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Objectives Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. Methods Following a case-cohort design, lung cancer screening trial participants ( N  = 3,673) who died ( N  = 196) during a median follow-up of 6 years (inter-quartile range: 5.7–6.3) were identified and added to a random sample of N  = 383 from the trial. We assessed vertebral fractures using Genant´s semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. Results The prevalence of vertebral fractures was 35 % (95 % confidence interval 30–40 %) among survivors and 51 % (44–58 %) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43–2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02–1.15). Conclusions Vertebral fractures and bone density are independently associated with all-cause mortality. Key Points • Lung cancer screening chest computed tomography contains additional, potentially useful information. • Vertebral fractures and bone density are independently predictive of mortality. • This finding has implications for screening and management decisions.

A homologous transformation system for the opportunistic fungal pathogen Aspergillus fumigatus was developed. It is based on the A. fumigatus pyrG gene, encoding orotidine 5′-monophosphate decarboxylase, which was cloned and sequenced. Transformation of both Aspergillus (Emericella) nidulans and A. fumigatus pyrG mutant strains by the use of protoplasts or electroporation established the functionality of the cloned gene. DNA sequencing of the A. fumigatus pyrG1 mutant allele revealed that it encodes a truncated, non-functional, PyrG protein. Transformation of an A. fumigatus pyrG1 mutant with a plasmid carrying the novel pyrG2 allele constructed by in vitro mutagenesis yielded prototrophic transformants following recombination between both mutation sites. Analysis of transformants carrying the entire plasmid showed that up to 45% of integration had occurred at the pyrG locus. This provides a tool to target defined genetic constructs at a specific locus in the A. fumigatus genome in order to study gene regulation and function.

Background  Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited. Methods This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires. Results Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases. Conclusions This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.

Objectives To determine inter-observer and inter-examination variability for aortic valve calcification (AVC) and mitral valve and annulus calcification (MC) in low-dose unenhanced ungated lung cancer screening chest computed tomography (CT). Methods We included 578 lung cancer screening trial participants who were examined by CT twice within 3 months to follow indeterminate pulmonary nodules. On these CTs, AVC and MC were measured in cubic millimetres. One hundred CTs were examined by five observers to determine the inter-observer variability. Reliability was assessed by kappa statistics (κ) and intra-class correlation coefficients (ICCs). Variability was expressed as the mean difference ± standard deviation (SD). Results Inter-examination reliability was excellent for AVC (κ = 0.94, ICC = 0.96) and MC (κ = 0.95, ICC = 0.90). Inter-examination variability was 12.7 ± 118.2 mm 3 for AVC and 31.5 ± 219.2 mm 3 for MC. Inter-observer reliability ranged from κ = 0.68 to κ = 0.92 for AVC and from κ = 0.20 to κ = 0.66 for MC. Inter-observer ICC was 0.94 for AVC and ranged from 0.56 to 0.97 for MC. Inter-observer variability ranged from -30.5 ± 252.0 mm 3 to 84.0 ± 240.5 mm 3 for AVC and from -95.2 ± 210.0 mm 3 to 303.7 ± 501.6 mm 3 for MC. Conclusions AVC can be quantified with excellent reliability on ungated unenhanced low-dose chest CT, but manual detection of MC can be subject to substantial inter-observer variability. Lung cancer screening CT may be used for detection and quantification of cardiac valve calcifications. Key points • Low - dose unenhanced ungated chest computed tomography can detect cardiac valve calcifications . • However , calcified cardiac valves are not reported by most radiologists . • Inter - observer and inter - examination variability of aortic valve calcifications is sufficient for longitudinal studies . • Volumetric measurement variability of mitral valve and annulus calcifications is substantial .

Malaria is the major parasitic infection in many tropical and subtropical regions, leading to more than one million deaths (principally young African children) out of 400 million cases each year (WHO world health report 2000). More than half of the worlds population live in areas where they remain at risk of malaria infection. During last years, the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several antimalarial drugs. Furthermore, the control of malaria is becoming more complicated by the parallel spread of resistance of the mosquito vector to currently available insecticides. Discovering new drugs in this field is therefore a health priority. Several new molecules are under investigation. This review describes the classical treatments of malaria and the latest discoveries in antimalarial agents, especially artemisinin and its recent derivatives as well as the novel peroxidic compounds.

Certification's limited contribution to sustainable aquaculture should complement public and private governance. Aquaculture, the farming of aquatic organisms, provides close to 50% of the world's supply of seafood, with a value of U.S. $125 billion. It makes up 13% of the world's animal-source protein (excluding eggs and dairy) and employs an estimated 24 million people ( 1 ). With capture (i.e., wild) fisheries production stagnating, aquaculture may help close the forecast global deficit in fish protein by 2020 ( 2 ). This so-called “blue revolution” requires addressing a range of environmental and social problems, including water pollution, degradation of ecosystems, and violation of labor standards.

The deep sea, the largest biome on Earth, has a series of characteristics that make this environment both distinct from other marine and land ecosystems and unique for the entire planet. This review describes these patterns and processes, from geological settings to biological processes, biodiversity and biogeographical patterns. It concludes with a brief discussion of current threats from anthropogenic activities to deep-sea habitats and their fauna. Investigations of deep-sea habitats and their fauna began in the late 19th century. In the intervening years, technological developments and stimulating discoveries have promoted deep-sea research and changed our way of understanding life on the planet. Nevertheless, the deep sea is still mostly unknown and current discovery rates of both habitats and species remain high. The geological, physical and geochemical settings of the deep-sea floor and the water column form a series of different habitats with unique characteristics that support specific faunal communities. Since 1840, 28 new habitats/ecosystems have been discovered from the shelf break to the deep trenches and discoveries of new habitats are still happening in the early 21st century. However, for most of these habitats the global area covered is unknown or has been only very roughly estimated; an even smaller - indeed, minimal - proportion has actually been sampled and investigated. We currently perceive most of the deep-sea ecosystems as heterotrophic, depending ultimately on the flux on organic matter produced in the overlying surface ocean through photosynthesis. The resulting strong food limitation thus shapes deep-sea biota and communities, with exceptions only in reducing ecosystems such as inter alia hydrothermal vents or cold seeps. Here, chemoautolithotrophic bacteria play the role of primary producers fuelled by chemical energy sources rather than sunlight. Other ecosystems, such as seamounts, canyons or cold-water corals have an increased productivity through specific physical processes, such as topographic modification of currents and enhanced transport of particles and detrital matter. Because of its unique abiotic attributes, the deep sea hosts a specialized fauna. Although there are no phyla unique to deep waters, at lower taxonomic levels the composition of the fauna is distinct from that found in the upper ocean. Amongst other characteristic patterns, deep-sea species may exhibit either gigantism or dwarfism, related to the decrease in food availability with depth. Food limitation on the seafloor and water column is also reflected in the trophic structure of heterotrophic deep-sea communities, which are adapted to low energy availability. In most of these heterotrophic habitats, the dominant megafauna is composed of detritivores, while filter feeders are abundant in habitats with hard substrata (e.g. mid-ocean ridges, seamounts, canyon walls and coral reefs). Chemoautotrophy through symbiotic relationships is dominant in reducing habitats. Deep-sea biodiversity is among of the highest on the planet, mainly composed of macro and meiofauna, with high evenness. This is true for most of the continental margins and abyssal plains with hot spots of diversity such as seamounts or cold-water corals. However, in some ecosystems with particularly \"extreme\" physicochemical processes (e.g. hydrothermal vents), biodiversity is low but abundance and biomass are high and the communities are dominated by a few species. Two large-scale diversity patterns have been discussed for deep-sea benthic communities. First, a unimodal relationship between diversity and depth is observed, with a peak at intermediate depths (2000-3000 m), although this is not universal and particular abiotic processes can modify the trend. Secondly, a poleward trend of decreasing diversity has been discussed, but this remains controversial and studies with larger and more robust data sets are needed. Because of the paucity in our knowledge of habitat coverage and species composition, biogeographic studies are mostly based on regional data or on specific taxonomic groups. Recently, global biogeographic provinces for the pelagic and benthic deep ocean have been described, using environmental and, where data were available, taxonomic information. This classification described 30 pelagic provinces and 38 benthic provinces divided into 4 depth ranges, as well as 10 hydrothermal vent provinces. One of the major issues faced by deep-sea biodiversity and biogeographical studies is related to the high number of species new to science that are collected regularly, together with the slow description rates for these new species. Taxonomic coordination at the global scale is particularly difficult, but is essential if we are to analyse large diversity and biogeographic trends. Because of their remoteness, anthropogenic impacts on deep-sea ecosystems have not been addressed very thoroughly until recently. The depletion of biological and mineral resources on land and in shallow waters, coupled with technological developments, are promoting the increased interest in services provided by deep-water resources. Although often largely unknown, evidence for the effects of human activities in deep-water ecosystems - such as deep-sea mining, hydrocarbon exploration and exploitation, fishing, dumping and littering - is already accumulating. Because of our limited knowledge of deep-sea biodiversity and ecosystem functioning and because of the specific life-history adaptations of many deep-sea species (e.g. slow growth and delayed maturity), it is essential that the scientific community works closely with industry, conservation organisations and policy makers to develop robust and efficient conservation and management options.

Background. Evidence-based guidelines for managing anterior cutaneous nerve entrapment syndrome (ACNES) in children are absent. The primary aim of this review was to scrutinize the evidence supporting currently used treatment interventions. In accordance with the World Health Organization (WHO) guidelines for managing chronic pain in children, these patients and their families and caregivers should be treated within the context of the biopsychosocial model; pain should not be treated purely as a biomedical problem. Therefore, our second aim was to evaluate whether these interventions are applied within the context of the biopsychosocial model, utilizing an inter- or multidisciplinary approach. Materials and Methods. A scoping review of the literature was conducted to explore treatment strategies for ACNES in children. To ensure a comprehensive overview of published literature on this topic, the search was not restricted based on study type. Two reviewers independently assessed titles and abstracts. After excluding records unrelated to children, full texts were screened for inclusion. Any discrepancies in judgement were resolved through discussion with a third reviewer. Results. Out of 35 relevant titles, 22 were included in this review. Only 4 articles provided information on long-term outcomes. The overall quality of the review was deemed low. The majority of reports did not address treatment or education within the psychological and social domains. A structural qualitative analysis was not feasible due to the substantial heterogeneity of the data. Conclusion. The evidence supporting current treatment strategies in children with ACNES is of low quality. More research is needed to establish an evidence-based treatment algorithm for patients with this challenging pain problem. In line with the WHO recommendation, greater emphasis should be placed on a biopsychosocial approach. The ultimate goal should be the development of a generic treatment algorithm outlining an approach to ACNES applicable to all professionals involved.

While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity. The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.