Large International Effort Research Articles

Validation of the coupled physical–biogeochemical ocean model NEMO–SCOBI for the North Sea–Baltic Sea system

Abstract. The North Sea and the Baltic Sea still experience eutrophication and deoxygenation despite large international efforts to mitigate such environmental problems. Due to the highly different oceanographic frameworks of the two seas, existing modelling efforts have mainly focused on only one of the respective seas, making it difficult to study interbasin exchange of mass and energy. Here, we present NEMO–SCOBI, an ocean model (NEMO-Nordic) coupled to the Swedish Coastal and Ocean Biogeochemical model (SCOBI), that covers the North Sea, the Skagerrak–Kattegat transition zone and the Baltic Sea. We address its validity to further investigate biogeochemical changes in the North Sea–Baltic Sea system. The model reproduces the long-term temporal trends, the temporal variability, the yearly averages and the general spatial distribution of all of the assessed biogeochemical parameters. It is particularly suitable for use in future multi-stressor studies, such as the evaluation of combined climate and nutrient forcing scenarios. In particular, the model performance is best for oxygen and phosphate concentrations. However, there are important differences between model results and observations with respect to chlorophyll a and nitrate in coastal areas of the southeastern North Sea, the Skagerrak–Kattegat transition zone, the Gulf of Riga, the Gulf of Finland and the Gulf of Bothnia. These are partially linked to different local processes and biogeochemical forcing that lead to a general overestimation of nitrate. Our model results are validated for individual areas that are in agreement with policy management assessment areas, thereby providing added value with respect to better contributing to international programmes aiming to reduce eutrophication in the North Sea–Baltic Sea system.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

A Genome-Wide Association Study of Outcome After Aneurysmal Subarachnoid Haemorrhage: Discovery Analysis

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10−4), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10−8) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment.

Updates in Cerebral Venous Thrombosis.

Purpose of ReviewCerebral venous thrombosis (CVT) is a rare cause of stroke that most commonly affects younger women. Here, we review new literature relevant to the management and prognosis of individuals with CVT and ongoing areas of uncertainty.Recent FindingsDirect-acting oral anticoagulants (DOACs) are being increasingly integrated into routine care but are not yet recommended by guidelines. Recent randomized clinical trials and available case series offer reassuring safety data. Routine use of endovascular therapy is not associated with improved outcomes. The relationship between recanalization and prognosis is uncertain.SummaryThe evidence base for management of CVT continues to improve. Ongoing areas of uncertainty include duration of therapy and whether certain subgroups of patients may benefit from neurointervention or personalized approaches to antithrombotic strategy. The state of knowledge will continue to benefit from large collaborative international efforts, and integration of patient partnerships to identify research priorities.

TIGER: The gene expression regulatory variation landscape of human pancreatic islets.

SUMMARYGenome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.

Chromatin accessibility and regulatory vocabulary across indicine cattle tissues

BackgroundSpatiotemporal changes in the chromatin accessibility landscape are essential to cell differentiation, development, health, and disease. The quest of identifying regulatory elements in open chromatin regions across different tissues and developmental stages is led by large international collaborative efforts mostly focusing on model organisms, such as ENCODE. Recently, the Functional Annotation of Animal Genomes (FAANG) has been established to unravel the regulatory elements in non-model organisms, including cattle. Now, we can transition from prediction to validation by experimentally identifying the regulatory elements in tropical indicine cattle. The identification of regulatory elements, their annotation and comparison with the taurine counterpart, holds high promise to link regulatory regions to adaptability traits and improve animal productivity and welfare.ResultsWe generate open chromatin profiles for liver, muscle, and hypothalamus of indicine cattle through ATAC-seq. Using robust methods for motif discovery, motif enrichment and transcription factor binding sites, we identify potential master regulators of the epigenomic profile in these three tissues, namely HNF4, MEF2, and SOX factors, respectively. Integration with transcriptomic data allows us to confirm some of their target genes. Finally, by comparing our results with Bos taurus data we identify potential indicine-specific open chromatin regions and overlaps with indicine selective sweeps.ConclusionsOur findings provide insights into the identification and analysis of regulatory elements in non-model organisms, the evolution of regulatory elements within two cattle subspecies as well as having an immediate impact on the animal genetics community in particular for a relevant productive species such as tropical cattle.

Recent Advances in the Management of Penile Cancer: A Contemporary Review of the Literature.

Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.

A First Global Oceanic Compilation of Observational Dissolved Aluminum Data With Regional Statistical Data Treatment

Large national and international observational efforts over recent decades have provided extensive and invaluable datasets of a range of ocean variables. Compiled large datasets, structured, or unstructured, are a powerful tool that allow scientists to access and synthesize data collected over large spatial and temporal scales. The data treatment approaches for any element in the ocean could lead to new global perspectives of their distribution patterns and to a better understanding of large-scale oceanic processes and their impact on other biogeochemical cycles, which may not be evident otherwise. Ocean chemistry Big Data analysis may not just be limited to distribution patterns, but may be used to assess how sampling efforts and analytical methodologies can be improved. Furthermore, a systematic global scale assessment of data is important to evaluate the gaps in knowledge and to provide avenues for future research. In this context, here we provide an extensive compilation of oceanic aluminum (Al) concentration data from global ocean basins, including data available in the GEOTRACES Intermediate Data product (Schlitzer et al., 2018), but also thus far unpublished data.

ScRNA-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation

BackgroundThe Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.ResultsThis study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types.We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific.ConclusionsIn conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

A Consensus Molecular Classification of Muscle-Invasive Bladder Cancer

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes. This diversity hampers the clinical application of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.

The Psychiatric Genomics Consortium For PTSD: Integration of Multi-System Markers of Risk And Resilience

Overall Abstract The Psychiatric Genomics Consortium for PTSD (PGC-PTSD) is the largest international effort focused on understanding the genomic and epigenomic architecture of PTSD. We have now aggregated genomic data from over 50 studies, including ~20,000 PTSD cases and over 50,000 trauma-exposed controls of diverse ancestries and traumatic events to conduct well-powered genome-wide association studies (GWAS) of PTSD. By expanding on this initial effort, we have leveraged our organizational structure to move beyond SNP-based associations with closely connected working groups centered on CNV analyses, epigenetics, gene expression, and intermediate phenotypes such as neuroimaging, psychophysiology, and physical health. An overarching theme across working groups includes sex-specific differences in PTSD risk and vulnerability. This symposium will first present our current GWAS results from the PGC-PTSD freeze 2 that highlight the genetic vulnerability for developing PTSD following trauma exposure, including SNP-based heritability and genetic correlation across psychiatric disorders and other phenotypes / traits of interest. Next, we will present epigenome-wide effects on risk of developing PTSD across civilian and military cohorts. The second half of the symposium will focus on findings from intermediate phenotypes and anthropometric traits. Our third talk will present neuroimaging data that reveals smaller amygdala and hippocampal volume in PTSD, particularly when exposed to childhood trauma. Lastly, we will present analyses investigating the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women, suggesting a putative causal relationship between genetically determined female body shape and PTSD. We will discuss our future strategies with a focus on harmonizing predictive variables such as trauma type, trauma severity, chronicity of exposure as well as outcome variables such as PTSD diagnoses, illness severity, and comorbid psychopathologies.

Broad cross-reactive IgG responses elicited by adjuvanted vaccination with recombinant influenza hemagglutinin (rHA) in ferrets and mice.

Annual immunization against influenza virus is a large international public health effort. Accumulating evidence suggests that antibody mediated cross-reactive immunity against influenza hemagglutinin (HA) strongly correlates with long-lasting cross-protection against influenza virus strains that differ from the primary infection or vaccination strain. However, the optimal strategies for achieving highly cross-reactive antibodies to the influenza virus HA have not yet to be defined. In the current study, using Luminex-based mPlex-Flu assay, developed by our laboratory, to quantitatively measure influenza specific IgG antibody mediated cross-reactivity, we found that prime-boost-boost vaccination of ferrets with rHA proteins admixed with adjuvant elicited higher magnitude and broader cross-reactive antibody responses than that induced by actual influenza viral infection, and this cross-reactive response likely correlated with increased anti-stalk reactive antibodies. We observed a similar phenomenon in mice receiving three sequential vaccinations with rHA proteins from either A/California/07/2009 (H1N1) or A/Hong Kong/1/1968 (H3N2) viruses admixed with Addavax, an MF59-like adjuvant. Using this same mouse vaccination model, we determined that Addavax plays a more significant role in the initial priming event than in subsequent boosts. We also characterized the generation of cross-reactive antibody secreting cells (ASCs) and memory B cells (MBCs) when comparing vaccination to viral infection. We have also found that adjuvant plays a critical role in the generation of long-lived ASCs and MBCs cross-reactive to influenza viruses as a result of vaccination with rHA of influenza virus, and the observed increase in stalk-reactive antibodies likely contributes to this IgG mediated broad cross-reactivity.

Progress in the clinical classification of systemic sclerosis.

Systemic sclerosis (SSc) subset classification criteria are a cornerstone of SSc research. Given changes in our understanding of the disease and limitations of the current criteria in the conduct of trials, the developments of new SSc subset criteria are underway. This article summarizes previous iterations of SSc subset criteria, highlights current thinking about the construct underlying SSc subsets in the modern era and provides an overview of the development of new SSc subset criteria. Using a combination of data-driven and expert-based innovative methodologies, a large international collaborative effort is developing new SSc subset criteria. It is anticipated that this new system of classification will shift the paradigm of how we study novel therapies in SSc.

Optomechanical devices for deep plasma cancer proteomics.

Most of the cancer deaths could be avoided by early detection of the tumor when it is confined to its primary site and it has not metastasized. To this aim, one of the most promising strategies is the discovery and detection of protein biomarkers shed by the young tumor to the bloodstream. Proteomic technologies, mainly mass spectrometry and multiplexed immunoassays, have rapidly developed during last years with improved limits of detection and multiplexing capability. Unfortunately, these developments together major investments and large international efforts have not resulted into new useful protein biomarkers. Here, we analyze the potential and limitations of current proteomic technologies for detecting protein biomarkers released into circulation by the tumor. We find that these technologies can hardly probe the deepest region of the plasma proteome, at concentrations below the pg/mL level, where protein biomarkers for early cancer detection may exist. This clearly indicates the need of incorporating novel ultrasensitive techniques to the proteomic tool-box that can cover the inaccessible regions of the plasma proteome. We here propose biological detectors based on nanomechanical systems for discovery and detection of cancer protein biomarkers in plasma. We review the modes of operation of these devices, putting our focus on recent developments on nanomechanical sandwich immunoassays and nanomechanical spectrometry. The first technique enables reproducible immunodetection of proteins at concentrations well below the pg/mL level, with a limit of detection on the verge of 10 ag/mL. This technology can potentially detect low abundance tumor-associated proteins in plasma at the very early stages of the tumor. The second technique enables the identification of individual intact proteins by two physical coordinates, the mass and stiffness, instead of the mass-to-charge ratio of the protein constituents. This technology enormously simplifies the identification of proteins and it can provide useful information on interactions and posttranslational modifications, that otherwise is lost in mass spectrometry.

Variations in the Genome: The Mutation Detection 2015 Meeting on Detection, Genome Sequencing, and Interpretation.

The content of the 13th Mutation Detection meeting (Leiden, April 2015) is summarized in this report. Topics discussed at the meeting included current challenges of clinical NGS, advances in bioinformatics, data quality control, single cell analysis and RNA sequencing, among others. Social, ethical and regulatory challenges of genomic data handling and data sharing were the focus of an expert panel debate. The 14th International Symposium on Variants in the Genome will take place in Santiago de Compostela, June 5-8, 2017. http://isv.variome.org.

A coordinate-independent characterization of a black hole shadow

A large international effort is under way to assess the presence of a shadow in the radio emission from the compact source at the centre of our Galaxy, Sagittarius A$^*$ (Sgr A$^*$). If detected, this shadow would provide the first direct evidence of the existence of black holes and that Sgr A$^*$ is a supermassive black hole. In addition, the shape of the shadow could be used to learn about extreme gravity near the event horizon and to determine which theory of gravity better describes the observations. The mathematical description of the shadow has so far used a number of simplifying assumptions that are unlikely to be met by the real observational data. We here provide a general formalism to describe the shadow as an arbitrary polar curve expressed in terms of a Legendre expansion. Our formalism does not presume any knowledge of the properties of the shadow, e.g. the location of its centre, and offers a number of routes to characterize the distortions of the curve with respect to reference circles. These distortions can be implemented in a coordinate independent manner by different teams analysing the same data. We show that the new formalism provides an accurate and robust description of noisy observational data, with smaller error variances when compared to previous approaches for the measurement of the distortion.

In Liberia, the end of the Ebola epidemic will be the beginning.

We were ready. When the vehicle arrived at the gate of the Monrovia Medical Unit (known as the MMU) in the late hours of the afternoon, we were already gathered in the donning area. A phone call from the Ministry of Health had alerted us to the new patient’s symptoms and background—fever, headache, malaise, nausea, vomiting, and diarrhea in a woman who lived and worked in a neighborhood thought to have a high transmission of the Ebola virus. We had been trained to move slowly, deliberately, and carefully in our preparation, and it took about 20 min before the first pair of nurses was fully dressed in their Personal Protective Equipment, including a gown, boots, two sets of gloves, mask, hood, apron, and face shield that would help protect them from the virus. In the hour before the patient’s arrival, we had moved more quickly, slipping in and out through zippered flaps in the olive-colored tents that make up the 25-bed Ebola Treatment Unit (ETU) staffed by Officers of the U.S. Public Health Service Commissioned Corps in Margibi County, Liberia. The pharmacists gathered the IV fluids and medications that we would likely give. The safety team filled buckets with chlorinated water: 0.05% for skin and 0.5% for everything else. The laboratory team checked that they had the purple tube to collect the blood to test for the virus. When it was time, we lifted the bright orange fencing that separated the donning area from the high-risk area and moved slowly down the short hallway to the Suspect Ward. We washed our gloved hands in chlorinated water from a bucket outside the ward, and then stepped in. She looked sick. She had vomited in the ambulance on the way over. Her face was flushed and sweaty, and the whites of her eyes were injected with red. An Ebola survivor who worked with us had warned us about patients with red eyes—‘‘a bad sign, a bad sign,’’ he had said. The test results came the next morning. She had run a high fever throughout the night, and we were ready for the confirmation of our suspicions. But our Ebola patient did not have Ebola. Instead, she had malaria. In August and September, according to the World Health Organization, at the peak of the epidemic in Liberia, there were over 300 new confirmed Ebola cases per week. Since it began, over 8300 people had been infected, and over 3500 had died (1). Health care workers have been disproportionately affected, with over 800 infections and almost 500 deaths in Liberia, Sierra Leone, and Guinea (1). In response to this crisis, the MMU was set up with the mission of providing hope through care to health care workers and responders in Liberia who may be infected with Ebola Virus Disease. Since it opened on November 7, 2014 until the time of writing in mid-January, it has provided care for 36 health care workers, 17 of whom tested positive for Ebola. The MMU is one part of a large international effort to stop the epidemic. The results of this hard Published online: February 18, 2015

Spatio-spectral structures in high-order harmonic beams generated with Terawatt 10-fs pulses.

A large international effort is nowadays devoted to increase the energy of the extreme ultraviolet pulses by using high-peak power ultrashort fundamental pulses (Terawatt level). Using such fundamental pulses brings specific constraints that need to be addressed. Here we study high-order harmonic generation in gases with 10 fs pulses at Terawatt peak power and demonstrate that extreme ultraviolet beams can be highly structured and complex in various conditions. We use a single-shot spatially resolved spectral detection and demonstrate direct observation of the spatio-temporal coupling occurring in the generating medium. Clear and reproducible complex spatio-spectral structures are observed in the far field. Similar structures are reproduced with simulations and we show that they are intimately associated to the high nonlinearity of high-order harmonic generation. Those findings are of prime importance for the generation of high-energy attosecond pulses and reveal important issues for their applications.

Solar Photoconversion to Photovoltaic Electricity and Solar Fuels: Forty Years of History, Progress, New Concepts, and Prognosis

Since the global oil crisis of 1973 that followed the Fujishima-Honda paper of 1972 showing that under certain conditions semiconductor photoelectrodes could be used to photolytically split H2O into H2 and O2, there have been large international research and development efforts to produce cost effective solar fuels, such as H2 from H2O splitting or renewable carbon-based fuels from the photoreduction of CO2 with H2O, as occurs in biological photosynthesis. Parallel efforts to develop cost effective solar electricity from photovoltaic cells were also accelerated. The intensity of both of these R&D efforts have waxed and waned over the ensuing 40 years depending upon political leadership, societal/political perceptions of the severity of the energy security problem and global climate change (and their respective relative priority), and the state of the national economy of nations funding R& D in this area. Over this rather significant time period there have been many importance advances in the associated and highly interdisciplinary science and technology, new innovations and concepts, and some persistently difficult technological barriers to penetrate that have prevented commercialization, especially in producing cost effective solar fuels. The scientific and technological history, advances, new concepts, persistent barriers, and present status of viable solar fuels and solar electricity production will be discussed.