Are Tanzanian patients attending public facilities or private retailers more likely to adhere to artemisinin-based combination therapy?

BACKGROUND: Artemisinin combination therapy (ACT) is first-line treatment for malaria in most endemic countries and is increasingly available in the private sector. Most studies on ACT adherence have been conducted in the public sector, with minimal data from private retailers. METHODS: Parallel studies were conducted in Tanzania, in which patients obtaining artemether-lumefantrine (AL) at 40 randomly selected public health facilities and 37 accredited drug dispensing outlets (ADDOs) were visited at home and questioned about doses taken. The effect of sector on adherence, controlling for potential confounders was assessed using logistic regression with a random effect for outlet. RESULTS: Of 572 health facility patients and 450 ADDO patients, 74.5% (95% CI: 69.8, 78.8) and 69.8% (95% CI: 64.6, 74.5), respectively, completed treatment and 46.0% (95% CI: 40.9, 51.2) and 34.8% (95% CI: 30.1, 39.8) took each dose at the correct time ('timely completion'). ADDO patients were wealthier, more educated, older, sought care later in the day, and were less likely to test positive for malaria than health facility patients. Controlling for patient characteristics, the adjusted odds of completed treatment and of timely completion for ADDO patients were 0.65 (95% CI: 0.43, 1.00) and 0.69 (95% CI: 0.47, 1.01) times that of health facility patients. Higher socio-economic status was associated with both adherence measures. Higher education was associated with completed treatment (adjusted OR = 1.68, 95% CI: 1.20, 2.36); obtaining AL in the evening was associated with timely completion (adjusted OR = 0.35, 95% CI: 0.19, 0.64). Factors associated with adherence in each sector were examined separately. In both sectors, recalling correct instructions was positively associated with both adherence measures. In health facility patients, but not ADDO patients, taking the first dose of AL at the outlet was associated with timely completion (adjusted OR = 2.11, 95% CI: 1.46, 3.04). CONCLUSION: When controlling for patient characteristics, there was some evidence that the adjusted odds of adherence for ADDO patients was lower than that for public health facility patients. Better understanding is needed of which patient care aspects are most important for adherence, including the role of effective provision of advice

A porcine model of heart failure with preserved ejection fraction:magnetic resonance imaging and metabolic energetics

Aims A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. Methods and results Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P <0.001, and two-fold increase in mass compared to sham control, P <0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P <0.05-P <0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. Conclusions Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies.

Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9-11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4).\ud Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops

Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance

The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β−catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β−catenin-driven malignancies

Neural and behavioral traces of error awareness

Monitoring for errors and behavioral adjustments after errors are essential for daily life. A question that has not been addressed systematically yet, is whether consciously perceived errors lead to different behavioral adjustments compared to unperceived errors. Our goal was to develop a task that would enable us to study different commonly observed neural correlates of error processing and post-error adjustments in their relation to error awareness and accuracy confidence in a single experiment. We assessed performance in a new number judgement error awareness task in 70 participants. We used multiple, robust, single-trial EEG regressions to investigate the link between neural correlates of error processing (e.g., error-related negativity (ERN) and error positivity (Pe)) and error awareness. We found that only aware errors had a slowing effect on reaction times in consecutive trials, but this slowing was not accompanied by post-error increases in accuracy. On a neural level, error awareness and confidence had a modulating effect on both the ERN and Pe, whereby the Pe was most predictive of participants’ error awareness. Additionally, we found partial support for a mediating role of error awareness on the coupling between the ERN and behavioral adjustments in the following trial. Our results corroborate previous findings that show both an ERN/Pe and a post-error behavioral adaptation modulation by error awareness. This suggests that conscious error perception can support meta-control processes balancing the recruitment of proactive and reactive control. Furthermore, this study strengthens the role of the Pe as a robust neural index of error awareness

Alcohol-Related Context Modulates Performance of Social Drinkers in a Visual Go/No-Go Task: A Preliminary Assessment of Event-Related Potentials

Background Increased alcohol cue-reactivity and altered inhibitory processing have been reported in heavy social drinkers and alcohol-dependent patients, and are associated with relapse. In social drinkers, these two processes have been usually studied separately by recording event-related potentials (ERPs) during rapid picture presentation. The aim of our study was to confront social drinkers to a task triggering high alcohol cue-reactivity, to verify whether it specifically altered inhibitory performance, by using long-lasting background picture presentation. Methods ERP were recorded during visual Go/No-Go tasks performed by social drinkers, in which a frequent Go signal (letter “M”), and a rare No-Go signal (letter “W”) were superimposed on three different types of background pictures: neutral (black background), alcohol-related and non alcohol-related. Results Our data suggested that heavy social drinkers made more commission errors than light drinkers, but only in the alcohol-related context. Neurophysiologically, this was reflected by a delayed No-Go P3 component. Conclusions Elevated alcohol cue-reactivity may lead to poorer inhibitory performance in heavy social drinkers, and may be considered as an important vulnerability factor in developing alcohol misuse. Prevention programs should be designed to decrease the high arousal of alcohol stimuli and strengthen cognitive control in young, at-risk individuals.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Aims/hypothesis: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. Methods: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case–control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30–75 ml min−1 [1.73 m]−2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. Results: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. Conclusions/interpretation: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30–75 ml min−1 [1.73 m]−2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers

Essential and unique roles of PIP5K-γ and -α in Fcγ receptor-mediated phagocytosis

The actin cytoskeleton is dynamically remodeled during Fcγ receptor (FcγR)-mediated phagocytosis in a phosphatidylinositol (4,5)-bisphosphate (PIP2)-dependent manner. We investigated the role of type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) γ and α isoforms, which synthesize PIP2, during phagocytosis. PIP5K-γ−/− bone marrow–derived macrophages (BMM) have a highly polymerized actin cytoskeleton and are defective in attachment to IgG-opsonized particles and FcγR clustering. Delivery of exogenous PIP2 rescued these defects. PIP5K-γ knockout BMM also have more RhoA and less Rac1 activation, and pharmacological manipulations establish that they contribute to the abnormal phenotype. Likewise, depletion of PIP5K-γ by RNA interference inhibits particle attachment. In contrast, PIP5K-α knockout or silencing has no effect on attachment but inhibits ingestion by decreasing Wiskott-Aldrich syndrome protein activation, and hence actin polymerization, in the nascent phagocytic cup. In addition, PIP5K-γ but not PIP5K-α is transiently activated by spleen tyrosine kinase–mediated phosphorylation. We propose that PIP5K-γ acts upstream of Rac/Rho and that the differential regulation of PIP5K-γ and -α allows them to work in tandem to modulate the actin cytoskeleton during the attachment and ingestion phases of phagocytosis