113 research outputs found
Labour induction near term for women aged 35 or over: an economic evaluation
Objective Induction of labour at 39 weeks for nulliparous women aged 35 years and over may prevent stillbirths and does not increase caesarean births, so it may be popular. But the overall costs and benefits of such a policy have not been compared.
Design A costâutility analysis alongside a randomised controlled trial (the 35/39 trial).
Setting Obstetric departments of 38 UK National Health Service hospitals and one UK primary-care trust.
Population Nulliparous women aged 35 years or over on their expected due date, with a singleton live fetus in a cephalic presentation.
Methods Costs were estimated from the National Health Service and Personal Social Services perspective and quality-adjusted life-years (QALYs) were calculated based on patient responses to the EQ-5D at baseline and 4 weeks.
Main outcome measures Data on antenatal care, mode of delivery, analgesia in labour, method of induction, EQ-5D (baseline and 4 weeks postnatal) and participant-administered postnatal health resource use data were collected.
Results The intervention was associated with a mean cost saving of ÂŁ263 and a small additional gain in QALYs (though this was not statistically significant), even without considering any possible QALY gains from stillbirth prevention.
Conclusion A policy of induction of labour at 39 weeks for women of advanced maternal age would save money
Improving the use of research evidence in guideline development: 11. Incorporating considerations of cost-effectiveness, affordability and resource implications
BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 11(th )of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on incorporating considerations of cost-effectiveness, affordability and resource implications in guidelines and recommendations. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: When is it important to incorporate cost-effectiveness, resource implications and affordability considerations in WHO guidelines (which topics)? ⢠For cost-effectiveness: The need for cost/effectiveness information should be dictated by the specific question, of which several may be addressed in a single guideline. It is proposed that the indications for undertaking a cost-effectiveness analysis (CEA) could be a starting point for determining which recommendation(s) in the guideline would benefit from such analysis. ⢠For resource implications/affordability: The resource implications of each individual recommendation need to be considered when implementation issues are being discussed. How can cost-effectiveness, resource implications and affordability be explicitly taken into account in WHO guidelines? ⢠For cost-effectiveness: â If data are available, the ideal time to consider cost-effectiveness is during the evidence gathering and synthesizing stage. However, because of the inconsistent availability of CEAs and the procedural difficulty associated with adjusting results from different CEAs to make them comparable, it is also possible for cost-effectiveness to be considered during the stage of developing recommendations. â Depending on the quantity and quality and relevance of the data available, such data can be considered in a qualitative way or in a quantitative way, ranging from a listing of the costs to a modelling exercise. At the very least, a qualitative approach like a commentary outlining the economic issues that need to be considered is necessary. If a quantitative approach is to be used, the full model should be transparent and comprehensive. ⢠For resource implications/affordability: â Resource implications, including health system changes, for each recommendation in a WHO guideline should be explored. At the minimum, a qualitative description that can serve as a gross indicator of the amount of resources needed, relative to current practice, should be provided. How does one provide guidance in contextualizing guideline recommendations at the country level based on considerations of cost-effectiveness, resource implications and affordability? ⢠All models should be made available and ideally are designed to allow for analysts to make changes in key parameters and reapply results in their own country. ⢠In the global guidelines, scenarios and extensive sensitivity/uncertainty analysis can be applied. Resource implications for WHO ⢠From the above, it is clear that guidelines development groups will need a health economist. There is need to ensure that this is included in the budget for guidelines and that there is in-house support for this as well
Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimerâs disease
This is the final version of the article. Available from the publisher via the DOI in this record.The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.This study was supported by the
Alzheimer's Research UK, the Medical Research
Council (MRC), the Wellcome Trust/MRC Joint Call in
Neurodegeneration Award (WT089698) to the UK
Parkinson's Disease Consortium (whose members
are from the University College London Institute of
Neurology, the University of Sheffield, and the MRC
Protein Phosphorylation Unit at the University of
Dundee), grants (P50 AG016574, U01 AG006786,
and R01 AG18023), the National Institute for Health
Research Biomedical Research Unit in Dementia at University College London Hospitals, University
College London; the Big Lottery (to Dr. Morgan); a
fellowship from Alzheimer's Research UK (to Dr.
Guerreiro); and the Intramural Research Programs of
the National Institute on Aging and the National
Institute of Neurological Disease and Stroke, National
Institutes of Health (Department of Health and Human
Services Project number, ZO1 AG000950-10). The
MRC London Neurodegenerative Diseases Brain
Bank and the Manchester Brain Bank from Brains for
Dementia Research are jointly funded from ARUK
and AS. Tissue samples were supplied by The
London Neurodegenerative Diseases Brain Bank,
which receives funding from the MRC and as part of
the Brains for Dementia Research programme, jointly
funded by Alzheimerâs Research UK and Alzheimerâs
Society
Synthesis of reaction-adapted zeolites as methanol-to-olefins catalysts with mimics of reaction intermediates as organic structure-directing agents
[EN] Catalysis with enzymes and zeolites have in common the presence of well-defined single active sites and pockets/cavities where the reaction transition states can be stabilized by longer-range interactions. We show here that for a complex reaction, such as the conversion of methanol-to-olefins (MTO), it is possible to synthesize reaction-adapted zeolites by using mimics of the key molecular species involved in the MTO mechanism. Effort has focused on the intermediates of the paring mechanism because the paring is less favoured energetically than the side-chain route. All the organic structure-directing agents based on intermediate mimics crystallize cage-based small-pore zeolitic materials, all of them capable of performing the MTO reaction. Among the zeolites obtained, RTH favours the whole reaction steps following the paring route and gives the highest propylene/ethylene ratio compared to traditional CHA-related zeolites (3.07 and 0.86, respectively).Li, C.; Paris, C.; MartĂnez-Triguero, J.; Boronat Zaragoza, M.; Moliner Marin, M.; Corma CanĂłs, A. (2018). Synthesis of reaction-adapted zeolites as methanol-to-olefins catalysts with mimics of reaction intermediates as organic structure-directing agents. Nature Catalysis. 1(7):547-554. https://doi.org/10.1038/s41929-018-0104-7S54755417Stocker, M. Methanol-to-hydrocarbons: catalytic materials and their behavior. Micro. Mesopor. Mater. 29, 3â48 (1999).Tian, P., Wei, Y., Ye, M. & Liu, Z. Methanol to olefins (MTO): from fundamentals to commercialization. ACS Catal. 5, 1922â1938 (2015).Ilias, S. & Bhan, A. Mechanism of the catalytic conversion of methanol to hydrocarbons. ACS Catal. 3, 18â31 (2013).Olsbye, U. et al. Conversion of methanol to hydrocarbons: how zeolite cavity and pore size controls product selectivity. Angew. Chem. Int. Ed. 24, 5810â5831 (2012).Hemelsoet, K., Van der Mynsbrugge, J., De Wispelaere, K., Waroquier, M. & Van Speybroeck, V. Unraveling the reaction mechanisms governing methanol-to-olefins catalysis by theory and experiment. ChemPhysChem 14, 1526â1545 (2013).Song, W., Haw, J. F., Nicholas, J. B. & Heneghan, C. S. Methylbenzenes are the organic reaction centers for methanol-to-olefin catalysis on HSAPO-34. J. Am. Chem. Soc. 122, 10726â10727 (2000).Arstad, B. & Kolboe, S. The reactivity of molecules trapped within the SAPO-34 cavities in the methanol-to-hydrocarbons reaction. J. Am. Chem. Soc. 123, 8137â8138 (2001).Xu, T. et al. Synthesis of a benzenium ion in a zeolite with use of a catalytic flow reactor. J. Am. Chem. Soc. 120, 4025â4026 (1998).Song, W., Nicholas, J. B., Sassi, A. & Haw, J. F. Synthesis of the heptamethylbenzene cation in zeolite beta: in situ NMR and theory. Catal. Lett. 81, 49â53 (2002).Xu, S. et al. Direct observation of cyclic carbenium ions and their role in the catalytic cycle of the metahnol-to-olefin reaction over chabazite zeolites. Angew. Chem. Int. Ed. 52, 11564â11568 (2013).Chen, J. et al. Elucidating the olefin formation mechanism in the methanol to olefin reaction over AlPO-18 and SAPO-18. Catal. Sci. Tech. 4, 3268â3277 (2014).Haw, J. F. et al. Roles for cyclopentenyl cations in the synthesis of hydrocarbons from methanol on zeolite catalyst HZSM-5. J. Am. Chem. Soc. 122, 4763â4775 (2000).Svelle, S. et al. Conversion of methanol into hydrocarbons over zeolite H-ZSM-5:âethene formation is mechanistically separated from the formation of higher alkenes. J. Am. Chem. Soc. 128, 14770â14771 (2006).Teketel, S., Olsbye, U., Lillerud, K. P., Beato, P. & S., S. Selectivity control through fundamental mechanistic insight in the conversion of methanol to hydrocarbons over zeolites. Micro. Mesopor. Mater. 136, 33â41 (2010).Zhang, M. et al. Methanol conversion on ZSM-22, ZSM-35 and ZSM-5 zeolites: effects of 10-membered ring zeolite structures on methylcyclopentenyl cations and dual cycle mechanism. RSC Adv. 6, 95855â95864 (2016).Sassi, A. et al. Methylbenzene chemistry on zeolite HBeta:âmultiple insights into methanol-to-olefin catalysis. J. Phys. Chem. B 106, 2294â2303 (2002).Sassi, A., Wildman, M. A. & Haw, J. F. Reactions of butylbenzene isomers on zeolite HBeta:âmethanol-to-olefins hydrocarbon pool chemistry and secondary reactions of olefins. J. Phys. Chem. B 106, 8768â8773 (2002).Bjørgen, M., Olsbye, U., Petersen, D. & Kolboe, S. The methanol-to-hydrocarbons reaction: insight into the reaction mechanism from [12C]benzene and [13C]methanol coreactions over zeolite H-beta. J. Catal. 221, 1â10 (2004).McCann, D. M. et al. A complete catalytic cycle for supramolecular methanol-to-olefins conversion by linking theory with experiment. Angew. Chem. Int. Ed. 47, 5179â5182 (2008).Arstad, B., Kolboe, S. & Swang, O. Theoretical study of the heptamethylbenzenium ion. intramolecular isomerizations and C2, C3, C4 alkene elimination. J. Phys. Chem. A 109, 8914â8922 (2005).De Wispelaere, K., Hemelsoet, K., Waroquier, M. & Van Speybroeck, V. Complete low-barrier side-chain route for olefin formation during methanol conversion in H-SAPO-34. J. Catal. 305, 76â80 (2013).Wang, C. M., Wang, Y. D. & Xie, Z. K. Verification of the dual cycle mechanism for methanol-to-olefin conversion in HSAPO-34: a methylbenzene-based cycle from DFT calculations. Catal. Sci. Technol. 4, 2631â2638 (2014).Wang, C. M., Wang, Y. D., Liu, H. X., Xie, Z. K. & Liu, Z. P. Theoretical insight into the minor role of paring mechanism in the methanol-to-olefins conversion within HSAPO-34 catalyst. Micro. Mesopor. Mater. 158, 264â271 (2012).Ilias, S. & Bhan, A. The mechanism of aromatic dealkylation in methanol-to-hydrocarbons conversion on H-ZSM-5: What are the aromatic precursors to light olefins? J. Catal. 311, 6â16 (2014).Erichsen, M. W. et al. Conclusive evidence for two unimolecular pathways to zeolite-catalyzed de-alkylation of the heptamethylbenzenium cation. ChemCatChem 7, 4143â4147 (2015).Bhawe, Y. et al. Effect of cage size on the selective conversion of methanol to light olefins. ACS Catal. 2, 2490â2495 (2012).Kang, J. H. et al. Further studies on how the nature of zeolite cavities that are bounded by small pores influences the conversion of methanol to light olefins. ChemPhysChem 19, 412â419 (2018).Martin, N. et al. Nanocrystalline SSZ-39 zeolite as an efficient catalyst for the methanol-to-olefin (MTO) process. Chem. Commun. 52, 6072â6075 (2016).Dusselier, M., Deimund, M. A., Schmidt, J. E. & Davis, M. E. Methanol-to-olefins catalysis with hydrothermally treated zeolite SSZ-39. ACS Catal. 5, 6078â6085 (2015).Yokoi, T., Yoshioka, M., Imai, H. & Tatsumi, T. Diversification of RTH-type zeolite and its catalytic application. Angew. Chem. Int. Ed. 48, 9884â9887 (2009).Ji, Y., Deimund, M. A., Bhawe, Y. & Davis, M. E. Organic-free synthesis of CHA-type zeolite catalysts for the methanol-to-olefins reaction. ACS Catal. 5, 4456â4465 (2015).Liu, M. et al. Differences in Al distribution and acidic properties between RTH-type zeolites synthesized with OSDAs and without OSDAs. Phys. Chem. Chem. Phys. 16, 4155â4164 (2014).Gallego, E. M. et al. âAb initioâ synthesis of zeolites for preestablished catalytic reactions. Science 355, 1051â1054 (2017).Zones, S. I. & Nakagawa, Y. Use of modified zeolites as reagents influencing nucleation in zeolite synthesis. Stud. Surf. Sci. Catal. 97, 45â52 (1995).Li, C., Moliner, M. & Corma, A. Building zeolites from pre-crystallized units: nanoscale architecture. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.201711422 (2018).Zones, S. I. Zeolite SSZ-13 and its method of preparation. US Patent 4,544,538 (1985).Li, Z., Navarro, M. T., MartĂnez-Triguero, J., Yu, J. & Corma, A. Synthesis of nano-SSZ-13 and its application in the reaction of methanol to olefins. Catal. Sci. Technol. 6, 5856â5863 (2016).Kumar, M., Luo, H., RomĂĄn-Leshkov, Y. & Rimer, J. D. SSZ-13 crystallization by particle attachment and deterministic pathways to crystal size control. J. Am. Chem. Soc. 137, 13007â13017 (2015).MartĂnez-Franco, R., Cantin, A., Moliner, M. & Corma, A. Synthesis of the small pore silicoaluminophosphate STA-6 by using supramolecular self-assembled organic structure directing agents. Chem. Mater. 26, 4346â4353 (2014).Schmidt, J. E., Deimund, M. A., Xie, D. & Davis, M. E. Synthesis of RTH-type zeolites using a diverse library of imidazolium cations. Chem. Mater. 27, 3756â3762 (2015).Moliner, M., Franch, C., Palomares, E., Grill, M. & Corma, A. 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(Gaussian, Wallingford, 2009).Van Speybroeck, V. et al. First principle chemical kinetics in zeolites: the methanol-to-olefin process as a case study. Chem. Soc. Rev. 43, 7326â7357 (2014)
Sustainable prevention of obesity through integrated strategies: The SPOTLIGHT project's conceptual framework and design
<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight and obesity in Europe is high. It is a major cause of the overall rates of many of the main chronic (or non communicable) diseases in this region and is characterized by an unequal socio-economic distribution within the population. Obesity is largely determined by modifiable lifestyle behaviours such as low physical activity levels, sedentary behaviour and consumption of energy dense diets. It is increasingly being recognised that effective responses must go beyond interventions that only focus on a specific individual, social or environmental level and instead embrace system-based multi-level intervention approaches that address both the individual and environment. The EU-funded project âsustainable prevention of obesity through integrated strategiesâ (SPOTLIGHT) aims to increase and combine knowledge on the wide range of determinants of obesity in a systematic way, and to identify multi-level intervention approaches that are strong in terms of Reach, Efficacy, Adoption, Implementation and Maintenance (RE-AIM).</p> <p>Methods/Design</p> <p>SPOTLIGHT comprises a series of systematic reviews on: individual-level predictors of success in behaviour change obesity interventions; social and physical environmental determinants of obesity; and on the RE-AIM of multi-level interventions. An interactive web-atlas of currently running multi-level interventions will be developed, and enhancing and impeding factors for implementation will be described. At the neighbourhood level, these elements will inform the development of methods to assess obesogenicity of diverse environments, using remote imaging techniques linked to geographic information systems. The validity of these methods will be evaluated using data from surveys of health and lifestyles of adults residing in the neighbourhoods surveyed. At both the micro- and macro-levels (national and international) the different physical, economical, political and socio-cultural elements will be assessed.</p> <p>Discussion</p> <p>SPOTLIGHT offers the potential to develop approaches that combine an understanding of the obesogenicity of environments in Europe, and thus how they can be improved, with an appreciation of the individual factors that explain why people respond differently to such environments. Its findings will inform governmental authorities and professionals, academics, NGOs and private sector stakeholders engaged in the development and implementation of policies to tackle the obesity epidemic in Europe.</p
Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.
Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD)
Twin Town in South Brazil: A Nazi's Experiment or a Genetic Founder Effect?
Cândido GodĂłi (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the âTwins' Townâ due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the âNazi's experimentâ and of the âfounder effectâ hypotheses. We surveyed a total of 6,262 baptism records from 1959â2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the âNazi's experiment hypothesisâ, there is no spurt in twinning between the years (1964â1968) when Mengele allegedly was in CG (Pâ=â0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (Pâ=â0.351), and no difference in twinning among CG districts considering two different periods: 1927â1958 and 1959â2008 (Pâ=â0.638). On the other hand, the âfounder effect hypothesisâ is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, Pâ=â0.019). In summary, our results show no evidence for the âNazi's experiment hypothesisâ and strongly suggest that the âfounder effect hypothesisâ is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified
Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease
The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias
Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models
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