197 research outputs found
Multidimensional population activity in an electrically coupled inhibitory circuit in the cerebellar cortex
Inhibitory neurons orchestrate the activity of excitatory neurons and play key roles in circuit function. Although individual interneurons have been studied extensively, little is known about their properties at the population level. Using random-access 3D two-photon microscopy, we imaged local populations of cerebellar Golgi cells (GoCs), which deliver inhibition to granule cells. We show that population activity is organized into multiple modes during spontaneous behaviors. A slow, network-wide common modulation of GoC activity correlates with the level of whisking and locomotion, while faster (<1 s) differential population activity, arising from spatially mixed heterogeneous GoC responses, encodes more precise information. A biologically detailed GoC circuit model reproduced the common population mode and the dimensionality observed experimentally, but these properties disappeared when electrical coupling was removed. Our results establish that local GoC circuits exhibit multidimensional activity patterns that could be used for inhibition-mediated adaptive gain control and spatiotemporal patterning of downstream granule cells
Sulfonated copolymers as heparin-mimicking stabilizer of fibroblast growth factor : size, architecture, and monomer distribution effects
Fibroblast growth factors (FGF) are involved in a wide range of biological processes such as cell proliferation and differentiation. In living organisms, the binding of FGF to its receptors are mediated through electrostatic interactions between FGF and naturally occurring heparin. Despite its prevalent use in medicine, heparin carries notable limitations, namely; its extraction from natural sources (expensive, low yield and extensive purification), viral contamination, and batch-to-batch heterogeneity. In this work a range of synthetic homopolymers and copolymers of sodium 2-acrylamido-2-methylpropane sulfonate (AMPS®) were evaluated as potential FGF stabilisers. This was studied by measuring the proliferation of BaF3-FR1c cells, as a model assay, and the results will be compared with the natural stabilisation and activation of FGF by heparin. This study explores the structure-activity relationship of these polysulfonated polymers with a focus on the effect of molecular weight, co-monomer type, charge dispersion and polymer architecture on protein stabilisation
Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program.
ABSTRACT: BACKGROUND: Violence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them. METHODS: FSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural-biological assessments (IBBAs 2005-2009; administered face-to-face). RESULTS: 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001). CONCLUSIONS: This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights
PHarmacist Avoidance or Reductions in Medical Costs in CRITically Ill Adults: PHARM-CRIT Study
OBJECTIVES: To comprehensively classify interventions performed by ICU clinical pharmacists and quantify cost avoidance generated through their accepted interventions.
DESIGN: A multicenter, prospective, observational study was performed between August 2018 and January 2019.
SETTING: Community hospitals and academic medical centers in the United States.
PARTICIPANTS: ICU clinical pharmacists.
INTERVENTIONS: Recommendations classified into one of 38 intervention categories (divided into six unique sections) associated with cost avoidance.
MEASUREMENTS AND MAIN RESULTS: Two-hundred fifteen ICU pharmacists at 85 centers performed 55,926 interventions during 3,148 shifts that were accepted on 27,681 adult patient days and generated 5,822,539 CA), resource utilization (12,630 interventions; 9,680,036 cost avoidance), prophylaxis (1,639 interventions; 1,339,621 cost avoidance), and administrative/supportive tasks (4,768 interventions; 418 per intervention, 7,435 per ICU pharmacist shift. The annualized cost avoidance from an ICU pharmacist is 3.3:1 and 3.3:1 and $9.6:1
Asymmetric triplex metallohelices with high and selective activity against cancer cells
Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli.
At a glanc
Dopaminergic and prefrontal basis of learning from sensory confidence and reward value
Deciding between stimuli requires combining their learned value with one’s sensory confidence. We trained mice in a visual task that probes this combination. Mouse choices reflected not only present confidence and past rewards but also past confidence. Their behavior conformed to a model that combines signal detection with reinforcement learning. In the model, the predicted value of the chosen option is the product of sensory confidence and learned value. We found precise correlates of this variable in the pre-outcome activity of midbrain dopamine neurons and of medial prefrontal cortical neurons. However, only the latter played a causal role: inactivating medial prefrontal cortex before outcome strengthened learning from the outcome. Dopamine neurons played a causal role only after outcome, when they encoded reward prediction errors graded by confidence, influencing subsequent choices. These results reveal neural signals that combine reward value with sensory confidence and guide subsequent learning
PHarmacist Avoidance or Reductions in Medical Costs in Patients Presenting the EMergency Department: PHARM-EM Study
Objectives: To comprehensively classify interventions performed by emergency medicine clinical pharmacists and quantify cost avoidance generated through their accepted interventions.
Design: A multicenter, prospective, observational study was performed between August 2018 and January 2019.
Setting: Community and academic hospitals in the United States.
Participants: Emergency medicine clinical pharmacists.
Interventions: Recommendations classified into one of 38 intervention categories associated with cost avoidance.
Measurements and Main Results: Eighty-eight emergency medicine pharmacists at 49 centers performed 13,984 interventions during 917 shifts that were accepted on 8,602 patients and generated 2,225,049 cost avoidance), resource utilization (628; 1,787,170), prophylaxis (24; 2,836,811), and administrative/supportive tasks (2,046; 538.61 per intervention, 8,213.59 per emergency medicine pharmacist shift. The annualized cost avoidance from an emergency medicine pharmacist was 1.4:1 and 1.4:1 and $10.6:1
Declines in violence and police arrest among female sex workers in Karnataka state, south India, following a comprehensive HIV prevention programme.
INTRODUCTION: Female sex workers (FSWs) frequently experience violence, harassment and arrest by the police or their clients, but there is little evidence as to the impact that such factors may have on HIV risk or whether community interventions could mitigate this impact. METHODS: As part of the evaluation of the Avahan programme in Karnataka, serial integrated behavioural and biological assessment (IBBA) surveys (four districts) (2005 to 2011) and anonymous polling booth surveys (PBS) (16 districts) (2007 to 2011) were conducted with random samples of FSWs. Logistic regression analysis was used to assess 1) changes in reported violence and arrests over time and 2) associations between violence by non-partners and police arrest and HIV/STI risk and prevalence. Mediation analysis was used to identify mediating factors. RESULTS: 5,792 FSWs participated in the IBBAs and 15,813 participated in the PBS. Over time, there were significant reductions in the percentages of FSWs reporting being raped in the past year (PBS) (30.0% in 2007, 10.0% in 2011, p<0.001), being arrested in the past year [adjusted odds ratio (AOR) 0.57 (0.35, 0.93), p=0.025] and being beaten in the past six months by a non-partner (clients, police, pimps, strangers, rowdies) [AOR 0.69 (0.49, 0.95), p=0.024)] (IBBA). The proportion drinking alcohol (during the past week) also fell significantly (32.5% in 2005, 24.9% in 2008, 16.8% in 2011; p<0.001). Violence by non-partners (being raped in the past year and/or beaten in the past six months) and being arrested in the past year were both strongly associated with HIV infection [AOR 1.59 (1.18, 2.15), p=0.002; AOR 1.91 (1.17, 3.12), p=0.01, respectively]. They were also associated with drinking alcohol (during the past week) [AOR 1.98 (1.54, 2.53), p<0.001; AOR 2.79 (1.93, 4.04), p<0.001, respectively], reduced condom self-efficacy with clients [AOR 0.36 (0.27, 0.47), p<0.001; AOR 0.62 (0.39, 0.98), p=0.039, respectively], symptomatic STI (during the past year) [AOR 2.62 (2.07, 3.30), p<0.001; AOR 2.17 (1.51, 3.13), p<0.001, respectively], gonorrhoea infection [AOR 2.79 (1.51, 5.15), p=0.001; AOR 2.69 (0.96, 7.56), p=0.060, respectively] and syphilis infection [AOR 1.86 (1.04, 3.31), p=0.036; AOR 3.35 (1.78, 6.28), p<0.001, respectively], but not with exposure to peer education, community mobilization or HIV testing uptake. Mediation analysis suggests that alcohol use and STIs may partially mediate the association between violence or arrests and HIV prevalence. DISCUSSION: Violence by non-partners and arrest are both strongly associated with HIV infection among FSWs. Large-scale, comprehensive HIV prevention programming can reduce violence, arrests and HIV/STI infection among FSWs
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