PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism.

BACKGROUND & AIMS: Hepatitis C virus (HCV) associates with lipoproteins to form "lipoviral particles" (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance. METHODS: HCV RNA, LVP (d1.07g/ml) fractions, were quantified in patients with HCV-G3 (n=39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP+non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n=51). RESULTS: In HCV-G3 LVP load correlated inversely with HDL-C (r=-0.421; p=0.008), and apoE (r=-0.428; p=0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R(2)=16.2%; p=0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 (p<0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1. CONCLUSIONS: The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3

The Dr. John Hall story: a case study in putative “Haunted People Syndrome”

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Research suggests a “Haunted People Syndrome (HP-S)” defined by recurrent and systematic perceptions of anomalous subjective and objective anomalies. Such signs or symptoms are traditionally attributed to “spirits and the supernatural,” but these themes are hypothesised to morph to “surveillance and stalking” in reports of “group-(or gang) stalking,” We tested this premise with a quali-quantitative exercise that mapped group-stalking experiences from a published first-hand account to a Rasch measure of haunt-type anomalies. This comparison found significant agreement in the specific “signs or symptoms” of both phenomena. Meta-patterns likewise showed clear conceptual similarities between the phenomenology of haunts and group-stalking. Findings are consistent with the idea that both anomalous episodes involve the same, or similar, attentional or perceptual processes and thereby support the viability of the HP-S construct

A randomized trial of an intervention to improve use and adherence to effective coronary heart disease prevention strategies

<p>Abstract</p> <p>Background</p> <p>Efficacious strategies for the primary prevention of coronary heart disease (CHD) are underused, and, when used, have low adherence. Existing efforts to improve use and adherence to these efficacious strategies have been so intensive that they are impractical for clinical practice.</p> <p>Methods</p> <p>We conducted a randomized trial of a CHD prevention intervention (including a computerized decision aid and automated tailored adherence messages) at one university general internal medicine practice. After obtaining informed consent and collecting baseline data, we randomized patients (men and women age 40-79 with no prior history of cardiovascular disease) to either the intervention or usual care. We then saw them for two additional study visits over 3 months. For intervention participants, we administered the decision aid at the primary study visit (1 week after baseline visit) and then mailed 3 tailored adherence reminders at 2, 4, and 6 weeks. We assessed our outcomes (including the predicted likelihood of angina, myocardial infarction, and CHD death over 10 years (CHD risk) and self-reported adherence) between groups at 3 month follow-up. Data collection occurred from June 2007 through December 2009. All study procedures were IRB approved.</p> <p>Results</p> <p>We randomized 160 eligible patients (81 intervention; 79 control) and followed 96% to study conclusion. Mean predicted CHD risk at baseline was 11.3%. The intervention increased self-reported adherence to chosen risk reducing strategies by 25 percentage points (95% CI 8% to 42%), with the biggest effect for aspirin. It also changed predicted CHD risk by -1.1% (95% CI -0.16% to -2%), with a larger effect in a pre-specified subgroup of high risk patients.</p> <p>Conclusion</p> <p>A computerized intervention that involves patients in CHD decision making and supports adherence to effective prevention strategies can improve adherence and reduce predicted CHD risk.</p> <p>Clinical trials registration number</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00494052">NCT00494052</a></p

An Action-Based Approach to Presence: Foundations and Methods

This chapter presents an action-based approach to presence. It starts by briefly describing the theoretical and empirical foundations of this approach, formalized into three key notions of place/space, action and mediation. In the light of these notions, some common assumptions about presence are then questioned: assuming a neat distinction between virtual and real environments, taking for granted the contours of the mediated environment and considering presence as a purely personal state. Some possible research topics opened up by adopting action as a unit of analysis are illustrated. Finally, a case study on driving as a form of mediated presence is discussed, to provocatively illustrate the flexibility of this approach as a unified framework for presence in digital and physical environment

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

When worlds collide

The UK has a strong tradition of innovative evaluative health care research. There are, however, considerable forces impeding collaboration between clinicians, academics, patients and their advocates and industry. This paper argues that, if the UK is to regain a position at the forefront of clinical research into evaluation of care, some of these forces need to be overcome. Now, with explicit encouragement from funders within the UK's NHS, it is urgent that all parties discover better ways of working together so that more broad and meaningful research can be produced in a timely fashion

The impact of a decision aid about heart disease prevention on patients' discussions with their doctor and their plans for prevention: a pilot randomized trial

BACKGROUND: Low utilization of effective coronary heart disease (CHD) prevention strategies may be due to many factors, but chief among them is the lack of patient involvement in prevention decisions. We undertook this study to test the effectiveness of an individually-tailored, computerized decision aid about CHD on patients' discussions with their doctor and their plans for CHD prevention. METHODS: We conducted a pilot randomized trial in a convenience sample of adults with no previous history of cardiovascular disease to test the effectiveness of an individually-tailored, computerized decision aid about CHD prevention against a risk factor list that patients could present to their doctor. RESULTS: We enrolled 75 adults. Mean age was 53. 59% were female, 73% white, and 23% African-American. 66% had some college education. 43% had a 10-year CHD risk of 0–5%, 25% a risk of 6–10%, 24% a risk of 11–20%, and 5% a risk of > 20%. 78% had at least one option to reduce their CHD risk, but only 45% accurately identified the strategies best supported by evidence. 41 patients received the decision aid, 34 received usual care. In unadjusted analysis, the decision aid increased the proportion of patients who discussed CHD risk reduction with their doctor from 24% to 40% (absolute difference 16%; 95% CI -4% to +37%) and increased the proportion who had a specific plan to reduce their risk from 24% to 37% (absolute difference 13%; 95% CI -7% to +34%). In pre-post testing, the decision aid also appeared to increase the proportion of patients with plans to intervene on their CHD risk (absolute increase ranging from 21% to 47% for planned medication use and 5% to 16% for planned behavioral interventions). CONCLUSION: Our study confirms patients' limited knowledge about their CHD risk and effective risk reduction options and provides preliminary evidence that an individually-tailored decision aid about CHD prevention might be expected to increase patients' discussions about CHD prevention with their doctor and their plans for CHD risk reduction. These findings should be replicated in studies with a larger sample size and patients at overall higher risk of CHD. Trial Registration: ClinicalTrials.gov NCT0031597

2D-Qsar for 450 types of amino acid induction peptides with a novel substructure pair descriptor having wider scope

<p>Abstract</p> <p>Background</p> <p>Quantitative structure-activity relationships (QSAR) analysis of peptides is helpful for designing various types of drugs such as kinase inhibitor or antigen. Capturing various properties of peptides is essential for analyzing two-dimensional QSAR. A descriptor of peptides is an important element for capturing properties. The atom pair holographic (APH) code is designed for the description of peptides and it represents peptides as the combination of thirty-six types of key atoms and their intermediate binding between two key atoms.</p> <p>Results</p> <p>The substructure pair descriptor (SPAD) represents peptides as the combination of forty-nine types of key substructures and the sequence of amino acid residues between two substructures. The size of the key substructures is larger and the length of the sequence is longer than traditional descriptors. Similarity searches on C5a inhibitor data set and kinase inhibitor data set showed that order of inhibitors become three times higher by representing peptides with SPAD, respectively. Comparing scope of each descriptor shows that SPAD captures different properties from APH.</p> <p>Conclusion</p> <p>QSAR/QSPR for peptides is helpful for designing various types of drugs such as kinase inhibitor and antigen. SPAD is a novel and powerful descriptor for various types of peptides. Accuracy of QSAR/QSPR becomes higher by describing peptides with SPAD.</p

Has education lost sight of children?

The reflections presented in this chapter are informed by clinical and personal experiences of school education in the UK. There are many challenges for children and young people in the modern education system and for the professionals who support them. In the UK, there are significant gaps between the highly selective education provided to those who pay privately for it and to the majority of those educated in the state-funded system. Though literacy rates have improved around the world, many children, particularly boys, do not finish their education for reasons such as boredom, behavioural difficulties or because education does not ‘pay’. Violence, bullying, and sexual harassment are issues faced by many children in schools and there are disturbing trends of excluding children who present with behavioural problems at school whose origins are not explored. Excluded children are then educated with other children who may also have multiple problems which often just make the situation worse. The experience of clinicians suggests that school-related mental health problems are increasing in severity. Are mental health services dealing with the consequences of an education system that is not meeting children’s needs? An education system that is testing- and performance-based may not be serving many children well if it is driving important decisions about them at increasingly younger ages. Labelling of children and setting them on educational career paths can occur well before they reach secondary schools, limiting potential very early on in their developmental trajectory. Furthermore, the emphasis at school on testing may come at the expense of creativity and other forms of intelligence, which are also valuable and important. Meanwhile the employment marketplace requires people with widely different skills, with an emphasis on innovation, creativity, and problem solving. Is education losing sight of the children it is educating

Observational evidence of a change in radiative forcing due to the indirect aerosol effect

Anthropogenic aerosols enhance cloud reflectivity by increasing the number concentration of cloud droplets, leading to a cooling effect on climate known as the indirect aerosol effect. Observational support for this effect is based mainly on evidence that aerosol number concentrations are connected with droplet concentrations, but it has been difficult to determine the impact of these indirect effects on radiative forcing(1-3). Here we provide observational evidence for a substantial alteration of radiative fluxes due to the indirect aerosol effect. We examine the effect of aerosols on cloud optical properties using measurements of aerosol and cloud properties at two North American sites that span polluted and clean conditions-a continental site in Oklahoma with high aerosol concentrations, and an Arctic site in Alaska with low aerosol concentrations. We determine the cloud optical depth required to fit the observed shortwave downward surface radiation. We then use a cloud parcel model to simulate the cloud optical depth from observed aerosol properties due to the indirect aerosol effect. From the good agreement between the simulated indirect aerosol effect and observed surface radiation, we conclude that the indirect aerosol effect has a significant influence on radiative fluxes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62920/1/nature02234.pd