Estimating a preference-based index for a menopause specific health quality of life questionnaire

BACKGROUND: The aim of the study was to develop a menopause-specific, preference-based healthrelated quality-of-life (HRQoL) index reflecting both menopausal symptoms and potential sideeffects of Hormone Replacement Therapy (HRT). METHODS: The study had three phases: the development of a health state classification, a prospective valuation survey and the estimation of a model to interpolate HRQoL indices for all remaining health states as defined by the classification. A menopausal health state classification was developed with seven dimensions: hot flushes, aching joints/muscles, anxious/frightened feelings, breast tenderness, bleeding, vaginal dryness and undesirable androgenic signs. Each dimension contains between three and five levels and defines a total of 6,075 health states. A sample of 96 health states was selected for the valuation survey. These states were valued by a sample of 229 women aged 45 to 60, randomly selected from 6 general practice lists in Sheffield, UK. Respondents were asked to complete a time trade-off (TTO) task for nine health states, resulting in an average of 16.5 values for each health state. RESULTS: Mean health states valued range from 0.48 to 0.98 (where 1.0 is full health and zero is for states regarded as equivalent to death). Symptoms, as described by the classification system, can be rank-ordered in terms of their impact (from high to low) on menopausal HRQoL as follows: aching joints and muscles, bleeding, breast tenderness, anxious or frightened feelings, vaginal dryness, androgenic signs. Hot flushes did not significantly contribute to model fit. The preferred model produced a mean absolute error of 0.053, but suffered from bias at both ends of the scale. CONCLUSION: This article presents an attempt to directly value a condition specific health state classification. The overall fit was disappointing, but the results demonstrate that menopausal symptoms are perceived by patients to have a significant impact on utility. The overall effect is modest compared to the more generic health state descriptions such as the EQ-5D. The resultant algorithm generates a preference-based index that can be used economic evaluation and that reflects the impact of this condition

Molecular dynamics simulation on the effect of transition metal binding to the N-terminal fragment of amyloid-β

We report molecular dynamics simulations of three possible adducts of Fe(II) to the N-terminal 1–16 fragments of the amyloid-β peptide, along with analogous simulations of Cu(II) and Zn(II) adducts. We find that multiple simulations from different starting points reach pseudo-equilibration within 100–300 ns, leading to over 900 ns of equilibrated trajectory data for each system. The specifics of the coordination modes for Fe(II) have only a weak effect on peptide secondary and tertiary structures, and we therefore compare one of these with analogous models of Cu(II) and Zn(II) complexes. All share broadly similar structural features, with mixture of coil, turn and bend in the N-terminal region and helical structure for residues 11–16. Within this overall pattern, subtle effects due to changes in metal are evident: Fe(II) complexes are more compact and are more likely to occupy bridge and ribbon regions of Ramachandran maps, while Cu(II) coordination leads to greater occupancy of the poly-proline region. Analysis of representative clusters in terms of molecular mechanics energy and atoms-in-molecules properties indicates similarity of four-coordinate Cu and Zn complexes, compared to five-coordinate Fe complex that exhibits lower stability and weaker metal–ligand bonding

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Aβ peptide that is implicated in the onset of Alzheimer’s disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced

Metal binding to amyloid-β1–42: a ligand field molecular dynamics study

Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β1–42 peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals

Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides

Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1–16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-β1–16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand

Effect of urban vs. rural residence on the association between atopy and wheeze in Latin America: findings from a case-control analysis.

BACKGROUND: The association between atopy and asthma is attenuated in non-affluent populations, an effect that may be explained by childhood infections such as geohelminths. OBJECTIVE: To investigate the association between atopy and wheeze in schoolchildren living in urban and rural areas of Ecuador and examine the effects of geohelminths on this association. METHODS: We performed nested case-control studies among comparable populations of schoolchildren living in rural communities and urban neighbourhoods in the Province of Esmeraldas, Ecuador. We detected geohelminths in stool samples, measured recent wheeze and environmental exposures by parental questionnaire, and atopy by specific IgE (sIgE) and skin prick test (SPT) reactivity to aeroallergens. RESULTS: Atopy, particularly sIgE to house dust mite (HDM), was more strongly associated with recent wheeze in urban than rural schoolchildren: (urban, adj. OR 5.19, 95% CI 3.37-8.00, P < 0.0001; rural, adj. OR 1.81, 95%CI 1.09-2.99, P = 0.02; interaction, P < 0.001). The population fractions of wheeze attributable to atopy were approximately two-fold greater in urban schoolchildren: SPT to any allergen (urban 23.5% vs. rural 10.1%), SPT to HDM (urban 18.5% vs. rural 9.6%), and anti-HDM IgE (urban 26.5% vs. rural 10.5%), while anti-Ascaris IgE was related to wheeze in a high proportion of rural (49.7%) and urban (35.4%) children. The association between atopy and recent wheeze was attenuated by markers of geohelminth infections. CONCLUSIONS: Our data suggest that urban residence modifies the association between HDM atopy and recent wheeze, and this effect is explained partly by geohelminth infections

Effects of High Dietary HEME Iron and Radiation on Cardiovascular Function

The radiation related health risks to astronauts is of particular concern to NASA. Data support that exposure to radiation is associated with a number of disorders including a heightened risk for cardiovascular diseases. Independent of radiation, altered nutrient status (e.g. high dietary iron) also increases ones risk for cardiovascular disease. However, it is unknown whether exposure to radiation in combination with high dietary iron further increases ones cardiovascular risk. The intent of our proposal is to generate compulsory data examining the combined effect of radiation exposure and iron overload on sensitivity to radiation injury to address HRP risks: 1) Risk Factor of Inadequate Nutrition; 2) Risk of Cardiac Rhythm Problems; and 3) Risk of Degenerative Tissue or other Health Effects from Space Radiation. Towards our goal we propose two distinct pilot studies using the following specific aims: Vascular Aim 1: To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function and cell viability and integrity. We hypothesize that animals that have high body iron stores and are exposed to gamma radiation will show a greater reduction in endothelial dependent nitric oxid production and larger pathological changes in endothelial integrity than animals that have only 1 of those treatments (either high iron stores or exposure to gamma radiation). Vascular Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with endothelial cell function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment. Cardiac Aim 1: To determine the short-term consequences of the independent and combined effects of gamma radiation and elevated body iron stores on measures of cardiac structure. We hypothesize that modifications to cardiac structure and function will be greater in rats with high body iron stores and exposed to gamma radiation than in rats that have only 1 of those treatments. Cardiac Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with cardiac structure and function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with cardiac contractile function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment

Lower Limb Venous Compliance is Different Between Men and Women Following 60 Days of Head-Down Bedrest but Is Not Associated with Venoconstriction Dysfunction

Space flight-induced orthostatic intolerance (OI) is more prevalent in female (F) than male (M) astronauts. The mechanisms explaining the higher incidence of OI in F are unclear. We tested the hypothesis that venous compliance would be higher in F more than M following 6 deg head-down bed rest (BR) and would be associated with constrictor dysfunction. Using 2-D ultrasound, dorsal hand (DHV) and dorsal foot (DFV) vein compliances were determined in 24 subjects (10 F, 14 M; 35 +/- 1 yr) by measuring mean diameter response to increasing congestion pressure (0, 20, 30, and 40 mmHg) before and after 60 d of BR. Constrictor function was assessed by intravenous infusions of Ketorolac (KE; 1.5 ig/min) Phenylephrine (PE; 3160 ng/min), and L-NMMA (50 ig/min). The effects of BR between F vs. M and hand vs. foot were determined using mixed-effects linear regression. DFV but not DHV compliance changed in response to BR (p=0.012). Mean DFV increased significantly (0.903 mm to 1.191mm) in F but decreased in M (1.353 mm to 1.154 mm). DFV constrictor response was not different between sexes in response to BR (KE; p=0.647, PE; p=0.717, and L-NMMA; p=0.825). These BR data suggest that the higher incidence of OI in F astronauts may be related to increased lower limb venous compliance, contributing to blood pooling upon standing. Notably, changes to DFV compliance was not accompanied by impaired constrictor function

Physical occupational exposures and health expectancies in a French occupational cohort.

OBJECTIVES: To examine the relationships of strenuous and hazardous working conditions and rotating shifts that involve night working with life expectancy in good perceived health and life expectancy without chronic disease. METHODS: The sample contained male gas and electricity workers from the French GAZEL cohort (n=13 393). Six measures of physical working conditions were examined: Self-reports from 1989 and 1990 of ergonomic strain, physical danger, rotating shifts that involve night working and perceived physical strain; company records of workplace injuries and a job-exposure matrix of chemical exposures. Partial healthy life expectancies (age 50-75) relating to (1) self-rated health and (2) chronic health conditions, obtained from annual questionnaires (1989-2014) and company records, were estimated using multistate life tables. The analyses were adjusted for social class and occupational grade. RESULTS: Participants with physically strenuous jobs and who had experienced industrial injuries had shorter partial life expectancy. More physically demanding and dangerous work was associated with fewer years of life spent in good self-rated health and without chronic conditions, with the exception of shift work including nights, where the gradient was reversed. CONCLUSIONS: Strenuous and hazardous work may contribute to lost years of good health in later life, which has implications for individuals' quality of life as well as healthcare use and labour market participation