A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development.Bill & Melinda Gates Foundation (51066

A complex intervention to reduce avoidable hospital admissions in nursing homes: a research programme including the BHiRCH-NH pilot cluster RCT

YesBackground: An unplanned hospital admission of a nursing home resident distresses the person, their family and nursing home staff, and is costly to the NHS. Improving health care in care homes, including early detection of residents’ health changes, may reduce hospital admissions. Previously, we identified four conditions associated with avoidable hospital admissions. We noted promising ‘within-home’ complex interventions including care pathways, knowledge and skills enhancement, and implementation support. Objectives: Develop a complex intervention with implementation support [the Better Health in Residents in Care Homes with Nursing (BHiRCH-NH)] to improve early detection, assessment and treatment for the four conditions. Determine its impact on hospital admissions, test study procedures and acceptability of the intervention and implementation support, and indicate if a definitive trial was warranted. Design: A Carer Reference Panel advised on the intervention, implementation support and study documentation, and engaged in data analysis and interpretation. In workstream 1, we developed a complex intervention to reduce rates of hospitalisation from nursing homes using mixed methods, including a rapid research review, semistructured interviews and consensus workshops. The complex intervention comprised care pathways, approaches to enhance staff knowledge and skills, implementation support and clarity regarding the role of family carers. In workstream 2, we tested the complex intervention and implementation support via two work packages. In work package 1, we conducted a feasibility study of the intervention, implementation support and study procedures in two nursing homes and refined the complex intervention to comprise the Stop and Watch Early Warning Tool (S&W), condition-specific care pathways and a structured framework for nurses to communicate with primary care. The final implementation support included identifying two Practice Development Champions (PDCs) in each intervention home, and supporting them with a training workshop, practice development support group, monthly coaching calls, handbooks and web-based resources. In work package 2, we undertook a cluster randomised controlled trial to pilot test the complex intervention for acceptability and a preliminary estimate of effect. Setting: Fourteen nursing homes allocated to intervention and implementation support (n = 7) or treatment as usual (n = 7). Participants: We recruited sufficient numbers of nursing homes (n = 14), staff (n = 148), family carers (n = 95) and residents (n = 245). Two nursing homes withdrew prior to the intervention starting. Intervention: This ran from February to July 2018. Data sources: Individual-level data on nursing home residents, their family carers and staff; system-level data using nursing home records; and process-level data comprising how the intervention was implemented. Data were collected on recruitment rates, consent and the numbers of family carers who wished to be involved in the residents’ care. Completeness of outcome measures and data collection and the return rate of questionnaires were assessed. Results: The pilot trial showed no effects on hospitalisations or secondary outcomes. No home implemented the intervention tools as expected. Most staff endorsed the importance of early detection, assessment and treatment. Many reported that they ‘were already doing it’, using an early-warning tool; a detailed nursing assessment; or the situation, background, assessment, recommendation communication protocol. Three homes never used the S&W and four never used care pathways. Only 16 S&W forms and eight care pathways were completed. Care records revealed little use of the intervention principles. PDCs from five of six intervention homes attended the training workshop, following which they had variable engagement with implementation support. Progression criteria regarding recruitment and data collection were met: 70% of homes were retained, the proportion of missing data was < 20% and 80% of individuallevel data were collected. Necessary rates of data collection, documentation completion and return over the 6-month study period were achieved. However, intervention tools were not fully adopted, suggesting they would not be sustainable outside the trial. Few hospitalisations for the four conditions suggest it an unsuitable primary outcome measure. Key cost components were estimated. Limitations: The study homes may already have had effective approaches to early detection, assessment and treatment for acute health changes; consistent with government policy emphasising the need for enhanced health care in homes. Alternatively, the implementation support may not have been sufficiently potent. Conclusion: A definitive trial is feasible, but the intervention is unlikely to be effective. Participant recruitment, retention, data collection and engagement with family carers can guide subsequent studies, including service evaluation and quality improvement methodologies. Future work: Intervention research should be conducted in homes which need to enhance early detection, assessment and treatment. Interventions to reduce avoidable hospital admissions may be beneficial in residential care homes, as they are not required to employ nurses.This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 2. See the NIHR Journals Library website for further project information

The Essential Role for Laboratory Studies in Atmospheric Chemistry

Laboratory studies of atmospheric chemistry characterize the nature of atmospherically relevant processes down to the molecular level, providing fundamental information used to assess how human activities drive environmental phenomena such as climate change, urban air pollution, ecosystem health, indoor air quality, and stratospheric ozone depletion. Laboratory studies have a central role in addressing the incomplete fundamental knowledge of atmospheric chemistry. This article highlights the evolving science needs for this community and emphasizes how our knowledge is far from complete, hindering our ability to predict the future state of our atmosphere and to respond to emerging global environmental change issues. Laboratory studies provide rich opportunities to expand our understanding of the atmosphere via collaborative research with the modeling and field measurement communities, and with neighboring disciplines

The Essential Role for Laboratory Studies in Atmospheric Chemistry

Laboratory studies of atmospheric chemistry characterize the nature of atmospherically relevant processes down to the molecular level, providing fundamental information used to assess how human activities drive environmental phenomena such as climate change, urban air pollution, ecosystem health, indoor air quality, and stratospheric ozone depletion. Laboratory studies have a central role in addressing the incomplete fundamental knowledge of atmospheric chemistry. This article highlights the evolving science needs for this community and emphasizes how our knowledge is far from complete, hindering our ability to predict the future state of our atmosphere and to respond to emerging global environmental change issues. Laboratory studies provide rich opportunities to expand our understanding of the atmosphere via collaborative research with the modeling and field measurement communities, and with neighboring disciplines

Phylogeny of Parasitic Parabasalia and Free-Living Relatives Inferred from Conventional Markers vs. Rpb1, a Single-Copy Gene

Parabasalia are single-celled eukaryotes (protists) that are mainly comprised of endosymbionts of termites and wood roaches, intestinal commensals, human or veterinary parasites, and free-living species. Phylogenetic comparisons of parabasalids are typically based upon morphological characters and 18S ribosomal RNA gene sequence data (rDNA), while biochemical or molecular studies of parabasalids are limited to a few axenically cultivable parasites. These previous analyses and other studies based on PCR amplification of duplicated protein-coding genes are unable to fully resolve the evolutionary relationships of parabasalids. As a result, genetic studies of Parabasalia lag behind other organisms.Comparing parabasalid EF1α, α-tubulin, enolase and MDH protein-coding genes with information from the Trichomonas vaginalis genome reveals difficulty in resolving the history of species or isolates apart from duplicated genes. A conserved single-copy gene encodes the largest subunit of RNA polymerase II (Rpb1) in T. vaginalis and other eukaryotes. Here we directly sequenced Rpb1 degenerate PCR products from 10 parabasalid genera, including several T. vaginalis isolates and avian isolates, and compared these data by phylogenetic analyses. Rpb1 genes from parabasalids, diplomonads, Parabodo, Diplonema and Percolomonas were all intronless, unlike intron-rich homologs in Naegleria, Jakoba and Malawimonas.The phylogeny of Rpb1 from parasitic and free-living parabasalids, and conserved Rpb1 insertions, support Trichomonadea, Tritrichomonadea, and Hypotrichomonadea as monophyletic groups. These results are consistent with prior analyses of rDNA and GAPDH sequences and ultrastructural data. The Rpb1 phylogenetic tree also resolves species- and isolate-level relationships. These findings, together with the relative ease of Rpb1 isolation, make it an attractive tool for evaluating more extensive relationships within Parabasalia

Potential controls of isoprene in the surface ocean

Isoprene surface ocean concentrations and vertical distribution, atmospheric mixing ratios, and calculated sea-to-air fluxes spanning approximately 125° of latitude (80°N–45°S) over the Arctic and Atlantic Oceans are reported. Oceanic isoprene concentrations were associated with a number of concurrently monitored biological variables including chlorophyll a (Chl a), photoprotective pigments, integrated primary production (intPP), and cyanobacterial cell counts, with higher isoprene concentrations relative to all respective variables found at sea surface temperatures greater than 20°C. The correlation between isoprene and the sum of photoprotective carotenoids, which is reported here for the first time, was the most consistent across all cruises. Parameterizations based on linear regression analyses of these relationships perform well for Arctic and Atlantic data, producing a better fit to observations than an existing Chl a-based parameterization. Global extrapolation of isoprene surface water concentrations using satellite-derived Chl a and intPP reproduced general trends in the in situ data and absolute values within a factor of 2 between 60% and 85%, depending on the data set and algorithm used

Climate Change, Coral Reef Ecosystems, and Management Options for Marine Protected Areas

Marine protected areas (MPAs) provide place-based management of marine ecosystems through various degrees and types of protective actions. Habitats such as coral reefs are especially susceptible to degradation resulting from climate change, as evidenced by mass bleaching events over the past two decades. Marine ecosystems are being altered by direct effects of climate change including ocean warming, ocean acidification, rising sea level, changing circulation patterns, increasing severity of storms, and changing freshwater influxes. As impacts of climate change strengthen they may exacerbate effects of existing stressors and require new or modified management approaches; MPA networks are generally accepted as an improvement over individual MPAs to address multiple threats to the marine environment. While MPA networks are considered a potentially effective management approach for conserving marine biodiversity, they should be established in conjunction with other management strategies, such as fisheries regulations and reductions of nutrients and other forms of land-based pollution. Information about interactions between climate change and more “traditional” stressors is limited. MPA managers are faced with high levels of uncertainty about likely outcomes of management actions because climate change impacts have strong interactions with existing stressors, such as land-based sources of pollution, overfishing and destructive fishing practices, invasive species, and diseases. Management options include ameliorating existing stressors, protecting potentially resilient areas, developing networks of MPAs, and integrating climate change into MPA planning, management, and evaluation

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research