Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis:selecting patients for controlled trials of neutrophil elastase inhibition

Background Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. Methods We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for “personalised medicine”. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). Results All three assays showed a high degree of day-to-day variability (0–233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into “high” or “low” groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI −6.0–29.0), sputum colour (β-estimate 10.4, 95% CI 4.3–16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4–11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4–5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for “high” NE (98.7%, 95% CI 7.0–99.6%). Conclusion These results show that patients with bronchiectasis and CF can be effectively divided into “high” or “low” groups, based on sputum NE assays or clinical inclusion criteria

A inovação aberta no processo de internacionalização de empresas: estudo de caso da Brasil Foods

TCC (graduação) - Universidade Federal de Santa Catarina. Centro Sócio-Econômico. Relações Internacionais.A presente monografia tem como objetivo o estudo do papel da inovação aberta no processo de internacionalização de empresas, a partir da revisão teórica dos conceitos na literatura e de um estudo de caso real de uma empresa brasileira de grande porte: a Brasil Foods. A presente pesquisa possui caráter de pesquisa exploratória. Para desenvolver o objetivo principal, o trabalho apresenta três objetivos específicos, que são: primeiro apresentar o conceito de inovação, seus graus de inserção e destacar a sua relevância no setor empresarial; segundo apresentar o conceito de inovação aberta e de inovação fechada e esclarecer a importância da difusão de informações; e, terceiro, apresentar os aspectos históricos da internacionalização de empresas, introduzindo duas teorias do processo: Modelo de Uppsala e Perspectiva de Networks. Assim, pode-se exibir, portanto, um modelo conceitual às relações entre as atividades de inovação aberta e a internacionalização de empresas em redes, levandose em consideração que a gestão de inovação nas empresas, atualmente, transcende a visão de inovação tecnológica, e, as redes internacionais ganham cada vez mais relevância como vantagem competitiva nas empresas ao atuar em mercados exteriores. Como resultado, concluiu-se que as estratégias de internacionalização de empresas em redes e as estratégias de inovação aberta, quando empregadas juntas, aumentam a velocidade de aprendizagem organizacional da Brasil Foods, acelerando os processos de internacionalização, confirmando que a inovação aberta estimula e intensifica a internacionalização de empresas que trabalham em redes

Mu opioid receptors on vGluT2‐expressing glutamatergic neurons modulate opioid reward

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward

Chikungunya seroprevalence, force of infection, and prevalence of chronic disability after infection in endemic and epidemic settings: a systematic review, meta-analysis, and modelling study.

BACKGROUND: Chikungunya is an arboviral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes with a growing global burden linked to climate change and globalisation. We aimed to estimate chikungunya seroprevalence, force of infection (FOI), and prevalence of related chronic disability and hospital admissions in endemic and epidemic settings. METHODS: In this systematic review, meta-analysis, and modelling study, we searched PubMed, Ovid, and Web of Science for articles published from database inception until Sept 26, 2022, for prospective and retrospective cross-sectional studies that addressed serological chikungunya virus infection in any geographical region, age group, and population subgroup and for longitudinal prospective and retrospective cohort studies with data on chronic chikungunya or hospital admissions in people with chikungunya. We did a systematic review of studies on chikungunya seroprevalence and fitted catalytic models to each survey to estimate location-specific FOI (ie, the rate at which susceptible individuals acquire chikungunya infection). We performed a meta-analysis to estimate the proportion of symptomatic patients with laboratory-confirmed chikungunya who had chronic chikungunya or were admitted to hospital following infection. We used a random-effects model to assess the relationship between chronic sequelae and follow-up length using linear regression. The systematic review protocol is registered online on PROSPERO, CRD42022363102. FINDINGS: We identified 60 studies with data on seroprevalence and chronic chikungunya symptoms done across 76 locations in 38 countries, and classified 17 (22%) of 76 locations as endemic settings and 59 (78%) as epidemic settings. The global long-term median annual FOI was 0·007 (95% uncertainty interval [UI] 0·003-0·010) and varied from 0·0001 (0·00004-0·0002) to 0·113 (0·07-0·20). The highest estimated median seroprevalence at age 10 years was in south Asia (8·0% [95% UI 6·5-9·6]), followed by Latin America and the Caribbean (7·8% [4·9-14·6]), whereas median seroprevalence was lowest in the Middle East (1·0% [0·5-1·9]). We estimated that 51% (95% CI 45-58) of people with laboratory-confirmed symptomatic chikungunya had chronic disability after infection and 4% (3-5) were admitted to hospital following infection. INTERPRETATION: We inferred subnational heterogeneity in long-term average annual FOI and transmission dynamics and identified both endemic and epidemic settings across different countries. Brazil, Ethiopia, Malaysia, and India included both endemic and epidemic settings. Long-term average annual FOI was higher in epidemic settings than endemic settings. However, long-term cumulative incidence of chikungunya can be similar between large outbreaks in epidemic settings with a high FOI and endemic settings with a relatively low FOI. FUNDING: International Vaccine Institute

The positions of primary and secondary schools in the English school field: a case of durable inequality

In interviews as part of a research study of structural reform in England, some tension between primary head teachers and their secondary peers was evident. This was symptomatic of a long-standing difference in status between the two phases. At a time when relations between stakeholders in local systems are subject to change, we seek to understand anew why that might be the case and how the tension we found was evidence of a current difference of power within interactions between representatives of the phases. We analyse differences of size, resources, workforce, pedagogy and history, and how they have resulted in different, and differently valued, practices and professional identities. We explore how attributes of the two phases have been counterposed and how, in complex interaction with wider discourses of politics, gender and age, this process has invested the differences with meanings and values that tend to relegate attributes associated with primary school. By focusing on the activation of cumulative inequality in interactions, we contribute a complementary perspective to studies of perceived relative status and highlight the implications for understanding school positioning in local arenas as the role of local authorities is reduced