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The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the ‘arms race’ with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.

Abstract Bovine tuberculosis is an infectious disease of global significance that remains endemic in many countries. Mycobacterium bovis infection in cattle is characterized by a cell-mediated immune response (CMI) that precedes humoral responses, however the timing and trajectories of CMI and antibody responses determined by newer generation assays remain undefined. Here we used defined-antigen interferon-gamma release assays (IGRA) and an eleven-antigen multiplex ELISA (Enferplex TB test) alongside traditional tuberculin-based IGRA and IDEXX M. bovis antibody tests to assess immune trajectories following experimental M. bovis infection of cattle. The results show CMI responses developed as early as two-weeks post-infection, with all infected cattle testing positive three weeks post-infection. Interestingly, 6 of 8 infected animals were serologically positive with the Enferplex TB assay as early as 4 weeks post-infection. As expected, application of the tuberculin skin test enhanced subsequent serological reactivity. Infrequent M. bovis faecal shedding was observed but was uncorrelated with observed immune trajectories. Together, the results show that early antibody responses to M. bovis infection are detectable in some individuals and highlight an urgent need to identify biomarkers that better predict infection outcomes, particularly for application in low-and-middle income countries where test-and-slaughter based control methods are largely unfeasible.

Bovine tuberculosis is usually diagnosed using tuberculin skin tests or at post-mortem. Recently, we have developed a serological test for bovine tuberculosis in cattle which shows a high degree of accuracy using serum samples. Here, we have assessed the performance of the test using individual bovine milk samples. The diagnostic specificity estimate using the high sensitivity setting of the test was 99.7% (95% CI: 99.2-99.9). This estimate was not altered significantly by tuberculin boosting. The relative sensitivity estimates of the test using the high sensitivity setting in milk samples from comparative skin test positive animals was 90.8% (95% CI: 87.1-93.6) with boosting. In animals with lesions, the relative sensitivity was 96.0% (95% CI: 89.6-98.7). Analysis of paired serum and milk samples from skin test positive animals showed correlation coefficients ranging from 0.756-0.955 for individual antigens used in the test. Kappa analysis indicated almost perfect agreement between serum and milk results, while McNemar marginal homogeneity analysis showed no statistically significant differences between the two media. The positive and negative likelihood ratio were 347.8 (95% CI: 112.3-1077.5) and 0.092 (95% CI: 0.07-0.13) respectively for boosted samples from skin test positive animals. The results show that the test has high sensitivity and specificity in individual milk samples and thus milk samples could be used for the diagnosis of bovine tuberculosis.

Abstract Bovine tuberculosis is a contagious bacterial disease of worldwide economic, zoonotic and welfare importance caused mainly by Mycobacterium bovis infection. Current regulatory diagnostic methods lack sensitivity and require improvement. We have developed a multiplex serological test for bovine tuberculosis and here we provide an estimate of the diagnostic accuracy of the test in cattle. Positive and negative reference serum samples were obtained from animals from Europe and the United States of America. The diagnostic specificity estimate was 98.4% and 99.7% using high sensitivity and high specificity settings of the test respectively. Tuberculin boosting did not affect the overall specificity estimate. The diagnostic sensitivity in samples from Mycobacterium bovis culture positive animals following tuberculin boosting was 93.9%.The relative sensitivity following boosting in tuberculin test positive, lesion positive animals and interferon gamma test positive, lesion positive animals was 97.2% and 96.9% respectively. In tuberculin test negative, lesion positive animals and in interferon gamma test negative, lesion positive animals, the relative sensitivity following tuberculin boosting was 88.2% and 83.6% respectively. The results show that the test has high diagnostic sensitivity and specificity and can detect infected animals that are missed by tuberculin and interferon gamma testing.

Digital transformation has far-reaching effects on business and society. While the literature to date has mainly considered the positive opportunities associated with digital innovations at the consumer interface in terms of products and services, the impact on asset-intensive organisations has not yet been examined in detail. Because asset-intensive organisations have unique requirements, a focused approach is essential. This study provided an in-depth analysis of digital transformation efforts in asset-intensive organisations by interviewing elite informants in the field. Our results provide an explanatory model for the digital transformation of asset-intensive organisations from a dynamic process perspective. Our results also allowed us to uncover the dark side of digital transformation, and we theorise on its implications.

Understanding the role of neutral atoms in the heliospheric interface (between the bow shock and heliopause) is critical to identifying dynamics within our local bubble. This article recommends building upon existing measurements with new, high-spectral resolution observations of H Lyman-α, from a heliospheric mapping mission, to resolve the momentum exchange in reactions between the solar wind and energetic neutral atoms that are key to identifying the most important heliospheric processes.

This study addressed the need in Great Britain for supplementary blood tests for deer and pig herds under movement restrictions due to confirmed Mycobacterium bovis infection—to enhance the overall sensitivity and reliability of tuberculosis (TB) testing and contribute to an exit strategy for these herds. We evaluated four antibody tests (lateral flow DPP VetTB Assay for Cervids, M. bovis IDEXX ELISA, Enferplex Cervid and Porcine antibody tests and an in-house comparative PPD ELISA) using serum samples from defined cohorts of TB-infected and TB-free deer and pigs. TB-infected deer included two separate cohorts; farmed deer that had received a tuberculin skin test less than 30 days prior, and park deer that had received no prior skin test. In this way, we were able to assess the effect of the skin test anamnestic boost upon antibody test sensitivity. We tested a total of 402 TB-free pigs and 416 TB-free deer, 77 infected farmed deer and 105 infected park deer, and 29 infected pigs (including 2 wild boar). For deer, we found an equivalent high performance of all four tests: specificity range 98.8–99.5% and sensitivity range 76.6–85.7% for skin test-boosted infected deer, and 51.4–58.1% for non-boosted infected deer. These data suggest an overall approximate 25% increase in test sensitivity for infected deer following a skin test boost. For pigs, the tests again had equivalent high specificity of 99–99.5% and a sensitivity range of 62.1–86.2%, with substantial agreement for three of the four tests. Retrospective application of the ELISA tests to individual culled park deer and wild boar that showed no obvious evidence of TB at larder inspection identified a significant seropositivity within wild boar suggestive of low-level M. bovis infection that would otherwise not have been detected. Overall this investigation provided a robust evaluation of four antibody tests, which is essential to generate confidence in test performance before a wider deployment within TB control measures can be considered.

Abstract Background Poor diet and lack of physical activity are strongly linked to non-communicable disease risk, but modifying them is challenging. There is increasing recognition that adolescence is an important time to intervene; habits formed during this period tend to last, and physical and psychological changes during adolescence make it an important time to help individuals form healthier habits. Improving adolescents’ health behaviours is important not only for their own health now and in adulthood, but also for the health of any future children. Building on LifeLab—an existing, purpose-built educational facility at the University of Southampton—we have developed a multi-component intervention for secondary school students called Engaging Adolescents in Changing Behaviour (EACH-B) that aims to motivate and support adolescents to eat better and be more physically active. Methods A cluster randomised controlled trial is being conducted to evaluate the effectiveness of the EACH-B intervention. The primary outcomes of the intervention are self-reported dietary quality and objectively measured physical activity (PA) levels, both assessed at baseline and at 12-month follow-up. The EACH-B intervention consists of three linked elements: professional development for teachers including training in communication skills to support health behaviour change; the LifeLab educational module comprising in-school teaching of nine science lessons linked to the English National Curriculum and a practical day visit to the LifeLab facility; and a personalised digital intervention that involves social support and game features that promote eating better and being more active. Both the taught module and the LifeLab day are designed with a focus on the science behind the messages about positive health behaviours, such as diet and PA, for the adolescents now, in adulthood and their future offspring, with the aim of promoting personal plans for change. The EACH-B research trial aims to recruit approximately 2300 secondary school students aged 12–13 years from 50 schools (the clusters) from Hampshire and neighbouring counties. Participating schools will be randomised to either the control or intervention arm. The intervention will be run during two academic years, with continual recruitment of schools throughout the school year until the sample size is reached. The schools allocated to the control arm will receive normal schooling but will be offered the intervention after data collection for the trial is complete. An economic model will be developed to assess the cost-effectiveness of the EACH-B intervention compared with usual schooling. Discussion Adolescents’ health needs are often ignored and they can be difficult to engage in behaviour change. Building a cheap, sustainable way of engaging them in making healthier choices will benefit their long-term health and that of their future children. Trial registration ISRCTN 74109264 . Registered on 30 August 2019. EACH-B is a cluster randomised controlled trial, funded by the National Institute for Health Research (RP-PG-0216-20004).

AimsInflammation is a hallmark of cancer whose activity is modulated within the tumor microenvironment by low tumoral pH. Recent evidence in the literature has suggested a link between low serum bicarbonate, low tumoral pH and cancer related inflammation. There is however little clinical evidence in human patients regarding the prognostic role of serum bicarbonate. Therefore, the primary aim of this study was to investigate the short and long-term prognostic utility of serum bicarbonate in colorectal cancer (CRC) patients undergoing resection of their primary tumor. The study also aimed to investigate the association of serum bicarbonate with known markers of systemic inflammation.MethodsA total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012. Of these, 2223 stage I-IV patients had available data for analysis. The association of serum bicarbonate with overall survival was assessed using univariate and multivariate cox regression analyses. The association of bicarbonate with other clinicopathological variables was assessed by chi squared and Fisher's exact tests.ResultsSerum bicarbonate was associated with peri-operative mortality in multivariate analysis (pConclusionsIn peri-operative colorectal cancer patients, serum bicarbonate was associated with 30-day survival but not 5-year survival.

BackgroundIn spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed.MethodsAn open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS.ResultsPhase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group.ConclusionsResults from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR.Trial registrationClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Abstract The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the “Rett syndrome community” with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families. Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a “cure” for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care. Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a “cure”. Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised.

This introduction to the special issue on Working the Boundaries of Law provides a context for the papers collected here. It locates the papers in a colloquium held in Oñati to discuss issues around this theme. It traces the significance of borders and boundaries as sites of social practice and considers how the boundaries of law are constructed and contested. The introduction then explores the sorts of practices – or labour – that go on at these boundaries – to maintain, challenge and traverse them. It points in particular to boundaries as sites of translation and emotional labour. Finally, it briefly introduces the papers that follow. Esta introducción al número especial Working the Boundaries of Law proporciona un contexto para los artículos que forman el número. Ubica los artículos en un coloquio que tuvo lugar en Oñati para debatir asuntos relacionados con el tema principal. Rastrea el significado de los límites y las fronteras como lugares de práctica social, y considera cómo se construyen y se contestan los límites de la legalidad. Después, esta introducción explora el tipo de prácticas -o trabajos- que suceden en estos límites -para mantenerlos, desafiarlos y atravesarlos. En particular, apunta a los límites como lugares de conversión y de gestión de las emociones. Por último, presenta brevemente los artículos que siguen. DOWNLOAD THIS PAPER FROM SSRN: http://ssrn.com/abstract=3062565

A central issue in the reform of welfare systems concerns the citizenship relationship. Citizenship is critical in three ways: • It has been the focus of political struggles to redraw the boundaries of citizenship: who counts as a citizen? • It has been the focus of reforms seeking to redraw the balance of ‘rights and responsibilities’ between the state and the citizen, making citizenship more conditional; and • It remains the focus of desires and demands for support and solidarity. Drawing on recent collaborative research with advice agencies (Citizens Advice in the UK), I explore how citizenship is imagined and practiced in different settings – from the policing of nationality to state welfare – contrasting the growing conditionality and exclusiveness of state-centric definitions with alternative imaginaries that celebrate expansive and horizontal forms of identification.

BackgroundRecent literature has suggested that tumor sidedness in colorectal cancer (CRC) is an independent prognostic and potentially predictive marker of survival. The aims of the study were to determine the prognostic significance of tumor sidedness in colorectal cancer patients undergoing primary tumor resection and to assess associated tumor biology.MethodsA total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012 were analyzed for association with tumor biologic factors and with overall survival. Metastatic patients were excluded from analysis.ResultsLeft sided CRCs were associated with a number of additional key prognostic markers including BRAFV600E wildtype status (PConclusionsTumor sidedness was not an independent prognostic marker of CRC. However, right sided CRCs were associated with several key independent prognostic markers supporting a hypothesis that tumor sidedness is a surrogate for other biomarkers.

Scalable quantum information processing requires controllable high-coherence qubits. Here, the authors present superconducting flux qubits with broad frequency tunability, strong anharmonicity and high reproducibility, identifying photon shot noise as the main source of dephasing for further improvements.

Background and purpose — Recent research on outcomes after total knee arthroplasty (TKA) has raised the question of the ability of traditional outcome measures to distinguish between treatments. We compared functional outcomes in patients undergoing TKA with and without patellar resurfacing, using the knee injury and osteoarthritis outcome score (KOOS) as the primary outcome and 3 traditional outcome measures as secondary outcomes. Patients and methods — 129 knees in 115 patients (mean age 70 (42–82) years; 67 female) were evaluated in this single-center, randomized, double-blind study. Data were recorded preoperatively, at 1 year, and at 3 years, and were assessed using repeated-measures mixed models. Results — The mean subscores for the KOOS after surgery were statistically significantly in favor of patellar resurfacing: sport/recreation, knee-related quality of life, pain, and symptoms. No statistically significant differences between the groups were observed with the Knee Society clinical rating system, with the Oxford knee score, and with visual analog scale (VAS) for patient satisfaction. Interpretation — In the present study, the KOOS—but no other outcome measure used—indicated that patellar resurfacing may be beneficial in TKA.