In the United States, pertussis circulation persists and primarily infects infants and children, despite routine vaccinations. To minimize infant morbidity and mortality from the disease before the ...first DTaP dose, the Advisory Committee on Immunization Practices recommends maternal Tdap vaccination in weeks 27-36 of pregnancy.
Cohorts of mother-infant pairs in the Medicaid Analytic eXtract (MAX) (2010-2014) and IBM MarketScan (2011-2015) databases were analyzed to estimate the effectiveness of prenatal Tdap vaccination compared with no vaccination to prevent infant pertussis in the first 6 months. Hazard ratios were estimated with Cox proportional hazards models and adjusted for potential confounders via inverse probability weights. The impact of preterm delivery on the risk of pertussis was analyzed. Results from the 2 databases were pooled.
In MarketScan, women received Tdap vaccination before delivery in 114,067 (25.6%) of 445,638 pregnancies and in MAX, 33,286 (4.8%) of 695,262 pregnancies. Among pregnancies with preterm delivery, only 21.2% and 3.8% in MarketScan and MAX had been vaccinated. The risk of pertussis in unvaccinated term infants was 3.5 (MarketScan) and 17 (MAX) per 10,000; and in preterm infants, it was 8.4 (MarketScan) and 19.8 (MAX) per 10,000. The pooled hazard ratio for Tdap vaccination any time before delivery versus no vaccination was 0.64 95% confidence interval (CI): 0.41-1.00. The hazard ratio was 0.11 (95% CI: 0.03-0.36) for preterm and 0.78 (95% CI: 0.48-1.29) for term infants vaccinated before 37 weeks. The incidence of pertussis was higher and the protective hazard ratio stronger during pertussis outbreaks.
Prenatal Tdap vaccination reduces the risk of pertussis infections in the infants' first 6 months by 36%. Vaccination soon after 27 weeks of pregnancy, before when deliveries began, ensures vaccination includes those born preterm, who are at highest risk for pertussis and benefit particularly from this vaccination.
We recently discovered that some bacteriophages establish a nucleus-like replication compartment (phage nucleus), but the core genes that define nucleus-based phage replication and their phylogenetic ...distribution were still to be determined. Here, we show that phages encoding the major phage nucleus protein chimallin share 72 conserved genes encoded within seven gene blocks. Of these, 21 core genes are unique to nucleus-forming phage, and all but one of these genes encode proteins of unknown function. We propose that these phages comprise a novel viral family we term Chimalliviridae. Fluorescence microscopy and cryoelectron tomography studies of Erwinia phage vB_EamM_RAY confirm that many of the key steps of nucleus-based replication are conserved among diverse chimalliviruses and reveal variations on this replication mechanism. This work expands our understanding of phage nucleus and PhuZ spindle diversity and function, providing a roadmap for identifying key mechanisms underlying nucleus-based phage replication.
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•Erwinia phage RAY is a nucleus-forming phage•Nucleus-forming phages cluster phylogenetically and share a core genome, including ChmA•We propose that all phage encoding ChmA form a family of nucleus-forming phages
Some bacteriophages have been shown to make a nucleus-like structure (the phage nucleus) during their infection cycle. These phages are widespread and infect numerous hosts. Prichard et al. find that these phages cluster together in phylogenetic trees, suggesting a common ancestry of all known nucleus-forming phages.
•Green and Blue Infrastructure (GBI) occurrence and change over time is quantified.•We cover different farming systems in Southwest, Central and Southeast Europe.•CAP is not actively encouraging the ...establishment of new biodiversity-fostering GBI.•GBI most valuable for biodiversity like grasslands have significantly decreased.•Farmers’ perception of GBI seems driven by production management decisions.
Agricultural intensification continues to threaten habitat and biological diversity in farmland. In Europe, the Common Agricultural Policy (CAP) has established several measures to support biodiversity-fostering elements such as landscape features, semi-natural habitats and extensive land uses, together referred to as Green and Blue Infrastructure (GBI). However, CAP measures’ effectiveness to support GBI has not been accurately evaluated yet. We assess GBI occurrence across a variety of European agricultural systems covering a gradient of farming intensity and analyse to what extent the CAP is supporting their presence by enhancing farmer's awareness and the uptake of measures that foster GBI. We carried out habitat surveys in 115 Landscape Test Squares (LTS) of 500m × 500m in six case study areas, including arable land, pastures and mixed farming systems in Spain, Germany and Bulgaria. We mapped GBI including small landscape elements, in-field elements (both semi-natural and productive) and connectivity features. We used historical imagery to map changes on GBI occurrence in LTS from 2012 to 2018. We also used questionnaires with farmers and stakeholders on their GBI awareness and compared their answers to elements mapped. Results showed that landscape and in-field GBI occurrence was higher in extensive than in intensive farming systems regardless of the region, whereas the opposite was found for connectivity features (e.g. grassy strips). The analysis of habitat changes showed a small increase of certain biodiversity-fostering in-field GBI, but no substantial change in connectivity features or landscape elements. Moreover, a significant reduction of valuable GBI like grasslands was observed. There were several mismatches between the patterns of GBI identified by farmers and stakeholders and their mapped abundances. Our results indicate that the CAP has not substantially increased the availability of biodiversity-fostering GBI in these regions and that adopted features were mostly related to neutral or negative effects on biodiversity. Farmers’ perception of GBI features seems driven by production management decisions rather than by biodiversity concerns.
To identify disease-causing mutations within coding regions of 11 known NPHP genes (NPHP1-NPHP11) in a cohort of 192 patients diagnosed with a nephronophthisis-associated ciliopathy, at low cost.
...Mutation analysis was carried out using PCR-based 48.48 Access Array microfluidic technology (Fluidigm) with consecutive next-generation sequencing. We applied a 10-fold primer multiplexing approach allowing PCR-based amplification of 475 amplicons (251 exons) for 48 DNA samples simultaneously. After four rounds of amplification followed by indexing all of 192 patient-derived products with different barcodes in a subsequent PCR, 2 × 100 paired-end sequencing was performed on one lane of a HiSeq2000 instrument (Illumina). Bioinformatics analysis was performed using 'CLC Genomics Workbench' software. Potential mutations were confirmed by Sanger sequencing and shown to segregate.
Bioinformatics analysis revealed sufficient coverage of 30 × for 168/192 (87.5%) DNA samples (median 449 ×) and of 234 out of 251 targeted coding exons (sensitivity: 93.2%). For proof-of-principle, we analysed 20 known mutations and identified 18 of them in the correct zygosity state (90%). Likewise, we identified pathogenic mutations in 34/192 patients (18%) and discovered 23 novel mutations in the genes NPHP3 (7), NPHP4 (3), IQCB1 (4), CEP290 (7), RPGRIP1L (1), and TMEM67 (1). Additionally, we found 40 different single heterozygous missense variants of unknown significance.
We conclude that the combined approach of array-based multiplexed PCR-amplification on a Fluidigm Access Array platform followed by next-generation sequencing is highly cost-efficient and strongly facilitates diagnostic mutation analysis in broadly heterogeneous Mendelian disorders.
BackgroundTumor microenvironment induced antigens present a unique opportunity to effectively target diseased tissue over normal and to modulate the immune suppression they might elicit. MICA and ...MICB (MICA/B) are stress-induced antigens expressed in a range of cancers. MICA/B antigens are recognized by NKG2D, an activating receptor on NK and CD8+ T cells. While the membrane-bound form of MICA/B is immuno-stimulatory, the cleaved soluble form found in the tumor microenvironment prevents NKG2D mediated tumor cell recognition. To stop tumor escape and, concurrently, stimulate the innate and adaptive immune responses, we developed antibodies targeting MICA/B. Anti-MICA/B antibodies block proteolytic cleavage, increase MICA/B membrane surface densities, and activate NK and CD8+ T cells by bringing membrane bound MICA/B to NKG2D. To enhance the anti-tumor activities of MICA/B antibodies, we designed multi-specific NK cell engaging antibodies that simultaneously target MICA/B antigens and an orthogonal activating receptor NKp46.MethodsExpanding on Xencor’s XmAb therapeutic protein platform, we developed multi-specific NK cell Engager (NKE) molecules that simultaneously activate several stimulatory pathways including NKG2D, NKp46, and FcγRIIIa via the Fc domain. The multi-specific NKEs were assessed for their ability to induce tumor cell cytotoxicity, secrete proinflammatory cytokines, and activate effector cells.ResultsTo address the polymorphic nature of MICA and MICB antigens, anti-MICA/B antibodies were developed that recognize multiple MICA/B allelic variants. Subsequent screens selected for antibodies that block the proteolytic cleavage of membrane bound MICA/B. These antibodies induce tumor cell lysis and stimulate IFNγ production by effector cells. The functional activity of these MICA/B antibodies is dependent on agonism of the NKG2D pathway. To enhance the activity of our MICA/B antibodies the Fc was engineered to have increased affinity for the FcγR receptors. Antibodies with enhanced Fc effector function showed superior activity over their IgG1 counterparts. To capitalize on the ability of NK cells to integrate activating and inhibitory signals, we designed NK cell engagers targeting MICA/B, agonism via the NKG2D pathway, and NKp46 to stimulate an orthogonal NK cell activation pathway. These multi-specific NKEs stimulate both activating receptors and show enhanced functional activity compared to antibodies only targeting MICA/B. These findings indicate that multi-specific NKE antibodies are superior for activating NK cells for the targeted killing of tumor cells.ConclusionsMulti-specific XmAb NKEs engineered to stimulate multiple activating pathways show potent tumor cell lysis and induce production of proinflammatory cytokines. Next steps include assessment of in vivo activity and safety profile evaluation.
Marine ecosystems, ranging from coastal seas and wetlands to the open ocean, accommodate a wealth of biological diversity from small microorganisms to large mammals. This biodiversity and its ...associated ecosystem function occurs across complex spatial and temporal scales and is not yet fully understood. Given the wide range of external pressures on the marine environment, this knowledge is crucial for enabling effective conservation measures and defining the limits of sustainable use. The development and application of omics-based approaches to biodiversity research has helped overcome hurdles, such as allowing the previously hidden community of microbial life to be identified, thereby enabling a holistic view of an entire ecosystem’s biodiversity and functioning. The potential of omics-based approaches for marine ecosystems observation is enormous and their added value to ecosystem monitoring, management, and conservation is widely acknowledged. Despite these encouraging prospects, most omics-based studies are short-termed and typically cover only small spatial scales which therefore fail to include the full spatio-temporal complexity and dynamics of the system. To date, few attempts have been made to establish standardised, coordinated, broad scaled, and long-term omics observation networks. Here we outline the creation of an omics-based marine observation network at the European scale, the European Marine Omics Biodiversity Observation Network (EMO BON). We illustrate how linking multiple existing individual observation efforts increases the observational power in large-scale assessments of status and change in biodiversity in the oceans. Such large-scale observation efforts have the added value of cross-border cooperation, are characterised by shared costs through economies of scale, and produce structured, comparable data. The key components required to compile reference environmental datasets and how these should be linked are major challenges that we address.
In Argentina, Chile and Ecuador, abortion at later durations of pregnancy is legally restricted. Feminist collectives in these contexts support people through self-managed medical abortion outside ...the healthcare system. The model of in-person abortion accompaniment represents an opportunity to examine a self-care practice that challenges and reimagines abortion provision. We formed a collaborative partnership built on a commitment to shared power and decision-making between researchers and partners. We conducted 28 key informant interviews with accompaniers in Argentina, Chile and Ecuador in 2019 about their model of in-person abortion accompaniment at later durations of pregnancy. We iteratively coded transcripts using a thematic analysis approach. Accompaniers premised their work in a feminist activist framework that understands accompaniment as addressing inequalities and expanding rights, especially for the historically marginalised. Through a detailed description of the process of in-person accompaniment, we show that the model, including the logistical considerations and security mechanisms put in place to ensure favourable abortion outcomes, emphasises peer-to-peer provision of supportive physical and emotional care of the accompanied person. In this way, it represents supported self-care through which individuals are centred as the protagonists of their own abortion, while being accompanied by feminist peers. This model of supported self-care challenges the idea that "self-care" necessarily means "solo care", or care that happens alone. The model's focus on peer-to-peer transfer of knowledge, providing emotional support, and centring the accompanied person not only expands access to abortion, but represents person-centred practices that could be scaled and replicated across contexts.
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