Impact of Population Based Indoor Residual Spraying with and without Mass Drug Administration with Dihydroartemisinin-Piperaquine on Malaria Prevalence in a High Transmission Setting: A Quasi-Experimental Controlled Before-and-After Trial in Northeastern Uganda

Background: Declines in malaria burden in Uganda have slowed. Modelling predicts that indoor residual spraying (IRS) and mass drug administration (MDA), when co-timed, have synergistic impact. This study investigated additional protective impact of population-based MDA on malaria prevalence, if any, when added to IRS, as compared with IRS alone and with standard of care (SOC). Methods: The 32-month quasi-experimental controlled before-and-after trial enrolled an open cohort of residents (46,765 individuals, 1st enumeration and 52,133, 4th enumeration) of Katakwi District in northeastern Uganda. Consented participants were assigned to three arms based on residential subcounty at study start: MDA+IRS, IRS, SOC. IRS with pirimiphos methyl and MDA with dihydroartemisinin- piperaquine were delivered in 4 co-timed campaign-style rounds 8 months apart. The primary endpoint was population prevalence of malaria, estimated by 6 cross-sectional surveys, starting at baseline and preceding each subsequent round. Results: Comparing malaria prevalence in MDA+IRS and IRS only arms over all 6 surveys (intention-to-treat analysis), roughly every 6 months post-interventions, a geostatistical model found a significant additional 15.5% (95% confidence interval (CI): [13.7%, 17.5%], Z = 9.6, p = 5e−20) decrease in the adjusted odds ratio (aOR) due to MDA for all ages, a 13.3% reduction in under 5’s (95% CI: [10.5%, 16.8%], Z = 4.02, p = 5e−5), and a 10.1% reduction in children 5–15 (95% CI: [8.5%, 11.8%], Z = 4.7, p = 2e−5). All ages residents of the MDA + IRS arm enjoyed an overall 80.1% reduction (95% CI: [80.0%, 83.0%], p = 0.0001) in odds of qPCR confirmed malaria compared with SOC residents. Secondary difference-in-difference analyses comparing surveys at different timepoints to baseline showed aOR (MDA + IRS vs IRS) of qPCR positivity between 0.28 and 0.66 (p \u3c 0.001). Of three serious adverse events, one (nonfatal) was considered related to study medications. Limitations include the initial non-random assignment of study arms, the single large cluster per arm, and the lack of an MDA-only arm, considered to violate equipoise. Conclusions: Despite being assessed at long time points 5–7 months post-round, MDA plus IRS provided significant additional protection from malaria infection over IRS alone. Randomized trials of MDA in large areas undergoing IRS recommended as well as cohort studies of impact on incidence

Detection of benzimidazole carbamates and amino metabolites in liver by surface plasmon resonance-biosensor

This research was funded by the Irish Department of Agriculture, Fisheries and Food under the Food Institutional Research Measure as part of the National Development Plan (Project 05/R&D/TN/355)peer-reviewedTwo surface plasmon resonance (SPR) biosensor screening assays were developed and validated to detect 11 benzimidazole carbamate (BZT) and four amino-benzimidazole veterinary drug residues in liver tissue. The assays used polyclonal antibodies, raised in sheep, to detect BZTs and amino-benzimidazoles. A modified Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) extraction method was developed to isolate benzimidazole carbamate residues. Liver samples were extracted using an acetonitrile extraction method. BZTs were purified by dispersive solid phase extraction (d-SPE) using C18 sorbent. Residues of amino-benzimidazoles were effectively cleaned-up using a simple cyclohexane defatting step. The assays were validated in accordance with the performance criteria described in 2002/657/EC. The BZT assay limit of detection was calculated to be 32 μg kg−1, the detection capability (CCβ) was determined to be 50 μg kg−1 and the mean recovery of analytes was in the range 77–132%. The amino-benzimidazole assay limit of detection was determined to be 41 μg kg−1, the CCβ was determined to be 75 μg kg−1 and analyte recovery was in the range 103–116%. Biosensor assay performance was tested by analysing liver tissue from animals treated with benzimidazole drugs and comparing the results with an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) confirmatory method. All non-compliant samples were identified using the biosensor assays.Department of Agriculture, Food and the Marin

Pharmacist-led management of chronic pain in primary care:results from a randomised controlled exploratory trial

To compare the effectiveness of pharmacist medication review, with or without pharmacist prescribing, with standard care, for patients with chronic pain

Boundary of oxidative and overflow metabolism (boom) controller for CHO cell feed control

There is limited literature for CHO cell cultures with low batch glucose concentrations (Gowtham et al. 2017; Lu et al. 2005; Wong et al. 2005). Work like Xu et al. (2016) and Berry et al. (2016) have shown positive results for controlled fed-batch cultures at low glucose concentrations following standard high glucose (5-6 g/L) batch cultures. However, the Xu et al. (2016) and Berry et al. (2016) approaches still accumulate lactate. Controlling glucose earlier could potentially avoid lactate accumulation and lead to even greater improvements in culture outcomes. The objective of this project was to develop an advanced feed controller for CHO cell cultures that maximizes cell growth by maintaining the culture in a state of maximal oxidative metabolism while minimizing overflow metabolism. The Boundary of Oxidative and Overflow Metabolism (BOOM) controller periodically manipulates the feed rate while monitoring online signals to gauge the remaining oxidative “space”, in order to decide whether feed can be increased while remaining in oxidative metabolism. The Oxygen Uptake Rate (OUR) is the primary signal of interest, since it plateaus when a culture shifts from oxidative to overflow metabolism, encoding vital information about metabolic state. This project’s approach is different from past work in that the batch glucose concentrations is much lower (on the order of 1 g/L), the glucose and/or glutamine feeding begins very early in the process, and glucose feed is triggered/controlled by the off-gas sensing of the metabolic state instead of a targeted glucose concentration. During early runs several chemistry effects were observed directly due to the bolus feed additions interfering with the media-dissolved gas equilibrium. For example, a bolus feed that only contained 5 mM bicarbonate, resulted in an observed short sharp decrease in CO2 off-gas as the feed absorbed CO2 from the 5% CO2 sparge gas. Continuous feeding was introduced in subsequent runs as a means to mitigate disrupting the media-dissolved gas-equilibrium and disturbing the off-gas sensing. In order to have effective continuous feeding, the feed pump used a pulse width modulation (PWM) with a 10-minute period to allow extremely low effective feed rates required for the 1-L vessel. Two runs were used to demonstrate that the PWM feed pump could provide these very low pump feed rates for the 1-L vessel containing as little as 500 mL media. Initial glucose concentrations between 0.6 to 2.0 g/L were used (compared to 8 g/L glucose in the standard media formulation). Feedings have started between 6- and 20-hour post-inoculation. Distinct qualitative and quantitative differences have been observed in the corresponding oxygen uptake rate (OTR) responses due to the feeding spikes, suggesting that metabolic state can be detected. The development of the state estimator to control glucose feeding will be presented

Player migration and opportunity: examining the efficacy of the UEFA home-grown rule in six European football leagues.

The introduction of UEFAs home-grown rule occurred for the start of the 2006–2007 season with the full quota in place from the 2008–2009 season, which imposed quotas on European clubs. From 2008, clubs are required to have at least 8 players classified as home-grown in the 25-player squad, up from 4 in 2006–2007 and 6 in 2007–2008. This study examines the efficacy of this rule across the six major European leagues (England, France, Germany, Holland, Italy and Spain) in relation to playing opportunities (minutes played and appearances) between 1999 and 2015. This was also examined in relation to age. Since the home-grown rule was introduced for the six nations hosting the major leagues, the rule had different impacts by nationality. Only Germany saw significant increases in the proportion of minutes played by their players when comparing the periods before and after the home-grown rules were imposed. Holland, albeit seeing a slight decrease overall, saw significant increases for playing time for under 21s and 22- to 25-year olds. England and Italy were the two nations where statistically significant decreases in indigenous playing opportunities were recorded since the home-grown rules were introduced

Use of a cAMP BRET Sensor to Characterize a Novel Regulation of cAMP by the Sphingosine 1-Phosphate/G13 Pathway

Regulation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP) is integral in mediating cell growth, cell differentiation, and immune responses in hematopoietic cells. To facilitate studies of cAMP regulation we developed a BRET (bioluminescence resonance energy transfer) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc), which can quantitatively and rapidly monitor intracellular concentrations of cAMP in vivo. This sensor was used to characterize three distinct pathways for modulation of cAMP synthesis stimulated by presumed Gs-dependent receptors for isoproterenol and prostaglandin E2. Whereas two ligands, uridine 5'-diphosphate and complement C5a, appear to use known mechanisms for augmentation of cAMP via Gq/calcium and Gi, the action of sphingosine 1-phosphate (S1P) is novel. In these cells, S1P, a biologically active lysophospholipid, greatly enhances increases in intracellular cAMP triggered by the ligands for Gs-coupled receptors while having only a minimal effect by itself. The enhancement of cAMP by S1P is resistant to pertussis toxin and independent of intracellular calcium. Studies with RNAi and chemical perturbations demonstrate that the effect of S1P is mediated by the S1P2 receptor and the heterotrimeric G13 protein. Thus in these macrophage cells, all four major classes of G proteins can regulate intracellular cAMP