Bovine tuberculosis (Tb) caused by Mycobacterium bovis has proved refractory to eradication from domestic livestock in countries with wildlife disease reservoirs. Vaccination of wild hosts offers a ...way of controlling Tb in livestock without wildlife culling. This study was conducted in a Tb-endemic region of New Zealand, where the introduced Australian brushtail possum (Trichosurus vulpecula) is the main wildlife reservoir of Tb. Possums were trapped and vaccinated using a prototype oral-delivery system to deliver the Tb vaccine bacille Calmette-Guerin. Vaccinated and control possums were matched according to age, sex and location, re-trapped bimonthly and assessed for Tb status by palpation and lesion aspiration; the site was depopulated after 2 years and post-mortem examinations were conducted to further identify clinical Tb cases and subclinical infection. Significantly fewer culture-confirmed Tb cases were recorded in vaccinated possums (1/51) compared with control animals (12/71); the transition probability from susceptible to infected was significantly reduced in both males and females by vaccination. Vaccine efficacy was estimated at 95 per cent (87-100%) for females and 96 per cent (82-99%) for males. Hence, this trial demonstrates that orally delivered live bacterial vaccines can significantly protect wildlife against natural disease exposure, indicating that wildlife vaccination, along with existing control methods, could be used to eradicate Tb from domestic animals.
A circular economy relies on demonstrating the quality and environmental safety of wastes that are recovered and reused as products. Policy-level risk assessments, using generalised exposure ...scenarios, and informed by stakeholder communities have been used to appraise the acceptability of necessary changes to legislation, allowing wastes to be valued, reused and marketed. Through an extensive risk assessment exercise, summarised in this paper, we explore the burden of proof required to offer safety assurance to consumer and brand-sensitive food sectors in light of attempts to declassify, as wastes, quality-assured, source-segregated compost and anaerobic digestate products in the United Kingdom. We report the residual microbiological and chemical risks estimated for both products in land application scenarios and discuss these in the context of an emerging UK bioeconomy worth £52bn per annum. Using plausible worst case assumptions, as demanded by the quality food sector, risk estimates and hazard quotients were estimated to be low or negligible. For example, the human health risk of E. coli 0157 illness from exposure to microbial residuals in quality-assured composts, through a ready-to-eat vegetable consumption exposure route, was estimated at ~10−8 per person per annum. For anaerobic digestion residues, 7 × 10−3cases of E. coli 0157 were estimated per annum, a potential contribution of 0.0007% of total UK cases. Hazard quotients for potential chemical contaminants in both products were insufficient in magnitude to merit detailed quantitative risk assessments. Stakeholder engagement and expert review was also a substantive feature of this study. We conclude that quality-assured, source-segregated products applied to land, under UK quality protocols and waste processing standards, pose negligible risks to human, animal, environmental and crop receptors, providing that risk management controls set within the standards and protocols are adhered to.
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•Quality assured, source-segregated composts and digestates have agronomic benefits.•Removal of these wastes from regulation requires prior risk assessment.•Risks to humans, animals, crops and the environment are negligible, assuming controls in place.•Products from these wastes play an important role in a circular bioeconomy.•The burden of proof to secure market confidence however is substantive.
Bats harbour a diverse array of viruses, including significant human pathogens. Extensive metagenomic studies of material from bats, in particular guano, have revealed a large number of novel or ...divergent viral taxa that were previously unknown. New Zealand has only two extant indigenous terrestrial mammals, which are both bats, Mystacina tuberculata (the lesser short-tailed bat) and Chalinolobus tuberculatus (the long-tailed bat). Until the human introduction of exotic mammals, these species had been isolated from all other terrestrial mammals for over 1 million years (potentially over 16 million years for M. tuberculata). Four bat guano samples were collected from M. tuberculata roosts on the isolated offshore island of Whenua hou (Codfish Island) in New Zealand. Metagenomic analysis revealed that this species still hosts a plethora of divergent viruses. Whilst the majority of viruses detected were likely to be of dietary origin, some putative vertebrate virus sequences were identified. Papillomavirus, polyomavirus, calicivirus and hepevirus were found in the metagenomic data and subsequently confirmed using independent PCR assays and sequencing. The new hepevirus and calicivirus sequences may represent new genera within these viral families. Our findings may provide an insight into the origins of viral families, given their detection in an isolated host species.
The work contained herein constitutes a report of the "Beyond the Standard Model'' working group for the Workshop "Physics at TeV Colliders", Les Houches, France, 2-20 May, 2005. We present reviews ...of current topics as well as original research carried out for the workshop. Supersymmetric and non-supersymmetric models are studied, as well as computational tools designed in order to facilitate their phenomenology.
Abstract
Replication initiator proteins (Reps) from the HUH-endonuclease superfamily process specific single-stranded DNA (ssDNA) sequences to initiate rolling circle/hairpin replication in viruses, ...such as crop ravaging geminiviruses and human disease causing parvoviruses. In biotechnology contexts, Reps are the basis for HUH-tag bioconjugation and a critical adeno-associated virus genome integration tool. We solved the first co-crystal structures of Reps complexed to ssDNA, revealing a key motif for conferring sequence specificity and for anchoring a bent DNA architecture. In combination, we developed a deep sequencing cleavage assay, termed HUH-seq, to interrogate subtleties in Rep specificity and demonstrate how differences can be exploited for multiplexed HUH-tagging. Together, our insights allowed engineering of only four amino acids in a Rep chimera to predictably alter sequence specificity. These results have important implications for modulating viral infections, developing Rep-based genomic integration tools, and enabling massively parallel HUH-tag barcoding and bioconjugation applications.
Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated ...the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty.
In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively.
There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline.
Allo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.
Genes encoding the subunits of the membrane-bound F 1 F 0 -ATPase (responsible for exporting protons from the cytoplasm and contributing to acid tolerance) were sequenced for 24 non-mutans ...streptococci isolated from carious lesions. Isolates, mostly Streptococcus salivarius, displayed a continuum of acid tolerance thresholds ranging from pH 4.55 to 3.39, but amino acid alignments of F 1 F 0 -ATPase subunits revealed few non-synonymous substitutions and these were unrelated to acid tolerance. Thus, the F 1 F 0 -ATPase is highly-conserved among S. salivarius isolates despite varying acid tolerance thresholds, supporting the contention that acid tolerance is determined by the level of gene/protein expression rather than variation in molecular structure.
Influenza infection induces an increase in the level of indoleamine 2,3-dioxygenase (IDO) activity in the lung parenchyma. IDO is the first and rate-limiting step in the kynurenine pathway where ...tryptophan is reduced to kynurenine and other metabolites. The depletion of tryptophan, and production of associated metabolites, attenuates the immune response to infection. The impact of IDO on the primary immune response to influenza virus infection was determined using the IDO inhibitor 1-methyl-D,L-tryptophan (1MT). C57BL/6 mice treated with 1MT and infected with A/HKx31 influenza virus had increased numbers of activated and functional CD4⁺ T-cells, influenza-specific CD8⁺ T-cells and effector memory cells in the lung. Inhibition of IDO increased the Th1 response in CD4⁺ T-cells as well as enhanced the Th17 response. These studies show that inhibition of IDO engenders a more robust T-cell response to influenza virus, and suggests an approach for enhancing the immune response to influenza vaccination by facilitating increased influenza-specific T-cell response.
ICD-11, ICD-10, ICD-10-CM, International Classification of Diseases, ontology, morbidity, interoperability, health information exchange, episode of care, value-based healthcare Introduction In 2007, ...the World Health Organization (WHO) began a revision and restructuring of the International Statistical Classification of Diseases and Related Health Problems, 1 Oth revision (ICD-10) to transform this classification system into a flexible clinical and research friendly structure aligned with advances in information technology. The model introduces ICD-11 Comprehensive Clinical Linearization, Evolution and Response (C-CLEAR), a fully coded comprehensive clinical linearization along with syntactical rules for combining these codes that can translate detailed natural clinical language into standardized coded patient records that exploit the significant advantages of ICD-11. While ICD-10-CM was seen as an improvement over the 9th Clinical Modification of ICD,5,6 a system used since 1979, the implementation was considered highly disruptive and time-consuming, and added significant financial and administrative burdens on physicians and other healthcare providers.7"10 More than four years have passed since the 11th revision was endorsed by the World Health Assembly.1 WHO also has ceased updates to ICD-10.3 As of February 2023, 64 Member States are in different stages of ICD-11 implementation.11 Compared to ICD-10, Harrison et al.12 noted in their review that, "ICD-11 is a different and more powerful health information system, based on formal ontology, designed to be implemented in modern information technology infrastructures, and flexible enough for future modification and use with other classifications and terminologies." Recognizing the NCVHS recommendations and ICD-ll's potential, the authors created a prototype innovation model with a volunteer group of professionals representing medicine, informatics, healthcare data, computer technology, analytics, performance evaluation, economics, and payment.
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