Influence of chronic exposure to thiamethoxam and chronic bee paralysis virus on winter honey bees.

Co-exposure to pesticides and viruses is likely to occur in honey bee colonies. Pesticides can be present in pollen, nectar, and persist in stored food (honey and bee bread), and viruses can be highly prevalent in honey bee colonies. Therefore, the present study describes the influence of chronic co-exposure to thiamethoxam and Chronic bee paralysis virus (CBPV) on bee survival, virus loads, expression level of immune and detoxication genes, and pesticide metabolism Experiments were performed on honey bees collected from a winter apiary with reduced viral contaminations. No synergistic effect of co-exposure was observed on bee survival, nor on the ability of bees to metabolise the pesticide into clothianidin. However, we found that co-exposure caused an increase in CBPV loads that reached the viral levels usually found in overt infections. The effect of co-exposure on CBPV replication was associated with down-regulation of vitellogenin and dorsal-1a gene transcription. Nevertheless, the observed effects might be different to those occurring in spring or summer bees, which are more likelyco-exposed to thiamethoxam and CBPV and exhibit a different physiology

Transcription profiling of HCN-channel isotypes throughout mouse cardiac development

Hyperpolarization-activated ion channels, encoded by four mammalian genes (HCN1-4), contribute in an important way to the cardiac pacemaker current If. Here, we describe the transcription profiles of the four HCN genes, the NRSF, KCNE2 and Kir2.1 genes from embryonic stage E9.5 dpc to postnatal day 120 in the mouse. Embryonic atrium and ventricle revealed abundant HCN4 transcription but other HCN transcripts were almost absent. Towards birth, HCN4 was downregulated in the atrium and almost vanished from the ventricle. After birth, however, HCN isotype transcription changed remarkably, showing increased levels of HCN1, HCN2 and HCN4 in the atrium and of HCN2 and HCN4 in the ventricle. HCN3 showed highest transcription at early embryonic stages and was hardly detectable thereafter. At postnatal day 10, HCN4 was highest in the sinoatrial node, being twofold higher than HCN1 and fivefold higher than HCN2. In the atrium, HCN4 was similar to HCN1 and sevenfold higher than HCN2. In the ventricle, in contrast, HCN2 was sixfold higher than HCN4, while HCN1 was absent. Subsequently all HCN isotype transcripts declined to lower adult levels, while ratios of HCN isotypes remained stable. In conclusion, substantial changes of HCN isotype transcription throughout cardiac development suggest that a regulated pattern of HCN isotypes is required to establish and ensure a stable heart rhythm. Furthermore, constantly low HCN transcription in adult myocardium may be required to prevent atrial and ventricular arrhythmogenesis

Cardiac Alterations in Human African Trypanosomiasis (T.b. gambiense) with Respect to the Disease Stage and Antiparasitic Treatment

In Human African Trypanosomiasis (HAT), neurological symptoms dominate and cardiac involvement has been suggested. Because of increasing resistance to the available drugs for HAT, new compounds are desperately needed. Evaluation of cardiotoxicity is one parameter of drug safety, but without knowledge of the baseline heart involvement in HAT, cardiologic findings and drug-induced alterations will be difficult to interpret. The electrocardiogram (ECG) is a tool to evaluate cardiac involvement and the risk of arrythmias. We analysed the ECG of 465 HAT patients and compared them with the ECG of 61 healthy volunteers. In HAT patients the QTc interval was prolonged. This comprises a risk of fatal arrhythmias if new drugs with antiarrhythmic potential will be used. Further, repolarization changes and low voltage were more frequent than in healthy controls. This could be explained by an inflammation of the heart. Treatment of HAT was associated with appearance of repolarization changes but not with a QTc prolongation. These changes appear to be associated with the disease, but not with a specific drug. The main conclusion of this study is that heart involvement is frequent in HAT and mostly well tolerated. However, it can become relevant, if new compounds with antiarrhythmic potential will be used

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A realist analysis of hospital patient safety in Wales:Applied learning for alternative contexts from a multisite case study

Background: Hospital patient safety is a major social problem. In the UK, policy responses focus on the introduction of improvement programmes that seek to implement evidence-based clinical practices using the Model for Improvement, Plan-Do-Study-Act cycle. Empirical evidence that the outcomes of such programmes vary across hospitals demonstrates that the context of their implementation matters. However, the relationships between features of context and the implementation of safety programmes are both undertheorised and poorly understood in empirical terms. Objectives: This study is designed to address gaps in conceptual, methodological and empirical knowledge about the influence of context on the local implementation of patient safety programmes. Design: We used concepts from critical realism and institutional analysis to conduct a qualitative comparative-intensive case study involving 21 hospitals across all seven Welsh health boards. We focused on the local implementation of three focal interventions from the 1000 Lives+ patient safety programme: Improving Leadership for Quality Improvement, Reducing Surgical Complications and Reducing Health-care Associated Infection. Our main sources of data were 160 semistructured interviews, observation and 1700 health policy and organisational documents. These data were analysed using the realist approaches of abstraction, abduction and retroduction. Setting: Welsh Government and NHS Wales. Participants: Interviews were conducted with 160 participants including government policy leads, health managers and professionals, partner agencies with strategic oversight of patient safety, advocacy groups and academics with expertise in patient safety. Main outcome measures: Identification of the contextual factors pertinent to the local implementation of the 1000 Lives+ patient safety programme in Welsh NHS hospitals. Results: An innovative conceptual framework harnessing realist social theory and institutional theory was produced to address challenges identified within previous applications of realist inquiry in patient safety research. This involved the development and use of an explanatory intervention–context–mechanism–agency–outcome (I-CMAO) configuration to illustrate the processes behind implementation of a change programme. Our findings, illustrated by multiple nested I-CMAO configurations, show how local implementation of patient safety interventions are impacted and modified by particular aspects of context: specifically, isomorphism, by which an intervention becomes adapted to the environment in which it is implemented; institutional logics, the beliefs and values underpinning the intervention and its source, and their perceived legitimacy among different groups of health-care professionals; and the relational structure and power dynamics of the functional group, that is, those tasked with implementing the initiative. This dynamic interplay shapes and guides actions leading to the normalisation or the rejection of the patient safety programme. Conclusions: Heightened awareness of the influence of context on the local implementation of patient safety programmes is required to inform the design of such interventions and to ensure their effective implementation and operationalisation in the day-to-day practice of health-care teams. Future work is required to elaborate our conceptual model and findings in similar settings where different interventions are introduced, and in different settings where similar innovations are implemented. Funding: The National Institute for Health Research Health Services and Delivery Research programme

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Efficacy and safety of pafuramidine versus pentamidine maleate for treatment of first stage sleeping sickness in a randomized, comparator-controlled, international phase 3 clinical trial

Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine.; This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673.; The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity

Drivers of Routine and Outbreak Vaccination Uptake in the Western Democratic Republic of Congo: An Exploratory Study in Ten Health Zones

We performed a cross-sectional survey on vaccination-related knowledge, attitudes, and practices (KAP) among randomly selected parents of <5 years-old children, elderly populations (aged ≥ 55 years), and health care workers (HCWs) in 10 health zones from 4 provinces of the Democratic Republic of Congo (DRC). Questionnaires targeted both routine (BCG, measles, polio) and outbreak-related (cholera, Ebola, COVID-19) vaccinations. In total, 2751 participants were included, 1165 parents, 1040 elderly, and 546 HCWs. In general, KAP expressed were supportive of vaccination uptake, although concerns regarding side effects and feelings of being insufficiently informed were more prevalent among parents and the elderly. Vaccine acceptance was lower for outbreak vaccinations (57%) than for routine vaccinations (90%). HCWs expressed the highest vaccine acceptance. Problems with the vaccine supply chain were reported by 20% of respondents. Despite a high level of positive KAP towards vaccination, parents and the elderly expressed a need to be better informed and had concerns regarding vaccine side-effects. A high acceptance for routine vaccinations was reported by participants, but somewhat less for outbreak vaccinations. In conclusion, HCWs in the communities could play a key role in the increased uptake of routine vaccinations and in optimizing uptake during outbreaks, provided that the supply chain is functioning well

Beta-Hemolytic Streptococcal Infective Endocarditis: Characteristics and Outcomes From a Large, Multinational Cohort

International audienceAbstract Background Beta-hemolytic streptococci (BHS) are an uncommon cause of infective endocarditis (IE). The aim of this study was to describe the clinical features and outcomes of patients with BHS IE in a large multinational cohort and compare them with patients with viridans streptococcal IE. Methods The International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS) is a large multinational database that recruited patients with IE prospectively using a standardized data set. Sixty-four sites in 28 countries reported patients prospectively using a standard case report form developed by ICE collaborators. Results Among 1336 definite cases of streptococcal IE, 823 were caused by VGS and 147 by BHS. Patients with BHS IE had a lower prevalence of native valve (P &lt; .005) and congenital heart disease predisposition (P = .002), but higher prevalence of implantable cardiac device predisposition (P &lt; .005). Clinically, they were more likely to present acutely (P &lt; .005) and with fever (P = .024). BHS IE was more likely to be complicated by stroke and other systemic emboli (P &lt; .005). The overall in-hospital mortality of BHS IE was significantly higher than that of VGS IE (P = .001). In univariate analysis, variables associated with in-hospital mortality for BHS IE were age (odds ratio [OR], 1.044; P = .004), prosthetic valve IE (OR, 3.029; P = .022), congestive heart failure (OR, 2.513; P = .034), and stroke (OR, 3.198; P = .009). Conclusions BHS IE is characterized by an acute presentation and higher rate of stroke, systemic emboli, and in-hospital mortality than VGS IE. Implantable cardiac devices as a predisposing factor were more often found in BHS IE compared with VGS IE