Representative bureaucracy: does female police leadership affect gender-based violence arrests?

Representative bureaucracy theory postulates that passive representation leads to active representation of minority groups. This article investigates the passive representation of female police officers at leadership levels and the active representation of women vis-a-vis gender-based violence arrest rates in the UK. Much of the extant research on representative bureaucracy is located at street level, with evidence showing that discretionary power of minority bureaucrats can lead to active representation. This article is focused on leadership levels of a public bureaucracy. The empirical research is based upon a panel dataset of female police officers as an independent variable and gender-based violence arrest rates as a dependent variable. The analysis reveals that there is little evidence of active representation of women by female police leadership

Intracranial internal carotid aneurysm causing diplopia

Internal carotid intracranial aneurysms are a relatively rare form of intracranial aneurysm that presents with diplopia, retro-orbital pain and unilateral headaches. The symptoms are progressive and the diagnosis should be considered in a patient presenting with these complaints. Underlying hypertension and advanced age are specific risk factors

Diabetes incidence and prevalence in Hong Kong, China during 2006-2014

postprin

Natalizumab in acute ischemic stroke (ACTION II): a randomized, placebo-controlled trial

OBJECTIVE: We evaluated the effect of two doses of natalizumab on functional outcomes in acute ischemic stroke (AIS) patients. METHODS: In this double-blind phase 2b trial, AIS patients aged 18-80 years with National Institutes of Health Stroke Scale scores of 5-23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg intravenous natalizumab or placebo, with randomization stratified by treatment window (≤9 or >9 to ≤24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score ≤1 and Barthel Index score ≥95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model; p values were not used for hypothesis testing. RESULTS: An excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 mg or 600 mg odds ratio 0.60; 95% confidence interval 0.39-0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90%, 92%, and 92%, respectively), serious adverse events (26%, 33%, and 21%, respectively), or deaths (7%, 5%, and 6%, respectively). CONCLUSIONS: Natalizumab administered ≤24 hours after AIS did not improve patient outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02730455 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo

Legacy Metal Contaminants and Excess Nutrients in Low Flow Estuarine Embayments Alter Composition and Function of Benthic Bacterial Communities.

Coastal systems such as estuaries are threatened by multiple anthropogenic stressors worldwide. However, how these stressors and estuarine hydrology shape benthic bacterial communities and their functions remains poorly known. Here, we surveyed sediment bacterial communities in poorly flushed embayments and well flushed channels in Sydney Harbour, Australia, using 16S rRNA gene sequencing. Sediment samples were collected monthly during the Austral summer-autumn 2014 at increasing distance from a large storm drain in each channel and embayment. Bacterial communities differed significantly between sites that varied in proximity to storm drains, with a gradient of change apparent for sites within embayments. We explored this pattern for embayment sites with analysis of RNA-Seq gene expression patterns and found higher expression of multiple genes involved in bacterial stress response far from storm drains, suggesting that bacterial communities close to storm drains may be more tolerant of localised anthropogenic stressors. Several bacterial groups also differed close to and far from storm drains, suggesting their potential utility as bioindicators to monitor contaminants in estuarine sediments. Overall, our study provides useful insights into changes in the composition and functioning of benthic bacterial communities as a result of multiple anthropogenic stressors in differing hydrological conditions

A novel real-world ecotoxicological dataset of pelagic microbial community responses to wastewater.

Real-world observational datasets that record and quantify pressure-stressor-response linkages between effluent discharges and natural aquatic systems are rare. With global wastewater volumes increasing at unprecedented rates, it is urgent that the present dataset is available to provide the necessary information about microbial community structure and functioning. Field studies were performed at two time-points in the Austral summer. Single-species and microbial community whole effluent toxicity (WET) testing was performed at a complete range of effluent concentrations and two salinities, with accompanying environmental data to provide new insights into nutrient and organic matter cycling, and to identify ecotoxicological tipping points. The two salinity regimes were chosen to investigate future scenarios based on a predicted salinity increase at the study site, typical of coastal regions with rising sea levels globally. Flow cytometry, amplicon sequencing of 16S and 18S rRNA genes and micro-fluidic quantitative polymerase-chain reactions (MFQPCR) were used to determine chlorophyll-a and total bacterial cell numbers and size, as well as taxonomic and functional diversity of pelagic microbial communities. This strong pilot dataset could be replicated in other regions globally and would be of high value to scientists and engineers to support the next advances in microbial ecotoxicology, environmental biomonitoring and estuarine water quality modelling

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

Prognostic value of the ABCD2 score beyond short-term follow-up after transient ischemic attack (TIA) - a cohort study

<p>Abstract</p> <p>Background</p> <p>Transient ischemic attack (TIA) patients are at a high vascular risk. Recently the ABCD²score was validated for evaluating short-term stroke risk after TIA. We assessed the value of this score to predict the vascular outcome after TIA during medium- to long-term follow-up.</p> <p>Methods</p> <p>The ABCD²score of 176 TIA patients consecutively admitted to the Stroke Unit was retrospectively calculated and stratified into three categories. TIA was defined as an acute transient focal neurological deficit caused by vascular disease and being completely reversible within 24 hours. All patients had to undergo cerebral MRI within 5 days after onset of symptoms as well as extracranial and transcranial Doppler and duplex ultrasonography. At a median follow-up of 27 months, new vascular events were recorded. Multivariate Cox regression adjusted for EDC findings and heart failure was performed for the combined endpoint of cerebral ischemic events, cardiac ischemic events and death of vascular or unknown cause.</p> <p>Results</p> <p>Fifty-five patients (32.0%) had an ABCD²score ≤ 3, 80 patients (46.5%) had an ABCD2 score of 4-5 points and 37 patients (21.5%) had an ABCD²score of 6-7 points. Follow-up data were available in 173 (98.3%) patients. Twenty-two patients (13.8%) experienced an ischemic stroke or TIA; 5 (3.0%) a myocardial infarction or acute coronary syndrome; 10 (5.7%) died of vascular or unknown cause; and 5 (3.0%) patients underwent arterial revascularization. An ABCD²score > 3 was significantly associated with the combined endpoint of cerebral or cardiovascular ischemic events, and death of vascular or unknown cause (hazard ratio (HR) 4.01, 95% confidence interval (CI) 1.21 to 13.27). After adjustment for extracranial ultrasonographic findings and heart failure, there was still a strong trend (HR 3.13, 95% CI 0.94 to 10.49). Whereas new cardiovascular ischemic events occurred in 9 (8.3%) patients with an ABCD²score > 3, this happened in none of the 53 patients with a score ≤ 3.</p> <p>Conclusions</p> <p>An ABCD²score > 3 is associated with an increased general risk for vascular events in the medium- to long-term follow-up after TIA.</p

Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials".

Pharmacolog