Background Using positron emission tomography (PET), we previously observed increases in 3,4-dihydroxy-6-18 Ffluoro-L-phenylalanine (18 F-DOPA) uptake in the striatum of subjects at ultra-high risk ...(UHR) for psychosis, indicating elevated presynaptic dopamine synthesis capacity. The purpose of this study was to test if this finding would be replicated in a second UHR cohort. Methods18 F-DOPA PET was used to estimate dopamine synthesis capacity in the striatum of an entirely new cohort of 26 individuals at UHR for psychosis (14 males, mean±SD age = 22.7±4.7 years) and 20 healthy volunteers matched for age and gender (11 males, mean±SD age = 24.5±4.5 years). Results Dopamine synthesis capacity was elevated in the whole t (44) = 2.6; p = .01, effect size = .81 and associative striatum t (44) = 2.6; p = .01, effect size = .73 of UHR compared with control subjects. When the two samples were combined to give a final sample of 32 control and 50 UHR subjects, the higher levels of dopamine synthesis capacity in the UHR group reached significance across the whole F (1,81) = 11.0; p = .001, associative F (1,81) = 12.7; p = .001, and sensorimotor F (1,81) = 4.7; p = .03, but not the limbic F (1,81) = 2.1; p = .2, striatum. Conclusions The findings indicate that elevated dopamine synthesis capacity in the dorsal striatum is a robust feature of individuals at UHR for psychosis and provide further evidence that dopaminergic abnormalities precede the onset of psychosis.
The burden and influence of health-care associated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is unknown. We aimed to examine the use of rapid SARS-CoV-2 sequencing ...combined with detailed epidemiological analysis to investigate health-care associated SARS-CoV-2 infections and inform infection control measures.
In this prospective surveillance study, we set up rapid SARS-CoV-2 nanopore sequencing from PCR-positive diagnostic samples collected from our hospital (Cambridge, UK) and a random selection from hospitals in the East of England, enabling sample-to-sequence in less than 24 h. We established a weekly review and reporting system with integration of genomic and epidemiological data to investigate suspected health-care associated COVID-19 cases.
Between March 13 and April 24, 2020, we collected clinical data and samples from 5613 patients with COVID-19 from across the East of England. We sequenced 1000 samples producing 747 high-quality genomes. We combined epidemiological and genomic analysis of the 299 patients from our hospital and identified 35 clusters of identical viruses involving 159 patients. 92 (58%) of 159 patients had strong epidemiological links and 32 (20%) patients had plausible epidemiological links. These results were fed back to clinical, infection control, and hospital management teams, leading to infection-control interventions and informing patient safety reporting.
We established real-time genomic surveillance of SARS-CoV-2 in a UK hospital and showed the benefit of combined genomic and epidemiological analysis for the investigation of health-care associated COVID-19. This approach enabled us to detect cryptic transmission events and identify opportunities to target infection-control interventions to further reduce health-care associated infections. Our findings have important implications for national public health policy as they enable rapid tracking and investigation of infections in hospital and community settings.
COVID-19 Genomics UK (supported by UK Research and Innovation, the National Institute of Health Research, the Wellcome Sanger Institute), the Wellcome Trust, the Academy of Medical Sciences and the Health Foundation, and the National Institute for Health Research Cambridge Biomedical Research Centre.
The synthesis of the first bismuth‐containing macromolecules that exhibit phosphorescence in the solid state and in the presence of oxygen is reported. These red emissive high molecular weight ...polymers (>300 kDa) feature benzobismoles appended to a hydrocarbon scaffold, and were built via an efficient ring‐opening metathesis (ROMP) protocol. Moreover, our general procedure readily allows for the formation of cross‐linked networks and block copolymers. Attaining stable red phosphorescence with non‐toxic elements remains a challenge and, thus, our new class of soluble (processable) polymeric phosphor is of great interest. Furthermore, the formation of bismuth‐rich cores within organic–inorganic block copolymer spherical micelles is possible, leading to patterned arrays of bismuth in the film state.
Turning on Bismuth: The synthesis of red and orange emitting bismuth‐based phosphors is reported. The modular synthetic approach allows for rapid ring‐opening metathesis polymerization to yield block copolymer spherical micelles that assemble into organized films with bismuth‐rich, metallized domains.
Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple immunotherapy strategies are under ...development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell vaccines, although these approaches are yet to yield significant clinical benefit. Potential reasons for the lack of success so far include the immunosuppressive tumor microenvironment, the blood-brain barrier, and systemic changes to the immune system driven by both the tumor and its treatment. Furthermore, while T cells are essential effector cells for tumor control, dendritic cells play an equally important role in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply compromised in glioblastoma patients. In this review, we describe the immunotherapy approaches currently under development for glioblastoma and the challenges faced, with a particular emphasis on the critical role of the dendritic cell-T cell axis. We suggest a number of strategies that could be used to boost dendritic cell number and function and propose that the use of these in combination with T cell-targeting strategies could lead to successful tumor control.
ConnectomeDB is a database for housing and disseminating data about human brain structure, function, and connectivity, along with associated behavioral and demographic data. It is the main archive ...and dissemination platform for data collected under the WU-Minn consortium Human Connectome Project. Additional connectome-style study data is and will be made available in the database under current and future projects, including the Connectome Coordination Facility. The database currently includes multiple modalities of magnetic resonance imaging (MRI) and magnetoencephalograpy (MEG) data along with associated behavioral data. MRI modalities include structural, task, resting state and diffusion. MEG modalities include resting state and task. Imaging data includes unprocessed, minimally preprocessed and analysis data. Imaging data and much of the behavioral data are publicly available, subject to acceptance of data use terms, while access to some sensitive behavioral data is restricted to qualified investigators under a more stringent set of terms. ConnectomeDB is the public side of the WU-Minn HCP database platform. As such, it is geared towards public distribution, with a web-based user interface designed to guide users to the optimal set of data for their needs and a robust backend mechanism based on the commercial Aspera fasp service to enable high speed downloads. HCP data is also available via direct shipment of hard drives and Amazon S3.
Abstract This study estimated the health and economic burden of child maltreatment in the East Asia and Pacific region, addressing a significant gap in the current evidence base. Systematic reviews ...and meta-analyses were conducted to estimate the prevalence of child physical abuse, sexual abuse, emotional abuse, neglect, and witnessing parental violence. Population Attributable Fractions were calculated and Disability-Adjusted Life Years (DALYs) lost from physical and mental health outcomes and health risk behaviors attributable to child maltreatment were estimated using the most recent comparable Global Burden of Disease data. DALY losses were converted into monetary value by assuming that one DALY is equal to the sub-region's per capita GDP. The estimated economic value of DALYs lost to violence against children as a percentage of GDP ranged from 1.24% to 3.46% across sub-regions defined by the World Health Organization. The estimated economic value of DALYs (in constant 2000 US$) lost to child maltreatment in the EAP region totaled US $151 billion, accounting for 1.88% of the region's GDP. Updated to 2012 dollars, the estimated economic burden totaled US $194 billion. In sensitivity analysis, the aggregate costs as a percentage of GDP range from 1.36% to 2.52%. The economic burden of child maltreatment in the East Asia and Pacific region is substantial, indicating the importance of preventing and responding to child maltreatment in this region. More comprehensive research into the impact of multiple types of childhood adversity on a wider range of putative health outcomes is needed to guide policy and programs for child protection in the region, and globally.
Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and ...expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological “space”, functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1+ tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.
Background. The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 ...(K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods. P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results. The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P= 1.97 × 10⁻¹²). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions. K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.
Abstract Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened ...pathology and poorer outcomes in many neurological disorders, we examined isoform-specific differences in the response of microglia, the primary cellular component of the brain's innate immune response, in detail. Our data demonstrate that microglia derived from APOE4 / 4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology, increased NO production associated with increased NOS2 mRNA levels, and higher pro-inflammatory cytokine production (TNFα, IL-6, IL12p40) compared to microglia derived from APOE3 / 3 targeted replacement mice. The effect is gene dose-dependent and increases with the number of APOE4 gene alleles. The APOE genotype-specific immune profile observed in the microglial immune response is also observed in the cortex of aged APOE3 / 3 and APOE4 / 4 mice treated with lipopolysacchride (LPS) and in peripheral (peritoneal) macrophages. To determine if APOE4 's action resulted from an isoform-specific difference in effective levels of the apolipoproteins, we generated mice expressing only a single allele of APOE3 . Immune-stimulated macrophages from APOE3 / 0 mice demonstrated an increased inflammatory response compared to APOE3 / 3 mice, but less than in APOE4 / 4 mice. These data suggest that inhibition of inflammation depends upon the dose of apoE3 protein available and that apoE4 protein may alter inflammation partly by dose effects and partly by being qualitatively different than apoE3. Overall, these data emphasize the important role of apolipoprotein E and of the APOE genotype on the immune responses that are evident in most, if not all, neurological disease.
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