211 research outputs found
Influenza pandemic: perception of risk and individual precautions in a general population. Cross sectional study
BACKGROUND: An influenza pandemic may have considerable impact on health and societal functioning. The aim of this study was to explore people's reflections on the consequences of a pandemic. METHODS: Cross-sectional web-based survey of 1,168 Norwegians aged 16–82 years. The main outcome measures were answers to questions about a potential pandemic ("serious influenza epidemic"): statements about personal precautions including stockpiling Tamiflu(®), the perceived number of fatalities, the perceived effects of Tamiflu(®), the sources of information about influenza and trust in public information. RESULTS: While 80% of the respondents stated that they would be "careful about personal hygiene", only a few would stay away from work (2%), or move to an isolated place (4%). While 27% of respondents were uncertain about the number of fatalities during an influenza pandemic, 48% thought it would be lower than the estimate of Norwegian health authorities (0.05%–1%) and only 3% higher. At least half of the respondents thought that Tamiflu(® )might reduce the mortality risk, but less than 1% had personally purchased the drug. The great majority had received their information from the mass media, and only 9% directly from health authorities. Still the majority (65%) trusted information from the authorities, and only 9% reported overt distrust. CONCLUSION: In Norway, considerable proportions of people seem to consider the mortality risk during a pandemic less than health authorities do. Most people seem to be prepared to take some, but not especially disruptive, precautions
Characteristics of patients receiving allergy vaccination: to which extent do socio-economic factors play a role?
Background: Little is known about characteristics of patients receiving allergen-specific immunotherapy. Identifying obstacles to appropriate treatment according to guidelines may facilitate the development of strategies aiming at improved treatment of patients with allergic respiratory diseases. The objective of this study was to investigate differences in disease severity, demographic and socioeconomic status between allergic rhinitis patients receiving allergen-specific immunotherapy and allergic rhinitis patients not receiving allergen-specific immunotherapy. Methods: A total of 366 patients were studied of whom 210 were going to receive subcutaneously administrated immunotherapy (SIT) against grass pollen and/or house dust mite allergy. The severity of rhino-conjunctivitis (hay fever) and/or asthma was classified according to international guidelines. The questionnaires included an EQ-5D visual analogue scale instrument and some socio-economic questions. Results: Severity of disease, young age, high level of education as well as greater perceived impairment of health-related quality of life due to allergic symptoms were significantly associated with use of SIT. Somewhat unexpectedly, household income was not associated with use of SIT. Conclusion: Use of SIT was associated with both disease severity measures and educational level, but not income level. These results suggest social inequality as reflected by lower use of SIT among patients with lower educational level may represent an obstacle to treatment with SIT
Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders
Prioritization, Incentives, and Resource Use for Sustainable Dentistry: The EU PRUDENT Project
Time to tweak the TTO: results from a comparison of alternative specifications of the TTO
Abstract This article examines the effect that different
specifications of the time trade-off (TTO) valuation task
may have on values for EQ-5D-5L health states. The new
variants of the TTO, namely lead-time TTO and lag-time
TTO, along with the classic approach to TTO were compared
using two durations for the health states (15 and
20 years). The study tested whether these methods yield
comparable health-state values. TTO tasks were administered
online. It was found that lag-time TTO produced
lower values than lead-time TTO and that the difference
was larger in the longer time frame. Classic TTO values
most resembled those of the lag-time TTO in a 20-year
time frame in terms of mean absolute difference. The relative
importance of different domains of health was systematically
affected by the duration of the health state. In
the tasks with a 10-year health-state duration, anxiety/
depression had the largest negative impact on health-state
values; in the tasks with a 5-year duration, the pain/discomfort
domain had the largest negative impact
The social value of a QALY : raising the bar or barring the raise?
Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England,
there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether
QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY
(SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were
released during a time of considerable debate about the NICE threshold, and authors with differing perspectives
have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of
results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for
those who conducted the research to contribute to the debate as to its implications for NICE.
Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the
current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and
age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’
answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in
values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values
of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing
the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the
other that greater weight could be given to QALYs gained by some groups.
Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling
evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be
moved up for some types of QALY and down for others. While many members of the public appear to be open to
the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have
any secure evidence base for introducing such a system
Cost-utility analysis of genetic screening in families of patients with germline MUTYH mutations
<p>Abstract</p> <p>Background</p> <p>MUTYH associated polyposis (MAP) is an autosomal recessive inherited disorder. Carriers of bi-allelic <it>MUTYH </it>germline mutations have a risk of approximately 60% to develop colorectal carcinoma (CRC). In the general population about 1.5% is a heterozygous <it>MUTYH </it>mutation carrier. Children of MAP patients have an increased risk of inheriting two <it>MUTYH </it>mutations compared to the general population, implicating an increased risk for developing CRC.</p> <p>Methods</p> <p>Using data from the literature and Dutch MAP patients (n = 40), we constructed a Markov model to perform a societal cost-utility analysis of genetic screening in MAP families. Genetic screening was done by testing the spouse first and, in case of a heterozygous spouse, also testing of the children.</p> <p>Results</p> <p>The cost of genetic screening of families of MAP patients, when compared to no genetic screening, was estimated at €25,000 per quality-adjusted life year (QALY). The presence of Fecal Occult Blood testing (FOBT) population screening only slightly increased this cost-utility ratio to €25,500 per QALY. For a MUTYH heterozygote index-patient, the ratio was €51,500 per QALY. The results of our analysis were sensitive to several of the parameters in the model, including the cost assumed for molecular genetic testing.</p> <p>Conclusion</p> <p>The costs per QALY of genetic screening in families of MAP patients are acceptable according to international standards. Therefore, genetic testing of spouses and/or children should be discussed with and offered to counselees.</p
Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors
Summary RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers
A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci
The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function
Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
RIPK2 mediates inflammatory signaling by the bacteria-sensing
receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a
proposed strategy to ameliorate NOD-mediated pathologies. Here,
we reveal that RIPK2 kinase activity is dispensable for NOD2
inflammatory signaling and show that RIPK2 inhibitors function
instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination
of RIPK2. We map the XIAP binding site on RIPK2 to the loop
between b2 and b3 of the N-lobe of the kinase, which is in close
proximity to the ATP-binding pocket. Through characterization of a
new series of ATP pocket-binding RIPK2 inhibitors, we identify the
molecular features that determine their inhibition of both the
RIPK2-XIAP interaction, and of cellular and in vivo NOD2 signaling.
Our study exemplifies how targeting of the ATP-binding pocket in
RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction
for modulation of NOD signaling
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