Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

OCCUPATIONAL HEALTH SURVEY OF LAGOS AND BENDEL STATES IN THE FEDERAL REPUBLIC OF NIGERIA.

Abstract not availabl

Pictet–Spengler reactions of oxetan-3-ones and related heterocycles

Pictet–Spengler reactions of oxetan-3-ones and azetidin-3-ones with tryptamine and tryptophan derivatives produce spirocyclic tetrahydro-β-carbolines in good yields. Molecular iodine (5 mol %) is an effective catalyst in most cases and high levels of diastereoselectivity are witnessed using 2-substituted oxetan-3-ones

The Pharmacological Inhibition of CaMKII Regulates Sodium Chloride Cotransporter Activity in mDCT15 Cells

The thiazide-sensitive sodium chloride cotransporter (NCC) in the distal convoluted tubule is responsible for reabsorbing up to one-tenth of the total filtered load of sodium in the kidney. The actin cytoskeleton is thought to regulate various transport proteins in the kidney but the regulation of the NCC by the actin cytoskeleton is largely unknown. Here, we identify a direct interaction between the NCC and the cytoskeletal protein filamin A in mouse distal convoluted tubule (mDCT15) cells and in the native kidney. We show that the disruption of the actin cytoskeleton by two different mechanisms downregulates NCC activity. As filamin A is a substrate of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), we investigate the physiological significance of CaMKII inhibition on NCC luminal membrane protein expression and NCC activity in mDCT15 cells. The pharmacological inhibition of CaMKII with the compound KN93 increases the active form of the NCC (phospho-NCC) at the luminal membrane and also increases NCC activity in mDCT15 cells. These data suggest that the interaction between the NCC and filamin A is dependent on CaMKII activity, which may serve as a feedback mechanism to maintain basal levels of NCC activity in the distal nephron

Spatial-Temporal Patterns of Ambient Fine Particulate Matter (PM 2.5) and Black Carbon (BC) Pollution in Accra

Sub-Saharan Africa (SSA) is rapidly urbanizing, and ambient air pollution has emerged as a major environmental health concern in growing cities. Yet, effective air quality management is hindered by limited data. We deployed robust, low-cost and low-power devices in a large-scale measurement campaign and characterized within-city variations in fine particulate matter (PM2.5) and black carbon (BC) pollution in Accra, Ghana. Between April 2019 and June 2020, we measured weekly gravimetric (filter-based) and minute-by-minute PM2.5 concentrations at 146 unique locations, comprising of 10 fixed (similar to 1 year) and 136 rotating (7 day) sites covering a range of land-use and source influences. Filters were weighed for mass, and light absorbance (10(-5)m(-1)) of the filters was used as proxy for BC concentration. Year-long data at four fixed sites that were monitored in a previous study (2006-2007) were compared to assess changes in PM2.5 concentrations. The mean annual PM2.5 across the fixed sites ranged from 26 mu g m(-3) at a peri-urban site to 43 mu g m(-3) at a commercial, business, and industrial (CBI) site. CBI areas had the highest PM2.5 levels (mean: 37 mu g m(-3)), followed by high-density residential neighborhoods (mean: 36 mu g m(-3)), while peri-urban areas recorded the lowest (mean: 26 mu g m(-3)). Both PM2.5 and BC levels were highest during the dry dusty Harmattan period (mean PM2.5: 89 mu g m(-3)) compared to non-Harmattan season (mean PM2.5: 23 mu g m(-3)). PM2.5 at all sites peaked at dawn and dusk, coinciding with morning and evening heavy traffic. We found about a 50% reduction (71 vs 37 mu g m(-3)) in mean annual PM2.5 concentrations when compared to measurements in 2006-2007 in Accra. Ambient PM2.5 concentrations in Accra may have plateaued at levels lower than those seen in large Asian megacities. However, levels are still 2- to 4-fold higher than the WHO guideline. Effective and equitable policies are needed to reduce pollution levels and protect public health

Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells

Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in >70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype. CONCLUSION: The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment

What You See Is What You Breathe? Estimating Air Pollution Spatial Variation Using Street-Level Imagery

High spatial resolution information on urban air pollution levels is unavailable in many areas globally, partially due to the high input data needs of existing estimation approaches. We introduced a computer vision method to estimate annual means for air pollution levels from street-level images. We used annual mean estimates of NO2 and PM2.5 concentrations from locally calibrated models as labels from London, New York, and Vancouver to allow for compilation of a sufficiently large dataset (similar to 250 k images for each city). Our experimental setup is designed to quantify intra- and intercity transferability of image-based model estimates. Performances were high and comparable to traditional land-use regression (LUR) and dispersion models when training and testing images from the same city (R-2 values between 0.51 and 0.95 when validated on data from ground monitoring stations). Similar to LUR models, transferability of models between cities in different geographies is more difficult. Specifically, transferability between the three cities (London, New York, and Vancouver), which have similar pollution source profiles, was moderately successful (R-2 values between zero and 0.67). Comparatively, performances when transferring models trained on cities with very different source profiles, such as Accra in Ghana and Hong Kong, were lower (R-2 between zero and 0.21). This suggests a need for local calibration, using additional measurement data from cities that share similar source profiles.ISSN:2072-429