model, with specificity values ranging from 0.89 to 0.91, and sensitivity values ranging from 0.64 to 0.95. CONCLUSIONS: We mapped the environmental suitability for three mosquito species with three different modelling techniques. For each species, the maps showed consistent spatial patterns, but the level of predicted environmental suitability differed; NLDA gave lower predicted probabilities of presence than the other two methods. The variables selected as important in the models were in agreement with the existing knowledge about these species. All model predictions had a satisfactory to excellent accuracy; best accuracy was obtained with random forest. The insights obtained can be used to gain more knowledge on vector and non-vector mosquito species. The output of this type of distribution modelling methods can, for example, be used as input for epidemiological models of vector-borne diseases.

R0 for vector-borne diseases: impact of the assumption for the duration of the extrinsic incubation period.

Mathematical modeling and notably the basic reproduction number R0 have become popular tools for the description of vector-borne disease dynamics. We compare two widely used methods to calculate the probability of a vector to survive the extrinsic incubation period. The two methods are based on different assumptions for the duration of the extrinsic incubation period; one method assumes a fixed period and the other method assumes a fixed daily rate of becoming infectious. We conclude that the outcomes differ substantially between the methods when the average life span of the vector is short compared to the extrinsic incubation period.

The "auto-dissemination" approach: a novel concept to fight Aedes albopictus in urban areas.

BACKGROUND: The main constraint to the fight against container-breeding mosquito vectors of human arboviruses is the difficulty in targeting the multiplicity of larval sources, mostly represented by small man-made water containers. The aim of this work is to assess the feasibility of the "auto-dissemination" approach, already tested for Aedes aegypti, as a possible alternative to traditional, inefficient control tools, against Ae. albopictus in urban areas. The approach is based on the possibility that wild adult females, exposed to artificial resting sites contaminated with pyriproxyfen, can disseminate this juvenile hormone analogue to larval habitats, thus interfering with adult emergence. METHODOLOGY: We carried out four field experiments in two areas of Rome that are typically highly infested with Ae. albopictus, i.e. the main cemetery and a small green area within a highly urbanised neighbourhood. In each area we used 10 pyriproxyfen "dissemination" stations, 10 "sentinel" sites and 10 covered, control sites. The sentinel and control sites each contained 25 Ae. albopictus larvae. These were monitored for development and adult emergence. PRINCIPAL FINDINGS: When a 5% pyriproxyfen powder was used to contaminate the dissemination sites, we observed significantly higher mortality at the pupal stage in the sentinel sites (50-70%) than in the controls (<2%), showing that pyriproxyfen was transferred by mosquitoes into sentinel sites and that it had a lethal effect. CONCLUSIONS: The results support the potential feasibility of the auto-dissemination approach to control Ae. albopictus in urban areas. Further studies will be carried out to optimize the method and provide an effective tool to reduce the biting nuisance caused by this aggressive species and the transmission risk of diseases such as Dengue and Chikungunya. These arboviruses pose an increasing threat in Europe as Ae. albopictus expands its range.

Impact of female sex on long-term outcomes in patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention.

BACKGROUND: Conflicting information exists about whether sex differences affect long-term outcomes in patients undergoing primary percutaneous coronary intervention (PCI). METHODS: This retrospective study enrolled consecutive patients with ST-elevation myocardial infarction undergoing primary PCI within 24 hours from symptom onset. Hazard ratios (HRs) of events with 95% confidence interval (CI) were calculated in the overall population and in a propensity score matched cohort of women and men. RESULTS: Among 481 patients, median age 66 years old, 138 (28.7%) were women. Women were older than men (72 vs 63 years, P<0.001), had a higher prevalence of hypertension (68% vs 54%, P=0.006), diabetes (27% vs 19%, P=0.04), and Killip class≥3 at admission (19% vs 10%, P=0.007). After a median follow-up of 1041 days women experienced a significant higher incidence of the composite of death, nonfatal myocardial infarction, and hospitalization for heart failure (31.9% vs 18.4%, unadjusted HR 1.86; 95% CI, 1.26-2.74; P=0.002), driven mainly by heart failure (unadjusted HR 2.47; 95% CI, 1.12-5.41; P=0.024), without significant differences in death (unadjusted HR 1.49; 95% CI, 0.88-2.53; P=0.13), or nonfatal myocardial infarction (unadjusted HR 1.59; 95% CI, 0.78-3.27; P=0.19) and no increase in target lesion revascularization (9.4% vs 12.5%, unadjusted HR 0.77; 95% CI, 0.42-1.44; P=0.42). After propensity score matching the hazard of the composite endpoint was largely attenuated (HR 1.32; 95% CI, 0.84-2.06; P=0.23). CONCLUSIONS: Women undergoing primary PCI experience worse long-term outcomes than men, but this difference is largely explained by their more adverse baseline cardiovascular profile.