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Summary The root-knot nematodes (RKN) Meloidogyne graminicola and M. incognita are responsible for rice yield losses worldwide, particularly in Asia and Africa. Previous studies demonstrated that nematode-secreted proteins are crucial for root invasion and establishment in the host. We present some characteristics of a pioneer effector, M. incognita-secreted protein 4 (Mi-SP4), which is conserved in RKN and required for infection in compatible rice-RKN interactions. In situ hybridisation assays revealed Mi-SP4 expression in the dorsal pharyngeal gland of M. incognita second-stage juveniles (J2). Meloidogyne-SP4 transcripts strongly accumulated in pre-parasitic J2 and decreased in later parasitic stages of M. incognita and M. graminicola. Transient expression of the nematode effector gene in Nicotiana benthamiana leaves and onion cells indicated that GFP-tagged Mi-SP4 was present in the cytoplasm and accumulated in the nucleus of the plant cells. In vitro RNA interference (RNAi) gene silencing, obtained by soaking J2 with small-interfering (si)RNA si4-1, decreased Mi -SP4 expression in J2 by 35% and significantly reduced M. incognita reproduction in rice by at least 30%. Similarly, host-mediated gene silencing of the nematode SP4 effector candidate gene in transgenic rice plants significantly reduced M. graminicola reproduction by 26% to 47%. The data obtained demonstrate that Mi -SP4 is a pioneer virulence effector, which plays an essential role in both M. incognita and M. graminicola pathogenicity on rice.

Using the theoretical lens of Family Quality of Life, this study evaluated perceptions of older compound caregivers (i.e., caring for more than one family member) regarding their need for services. Quantitative analysis of cross-sectional data collected from 112 caregivers (50 years and older) demonstrated that compound caregivers faced more barriers in accessing services for their families than noncompound caregivers. Although all caregivers shared similar perceptions on the importance, opportunities, initiative, and attainment of service support for their families, compound caregivers had lower stability and satisfaction than noncompound caregivers. Findings highlight the need to develop support programs to equip older caregivers in managing their daily challenges at the individual and family level.

We present the process, collaborative management, and impact of a pilot leadership programme created to help teachers of Religion and Worldviews (R&W) (We are using the phrase ‘religion and worldviews’ to reflect a change in approach advocated in the Commission on RE (2018). We use the abbreviation R&W throughout. We acknowledge and accept that many are using the phrase ‘religious education’ or ‘RE’ to refer to the school subject.) find their voice as leaders. At the heart of the project’s successful impact is a steering group which not only manages the programme, but models collaboration across the R&W eco-system. Here we reflect as a team on the process of programme development particularly during the Covid-19 pandemic. We consider what we have learned individually and as a team, and how we each perceive the impact of the programme so far. We use a collective writing method, identifying key themes arising from the different perspectives and draw conclusions. This approach mirrors the way in which the team worked together reflecting the values of the joint funders such as integrity, openness, empowerment, and service. We conclude by offering this model as a way of working strategically across multiple diverse organisations.

The authors have requested that this preprint be removed from Research Square.

We present a distinctive approach to knowledge exchange used in the ‘Shared Space’ project; an inter-disciplinary researcher–teacher partnership using Allport’s contact theory contact theory as a l...

Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.

European Administrative Networks (EANs) are well-studied platforms of collaboration between national authorities. To understand EANs, the literature typically relies on few explanatory variables: network origins, objectives, and outputs. This external view of EANs leaves important questions unanswered, notably concerning power redistribution and regulators’ perception of EANs. This article highlights the importance of network internal structures as an explanatory variable for understanding EANs. We contend that internal structures are ‘opportunity structures’ for regulators to set agendas and share resources. We investigate the case of the European Competition Network (ECN)–a highly structured, hierarchical and formalized enforcement network–drawing on structured interviews with 15 National Competition Agencies (NCAs) carried out in 2014. We find that the ECN’s formal internal structures afford all NCAs access to the agenda, foster perceptions of effectiveness, and promote informal sharing of expertise outside the network. Future research should incorporate internal structures into analyses of administrative networks.

Mycobacterium abscessus infections are of increasing global prevalence and are often difficult to treat due to complex antibiotic resistance profiles. While there are similarities between the pathogenesis of M. abscessus and tuberculous mycobacteria, including granuloma formation and stromal remodeling, there are distinct molecular differences at the host-pathogen interface. Here we have used a zebrafish-M. abscessus model and host-directed therapies that were previously identified in the zebrafish-M. marinum model to identify potential host-directed therapies against M. abscessus infection. We find efficacy of anti-angiogenic and vascular normalizing therapies against rough M. abscessus infection, but no effect of anti-platelet drugs.

Regulation of host microRNA (miRNA) expression is a contested node that controls the host immune response to mycobacterial infection. The host must overcome concerted subversive efforts of pathogenic mycobacteria to launch and maintain a protective immune response. Here we examine the role of miR-126 in the zebrafish model of Mycobacterium marinum infection and identify a protective role for this infection-induced miRNA through multiple effector pathways. Specifically, we analyse the impact of the miR-126 knockdown-induced tsc1a and cxcl12a/ccl2/ccr2 signalling axes during early host-M. marinum interactions. We find a strong detrimental effect of tsc1a upregulation that renders zebrafish embryos susceptible to higher bacterial burden and increased cell death despite dramatically higher recruitment of macrophages to the site of infection. We demonstrate that infection-induced miR-126 suppresses tsc1 and cxcl12a expression thus improving macrophage function early in infection, partially through activation of mTOR signalling and strongly through preventing the recruitment of Ccr2+ permissive macrophages, resulting in the recruitment of protective tnfa-expressing macrophages. Together our results demonstrate an important role for infection-induced miR-126 in shaping an effective immune response to M. marinum infection in zebrafish embryos.

Cigarette smoke (CS)-induced inflammation leads to a range of diseases including chronic obstructive pulmonary disease and cancer. The gut microbiota is a major modifying environmental factor that determine the severity of cigarette smoke-induced pathology. Microbiomes and metabolites from CS-exposed mice exacerbate lung inflammation via the gut-lung axis of shared mucosal immunity in mice but these systems are expensive to establish and analyse. Zebrafish embryos and larvae have been used to model the effects of cigarette smoking on a range of physiological processes and offer an amenable platform for screening modifiers of cigarette smoke-induced pathologies with key features of low cost and rapid visual readouts. Here we exposed zebrafish larvae to cigarette smoke extract (CSE) and characterised a CSE-induced leukocytic inflammatory phenotype with increased neutrophilic and macrophage inflammation in the gut. The CSE-induced phenotype was exacerbated by co-exposure to microbiota from the faeces of CS-exposed mice, but not control mice. Microbiota could be recovered from the gut of zebrafish and studied in isolation in a screening setting. This demonstrates the utility of the zebrafish-CSE exposure platform for identifying environmental modifiers of cigarette smoking-associated pathology and demonstrates that the CS-exposed mouse gut microbiota potentiates the inflammatory effects of CSE across host species.

A concerted effort is being made within the EU to crack down on money laundering. This is reflected by both the European Money Laundering Directives, which have led to changes in the UK legislation, in particular the Money Laundering, Terrorist Financing and Transfer of Funds (Information on the Payer) Regulations (MLR). Solicitors are usually unwittingly involved in a money laundering scheme. They can avoid this by being conversant with the requirements of the money laundering legislation and fully complying with it. This chapter explains the process of money laundering; the primary legislation and offences; and the relevance of the legislation to solicitors.

This chapter discusses the law underlying the entitlement to a person’s property on his or her death. It considers the law of ‘testate succession’ where the deceased has left a will; the law of ‘intestate succession’ if there is no will, or if any will left by the deceased is not wholly effective to dispose of their estate; the law governing devolution of property not passing under the terms of the deceased’s will or the operation of the intestacy rules; and the law enabling members of the family or dependants of the deceased to make claims for provision against the estate.

Background In 2015, the Partnership for a Healthier America launched the branded Fruits & Veggies (FNV) Campaign to apply a unique industry-inspired marketing approach to promote fruit and vegetable sales and intake to moms and teens in two US pilot markets: Fresno, California and Hampton Roads, Virginia. The aims of this cross-sectional study were to: 1) assess brand awareness and fruit- and vegetable-related outcomes among FNV Campaign target audiences in the California and Virginia market locations; and 2) examine whether reported awareness of the FNV Campaign was associated with differences in fruit- and vegetable-related cognitive and behavioral outcomes. Methods Data for this cross-sectional study were collected using an online survey administered to a non-probability convenience sample (n = 1604; February–July 2017) of youth aged 14–20 years (n = 744) and moms aged 21–36 years (n = 860) in the two pilot markets. Descriptive statistics were computed and outcomes compared between unaware and aware respondents, controlling for sociodemographic covariates. Multivariate analysis of covariance (MANCOVA) was conducted to assess whether fruit- and vegetable-related attitude, belief, and encouragement outcomes differed by FNV Campaign awareness; logistic regression was used to examine associations between FNV brand awareness and dichotomous variables (fruit- and vegetable-related behavioral intentions, trying new fruits and vegetables); and ANCOVA was used to assess associations with daily fruit and vegetable intake frequency. Results Approximately 20% (n = 315/1604) of respondents reported awareness of the FNV Campaign. Youth that reported awareness of the FNV Campaign (n = 167, 22.4%) had higher intentions to buy (p = 0.003) and eat (p = 0.009) fruits and vegetables than unaware respondents. Mothers that reported awareness of the FNV Campaign (n = 148, 17.2%) reported greater encouragement for friends and family to eat fruits and vegetables (p = 0.013) and were approximately 1.5 times more likely to report trying a new fruit or vegetable (p = 0.04) than mothers unaware of the Campaign. Daily fruit and vegetable intake frequency did not differ by Campaign awareness. Conclusions FNV Campaign awareness was associated with limited but positive short- and intermediate-term cognitive and behavioral outcomes among target audience respondents. These findings can inform future research to enhance understanding and improve the FNV Campaign as it is expanded to new markets nationwide.

Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas., Author summary Mycobacterial infections cause significant disease burden to humans and animals, the most widely known example being tuberculosis which has killed more humans than any other infectious disease throughout history. Infectious mycobacteria are highly evolved to hijack host processes, including the very immune cells tasked with destroying them. MicroRNAs are host molecules that control wide-ranging programs of host gene expression and are important in the immune response to infections. Here we use the zebrafish model of mycobacterial infection to determine the role of the infection-induced microRNA miR-206 in the host response to infection. We found pathogenic mycobacteria trigger the host to produce more miR-206 in order to suppress the otherwise protective recruitment of neutrophils to sites of infection via the host Cxcl12/Cxcr4 signalling pathway. Our study provides new insight into the role of mycobacterial infection-induced miR-206 function in the context of a whole host.

Introduction Alcohol-related liver disease (ArLD) remains a leading cause of premature mortality in the UK. In 2018/9 there were over 330,000 alcohol-specific hospital admissions and 5600 deaths. Although many of these patients have advanced disease and multiple admissions, there is a lack of data around access to liver transplantation. Method A spot audit of all inpatients with ArLD was performed in 9 hospitals in the South West on a single day in February 2020. Anonymised data was collected using a standardised collection form on patient characteristics and documentation of consideration for transplantation. Result 9 hospitals provided data: 1 tertiary, 2 large acute trusts and 6 district generals. 31 inpatients (20 [65%] male; median age 62 years [IQR 50–70]) were included. None were liver transplant recipients. 11 patients (35%) had alcoholic hepatitis. 90% had decompensation of ArLD: 84% had ascites (15% treated for SBP), 39% hepatic encephalopathy and 13% upper GI bleeding. Median UKELD was 58 (IQR 55–62) and MELD 21.5 (IQR 19–25). 56% had Child Pugh C and 39% Child Pugh B severity. 55% of patients were drinking alcohol at admission. 48% were known to alcohol services. Where data were available (14 cases) median intake of alcohol was 63 units/week (IQR 32–96). In the abstinent group, median duration of abstinence was 6 months (IQR 1.6–12). Only 2 patients (6%) had documentation in the notes of being considered for transplantation (both deemed ‘too early’). 1 patient had been referred for assessment at a transplant unit. There was no documentation in patient records in the remaining 28 patients (90%). In this group, eligibility for transplantation was considered. 19 patients were deemed illegible. Data were not available for 9 patients (figure 1). Conclusion This regional spot audit demonstrates that inpatients with ArLD have advanced disease and suggests that this group is not routinely being considered for liver transplantation. We acknowledge that our data are limited by availability and accuracy of documentation in patient records. Although a small sample size, this represents inpatients in a variety of hospital settings across the whole of the South West. We aim to use this as a pilot for a national audit to evaluate access of ArLD patients to liver transplantation.

Prevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities. After initial colonisation, M. abscessus smooth colony (S) variants can undergo an irreversible genetic switch into highly inflammatory, rough colony (R) variants, often associated with a decline in pulmonary function. Here, we use an adult zebrafish model of chronic infection with R and S variants to study M. abscessus pathogenesis in the context of fully functioning host immunity. We show that infection with an R variant causes an inflammatory immune response that drives necrotic granuloma formation through host TNF signalling, mediated by the tnfa, tnfr1 and tnfr2 gene products. T cell-dependent immunity is stronger against the R variant early in infection, and regulatory T cells associate with R variant granulomas and limit bacterial growth. In comparison, an S variant proliferates to high burdens but appears to be controlled by TNF-dependent innate immunity early during infection, resulting in delayed granuloma formation. Thus, our work demonstrates the applicability of adult zebrafish to model persistent M. abscessus infection, and illustrates differences in the immunopathogenesis induced by R and S variants during granulomatous infection.

This chapter provides an introduction to the European Convention on Human Rights and the Human Rights Act 1998, taking into account the origins of the Convention and the Human Rights Act 1998 and their incorporation into UK legislation; the general principles of European jurisprudence; the Articles and the Protocols themselves; and areas where potential breaches may occur.

Background The Partnership for a Healthier America launched the branded Fruits & Veggies (FNV) Campaign in 2015 to promote fruit and vegetable sales and intake to mothers and teens in two US pilot media market areas: Fresno, California and Hampton Roads, Virginia. Limited evidence is available on the effectiveness of marketing strategies to influence consumers’ fruit and vegetable demand. This cross-sectional study assessed associations between awareness of the FNV Campaign and attitudes, beliefs, intentions, and behaviors related to fruit and vegetable purchases and consumption among targeted audiences from the California and Virginia pilot markets. Methods Data were collected using an online survey between February and July 2017 using a purposive sample (n = 1604) of youth aged 14–20 years (n = 744) and mothers aged 21–36 years (n = 860). Results Approximately 20% (n = 315) of respondents reported awareness of the FNV Campaign. Youth aware of the FNV Campaign (n = 167) reported higher intentions to buy (p = 0.003) and eat (p = 0.009) fruits and vegetables than unaware youth respondents. Mothers aware of the FNV Campaign (n = 148) reported greater encouragement for friends and family to eat fruits and vegetables (p = 0.013) and had approximately 1.5 times higher odds of reporting trying a new fruit or vegetable (p = 0.04) than unaware mothers. Daily fruit and vegetable intake frequency did not differ by Campaign awareness. Conclusions Awareness of the FNV Campaign was associated with limited but positive cognitive and behavioral outcomes among target audience respondents. The present findings can inform future research to enhance understanding and improve effectiveness of FNV Campaign marketing practices as it expands throughout new markets nationwide.

Introduction The risk and benefit of restarting oral anticoagulation (OAC) therapy among patients with atrial fibrillation or flutter (AF) and an episode of anticoagulation-associated intracerebral hemorrhage (ICH) remain unclear. Whether or not to resume OAC after an OAC-associated ICH will remain an unanswered clinical question until we have sufficient data through randomized clinical trials. Here, we analyzed the long-term outcome of patients with AF who did or did not resume OAC after an OAC-associated ICH. Patients and methods We studied consecutive patients with AF who were discharged from our institution after an OAC-associated ICH event between 2010 and 2017. Baseline characteristics of patients, past medical history, and history or OAC use were recorded. Outcome measures in our study included recurrent ICH, ischemic stroke or systemic emboli, and death. Results Out of 115 patients with AF and OAC-associated ICH, 93 patients (mean age 76.2 ± 10.3 years [44–91 years old], 54.3% men) were included in this study. Thirty-eight (40.9%) patients resumed OAC after the episode of OAC-associated ICH. More than 70% of patients had resumed OAC within two months of ICH (mean delay 56.0 ± 52.5 days). There was no significant difference between the group who resumed OAC and the group who did not in terms of mean follow-up duration (1.9 vs. 2.4 years), the type of initial ICH, as well as history of hypertension, diabetes, previous ischemic stroke, congestive heart failure, coronary artery disease, and tobacco use. There was no significant difference between the two groups considering the incidence rate of recurrent ICH (relative risk 2.9; 95% CI, 0.3–30.8). There was also no significant difference between the two groups regarding the incidence rate of ischemic stroke or systemic emboli (relative risk 0.9; 95% CI, 0.3–2.7). There was no significate difference between patients who did and did not resume OAC was 96 and 121 per 1000 patient-years, respectively (relative risk 0.8; 95% CI, 0.3–1.9). Conclusions We did not observe any significant difference between the group of patients who resumed OAC and the patients who did not in terms of recurrent ICH, ischemic stroke or systemic emboli, and death. However, there was a tendency toward a higher long-term risk of recurrent ICH among patients who resumed OAC., Highlights • Outcome of AF patients who did/did not resume OAC after an OAC-ICH was studied. • No significant difference between two groups in terms of recurrent ICH and death. • Tendency toward a higher long-term risk of recurrent ICH in patients who resumed OAC.

Objective: Delay in endovascular reperfusion in patients with acute large-vessel cerebral occlusion decreases the likelihood of functional independence. Given the large contribution of the pre-puncture, in-hospital time period to the overall speed of reperfusion therapy we evaluated the benefits and impediments of utilizing an immediately available OR team to reduce door-to-puncture time compared to a traditional model of an on-call team. Methods: Prospectively collected data were retrospectively analyzed to compare the readiness strategies of 2 comprehensive stroke centers of the Geisinger Health System serving stroke patients in rural and suburban Pennsylvania with different hospital level characteristics: Center A with an in-hospital available operating room team cross-trained in both operating and neuroendovascular procedures and center B with a dedicated on-call neuroendovascular team. Data compared included patient demographics and presentation characteristics, stroke severity, door-to-puncture time, and successful reperfusion ( t test, Fisher exact test, Chi square test). Results: There was no significant difference in the baseline stroke patient characteristics at center A (n=31) and center B (n= 45): 61% vs. 62% females; mean age 72 (range 47 to 93) vs. 69 (range 28 to 96) (p=0.35); admission NIHSS 17 vs 17, respectively. Successful reperfusion (TICI 2b-3) was achieved in 98% and 97% of cases in center A and B, respectively (p=0.79) but door-to-puncture time differed significantly between 50 in center A compared to 121 minutes in center B (58% reduction, p Conclusion: Crossed-training in-hospital operating room staff in neuroendovascular procedures significantly reduces door-to-puncture time in thrombectomy patients when compared to a traditional on-call neuroendovascular call team. Based on existing data, this achievement in earlier reperfusion is expected to translate directly to improve clinical outcome.

The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion.Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and β cell function were measured before and following each stimulus.Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generallyNGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of β cell function.Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/β cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.

To facilitate faster phenotyping of onions (Allium cepa L.), Fourier-transform mid infrared (FT-MIR) spectroscopy with partial least squares (PLS) regression modelling was evaluated for the determination of pungency (pyruvate), sweetness (free sugars) and fructan in juice samples (n = 605) expressed from bulbs from breeding populations.; Results: Fourier-transform infrared (FTIR) spectra (range 1700-900 cm-1 ) were obtained from droplets (30 μL) of unprocessed juice. Goodness-of-fit (r2 ) and prediction errors (standard error of cross validation) for optimal PLS models were: soluble solids (0.997, 0.1 °Brix), pyruvate [0.825, 0.8 μmol g-1 fresh weight (FW)], fructan (0.98, 1.9 mg g-1 FW), glucose (0.941, 1.1 mg g-1 FW), fructose (0.967, 1.0 mg g-1 FW) and sucrose (0.919, 1.7 mg g-1 FW). FTIR models for industry sweetness indices based on glucose or sucrose equivalents were also developed. Because of its very low concentration (0.8-12 μmol g-1 FW) relative to other compounds, pyruvate was the weakest model developed. Fructan could be determined spectroscopically without the need for enzymatic digestion.; Conclusions: All of the chemometric models developed are acceptable for screening purposes. Those for soluble solids, fructan and fructose are also suitable for routine analysis. FT-MIR can therefore be utilised for the simultaneous determination of pungency, sweetness and fructan in this crop. © 2018 Society of Chemical Industry.; © 2018 Society of Chemical Industry.

Insulin is the principal postprandial anabolic hormone and resistance to its action could contribute to sarcopenia. We developed different types of hyperinsulinemic clamp protocols to measure simultaneously glucose and protein metabolism in insulin resistant states (older adults, obesity, diabetes, etc.). To define effects of healthy aging in response to insulin, we employed the hyperinsulinemic, euglycemic and isoaminoacidemic (HYPER-1) clamp. The net whole-body anabolic (protein balance) response to hyperinsulinemia was lower in the elderly vs young (p = 0.007) and was highly correlated with the clamp glucose rate of disposal (r = 0.671, p 0.001), indicating insulin resistance of protein metabolism concurrent with that of glucose. Differences in insulin resistance due to aging were observed predominantly in men, with older ones exhibiting significant lower anabolism compared with young ones. As most of the anabolism occurs during feeding, we studied the fed-state metabolic responses with aging using the hyperinsulinemic, hyperglycemic and hyperaminoacidemic clamp, including muscle biopsies. Older women showed comparable whole-body protein anabolic responses and stimulation of mixed-muscle protein synthesis by feeding to the young. The responses of skeletal muscle insulin signaling through the Akt-mTORC1 pathway were also unaltered, and therefore consistent with muscle protein synthesis results. Given that type 2 diabetes infers insulin resistance of protein metabolism with aging, we studied 10 healthy, 8 obese, and 8 obese type 2 diabetic elderly women using the HYPER-1 clamp. When compared to the group of young lean women to define the effects of obesity and diabetes with aging, whole-body change in net protein balance with hyperinsulinemia was similarly blunted in obese and diabetic older women. However, only elderly obese women with diabetes had lower net balance than lean older women. We conclude that with usual aging, the blunted whole-body anabolic response in elderly subjects is mediated by the failure of insulin to stimulate protein synthesis to the same extent as in the young, especially in men. This blunted response can be overcome at the whole-body and muscle levels during an intravenous fed state supplying a generous amount of protein, in active healthy elderly women. Obese elderly women with and without type 2 diabetes have insulin resistance of protein anabolism at the whole-body level, but this resistance is worsened with diabetes when glucose metabolism is further impaired. More investigation is needed to determine the exact role of insulin in promoting anabolism with aging. The findings from our group are relevant for the field of sarcopenia research as they provide a rationale to offer low cost nutritional interventions for overcoming this detrimental condition associated with aging and diabetes.

Copyright © 2019 American Society for Microbiology. All Rights Reserved. Paratuberculosis and bovine tuberculosis are two mycobacterial diseases of ruminants which have a considerable impact on livestock health, welfare, and production. These are chronic "iceberg" diseases which take years to manifest and in which many subclinical cases remain undetected. Suggested biomarkers to detect infected or diseased animals are numerous and include cytokines, peptides, and expression of specific genes; however, these do not provide a strong correlation to disease. Despite these advances, disease detection still relies heavily on dated methods such as detection of pathogen shedding, skin tests, or serology. Here we review the evidence for suitable biomarkers and their mechanisms of action, with a focus on identifying animals that are resilient to disease. A better understanding of these factors will help establish new strategies to control the spread of these diseases.

This chapter deals with inheritance tax (IHT). It explains the charge to IHT; potentially exempt transfers (PETs); the transfer of value on death; the occasions to tax; the charge to tax and a lifetime chargeable transfer (LCT); the charge to tax and a LCT where the transferor dies within seven years of the LCT; the charge to tax and a PET; the charge to tax and death; gifts subject to a reservation; liability, burden, and payment of tax; and tax planning.

This chapter begins with a description of how the legal services market is undergoing change, with the Solicitors Regulation Authority’s (SRA) code of conduct, referred to as the outcomes-focused regulation code (OFR Code), being replaced by the SRA Standards and Regulations (‘Standards and Regulations’). It considers what being a member of the profession and a good solicitor means, the Handbook, the regulations of the OFR Code currently in force, and the proposed changes expected when the Standards and Regulations come into force. It then looks at the practical application of the principles, outcomes, and indicative behaviours which are most relevant to readers at this stage of their legal career as a student and trainee.

Foundations for the LPC covers the compulsory foundation areas of the Legal Practice Course as set out in the LPC Outcomes: Professional Conduct, Tax/Revenue Law, and Wills and Administration of Estates. The volume also features content on human rights law. The volume uses worked examples and scenarios throughout to illustrate key points. To aid understanding and test comprehension of the core material, checkpoints and summaries feature in every chapter. The book covers topics such as professional conduct (including financial services and money laundering), revenue law (including income tax, capital gains tax, VAT, corporation tax, and inheritance tax), wills and administration of estates, and issues related to human rights.

All companies incorporated in the UK which actively carry on business are liable to pay corporation tax (CT) on their taxable profits. This chapter considers the charge to CT with particular focus on calculating chargeable income profits and allowable deductions; the treatment of company capital gains and capital losses; trading loss relief; capital allowances; and close companies.

Income tax is an essential part of a lawyer’s knowledge and professional training. Whilst it is not necessary to have knowledge to the extent that a specialist tax lawyer would have, it is necessary to have knowledge and understanding sufficient to recognise its implications as they arise and affect the client and ourselves. This chapter discusses sources of income tax law; collection and payment of income tax; rates of income tax and allowances; calculation of income tax; sources of taxable income; and charitable giving. This chapter covers the changes introduced by the Autumn 2017 Budget.

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, pInterpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.Funding: UK National Institute for Health Research, Health Technology Assessment Programme.