Performance of the Alere i RSV assay for point-of-care detection of respiratory syncytial virus in children

Background: Respiratory syncytial virus (RSV) is the most important cause of severe acute respiratory tract infection in young children. Alere i RSV is a novel molecular rapid test which identifies respiratory syncytial virus in less than 13 min. Methods: We evaluated the clinical performance of the Alere i RSV assay in a pediatric point-of-care setting during winter season 2016 / 2017. Test results from 518 nasopharyngeal swab samples were compared to a real-time reverse transcription PCR reference standard. Results: The overall sensitivity and specificity of the Alere i RSV test assay was 93% (CI95 89% – 96%) and 96% (CI95 93% – 98%), respectively. Alere i RSV performed well in children of all age groups. An optimal sensitivity of 98% (CI95 94% - 100%) and specificity of 96% (CI95 90% - 99%) was obtained in children < 6 months. In children ≥ 2 years, sensitivity and specificity remained at 87% (CI95 73% – 96%) and 98% (CI95 92% – 100%), respectively. False negative Alere i RSV test results mostly occurred in samples with low viral load (mean CT value 31.1; CI95 29.6 – 32.6). The Alere i RSV assay is easy to use and can be operated after minimal initial training. Test results are available within 13 min, with most RSV positive samples being identified after approximately 5 min. Conclusion: The Alere i RSV assay has the potential to facilitate the detection of RSV in pediatric point-of-care settings

Molecular epidemiology and disease severity of influenza virus infection in patients with haematological disorders

nfluenza virus infection is a common cause of self‐limiting respiratory tract infection(RTI), however immunocompromised patients are at an increased risk for a severecourse of disease or fatal outcome. We therefore aimed to gain a betterunderstanding of the molecular epidemiology of influenza viruses from patientswith haematological disorders and their impact on the clinical course of disease.Molecular analysis using polymerase chain reaction (PCR) of nasopharyngeal swabswas performed for influenza virus in haematological patients at the HeidelbergUniversity Hospital. Clinical data was evaluated to identify associated risk factors.For phylogenetic analysis, the hemagglutinin (HA) gene was sequenced. Out of 159influenza positive patients, 117 patients developed upper RTI (influenza A:n= 73;influenza B:n= 44). Lower RTI was observed inn= 42 patients (26%),n= 22/42patients developed severe disease andn= 16/159 (10.1%) patients died. Risk factorsfor lower RTI were nosocomial infection (p= 0.02), viral shedding for≥14 days(p= 0.018), IgG levels <6 g/dL (p= 0.046), bacterial/fungal co‐infections (p< 0.001).Risk factors for fatal outcome were age≥65 years (p= 0.032), bacterial/fungal(p≤0.001) co‐infections and high viral load (p= 0.026). Sequencing of the HA gene(n= 115) revealed subtype A(H3N2) (n= 46), A(H1N1)pdm09 (n= 24), B/Victoria(n= 34), B/Yamagata (n= 11). There was no correlation between influenza (sub)typeand lower RTI. Influenza infection in haematological patients is associated withsignificant morbidity and mortality, the risk for aggravating co‐infections, prolongedviral shedding and nosocomial transmission emphasizing the need for infectioncontrol.Peer Reviewe

Severe Human Bocavirus 1 Respiratory Tract Infection in an Immunodeficient Child With Fatal Outcome

We report a case of lower respiratory tract infection with human bocavirus 1 (HboV1) in an immunodeficient 6-month-old boy leading to respiratory failure with fatal outcome. Polymerase chain reaction of serum/tracheal secretions revealed exceptionally high HboV1-DNA levels and immunoassays showed seroconversion indicating an acute primary HboV1 infection. All assays for other pathogens were negative, strongly suggesting that HboV1 was the causative agent in this case.Peer reviewe

Dynamics & Predictions in the Co-Event Interpretation

Sorkin has introduced a new, observer independent, interpretation of quantum mechanics that can give a successful realist account of the 'quantum microworld' as well as explaining how classicality emerges at the level of observable events for a range of systems including single time 'Copenhagen measurements'. This 'co-event interpretation' presents us with a new ontology, in which a single 'co-event' is real. A new ontology necessitates a review of the dynamical & predictive mechanism of a theory, and in this paper we begin the process by exploring means of expressing the dynamical and predictive content of histories theories in terms of co-events.Comment: 35 pages. Revised after refereein

Mouse models of diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies

The Kochen-Specker Theorem Revisited in Quantum Measure Theory

The Kochen-Specker Theorem is widely interpreted to imply that non-contextual hidden variable theories that agree with the predictions of Copenhagen quantum mechanics are impossible. The import of the theorem for a novel observer independent interpretation of quantum mechanics, due to Sorkin, is investigated.Comment: 17 pages. Revised after refereein

Twistor form of massive 6D superparticle

The massive six-dimensional (6D) superparticle with manifest (n, 0) supersymmetry is shown to have a supertwistor formulation in which its “hidden” (0, n) supersymmetry is also manifest. The mass-shell constraint is replaced by Spin(5) spin-shell constraints which imply that the quantum superparticle has zero superspin; for n = 1 it propagates the 6D Proca supermultiplet.PKT acknowledges support from the UK Science and Technology Facilities Council (grant ST/L000385/1). AJR is supported by a grant from the London Mathematical Society.This is the final version of the article. It was first available from IOP Science via http://dx.doi.org/10.1088/1751-8113/49/2/02540

Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal AnalySiS Consortium

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas (TCGA) and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal AnalySiS Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient population in need

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill &amp; Melinda Gates Foundation

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions