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

Spaceflight-Induced Cardiovascular Changes and Recovery During NASA's Functional Task Test

Microgravity-induced physiological changes could impair a crewmember s performance upon return to a gravity environment. The Functional Task Test (FTT) is designed to correlate these physiological changes to performance in mission-critical tasks. The Recovery from Fall/Stand Test (RFST) simulates one such task, measuring the ability to recover from a prone position and the cardiovascular response to orthostasis. The purpose of this study was to evaluate spaceflight-induced cardiovascular changes during the FTT. METHODS: Five astronauts participated in the FTT before 10-15 day missions, on landing day (R+0), and one (R+1), six (R+6) and thirty (R+30) days after landing. The RFST consisted of a 2-minute prone rest followed by a 3-minute stand during which heart rate (HR, Holter) and continuous blood pressure (BP, Finometer) were measured. Spectral heart rate variability (HRV) was calculated during the RFST to approximate autonomic function. Statistical analysis was performed with two-factor repeated measures ANOVA. RESULTS: During RFST, HR was higher on R+0 than preflight (p<0.004). This increase in HR persisted on R+1 and R+6 during the stand portion of RFST (p<0.026). BP was well-regulated on all test days. Parasympathetic activity was diminished on R+0 (p=0.035). Sympathovagal balance tended to be affected by spaceflight (main effect, p=0.072), appearing to be slightly elevated during postflight RFST except on R+30. Additionally, analysis of HR during the functional tasks yielded a higher HR on R+0 than preflight during 8 of 11 tasks analyzed, where all tasks had HR return to preflight values by R+30 (p<0.05). CONCLUSION: Spaceflight causes an increase in HR, decrease in parasympathetic activity, and increase in sympathovagal balance, which we confirmed during RFST. These spaceflight-induced changes seen in the RFST, along with the increased postflight HR in most functional tasks, can be used to assess functional performance after short-duration spaceflight

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

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Heart Rate Response During Mission-Critical Tasks After Space Flight

Adaptation to microgravity could impair crewmembers? ability to perform required tasks upon entry into a gravity environment, such as return to Earth, or during extraterrestrial exploration. Historically, data have been collected in a controlled testing environment, but it is unclear whether these physiologic measures result in changes in functional performance. NASA?s Functional Task Test (FTT) aims to investigate whether adaptation to microgravity increases physiologic stress and impairs performance during mission-critical tasks. PURPOSE: To determine whether the well-accepted postflight tachycardia observed during standard laboratory tests also would be observed during simulations of mission-critical tasks during and after recovery from short-duration spaceflight. METHODS: Five astronauts participated in the FTT 30 days before launch, on landing day, and 1, 6, and 30 days after landing. Mean heart rate (HR) was measured during 5 simulations of mission-critical tasks: rising from (1) a chair or (2) recumbent seated position followed by walking through an obstacle course (egress from a space vehicle), (3) translating graduated masses from one location to another (geological sample collection), (4) walking on a treadmill at 6.4 km/h (ambulation on planetary surface), and (5) climbing 40 steps on a passive treadmill ladder (ingress to lander). For tasks 1, 2, 3, and 5, astronauts were encouraged to complete the task as quickly as possible. Time to complete tasks and mean HR during each task were analyzed using repeated measures ANOVA and ANCOVA respectively, in which task duration was a covariate. RESULTS: Landing day HR was higher (P < 0.05) than preflight during the upright seat egress (7%+/-3), treadmill walk (13%+/-3) and ladder climb (10%+/-4), and HR remained elevated during the treadmill walk 1 day after landing. During tasks in which HR was not elevated on landing day, task duration was significantly greater on landing day (recumbent seat egress: 25%+/-14 and mass translation: 26%+/-12; P < 0.05). CONCLUSION: Elevated HR and increased task duration during postflight simulations of mission-critical tasks is suggestive of spaceflight-induced deconditioning. Following short-duration microgravity missions (< 16 d), work performance may be transiently impaired, but recovery is rapid