development of measures of polyneuropathy impairment in hattr amyloidosis from nis to mnis 7

Abstract Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. Measures used to assess polyneuropathy in other diseases have been tested as endpoints in hATTR amyloidosis clinical trials (i.e. Neuropathy Impairment Score [NIS], NIS-lower limb, and NIS + 7), yet the unique nature of the polyneuropathy in this disease has necessitated modifications to these scales. In particular, the heterogeneous impairment and the aggressive disease course have been key drivers in developing scales that better capture the disease burden and progression of polyneuropathy in hATTR amyloidosis. The modified NIS + 7 (mNIS + 7) scale was specifically designed to assess polyneuropathy impairment in patients with hATTR amyloidosis, and has been the primary endpoint in two recent, phase III studies in this disease. The mNIS + 7 uses highly standardized, quantitative, and referenced assessments to quantify decreased muscle weakness, muscle stretch reflexes, sensory loss, and autonomic impairment. Physicians using this scale in clinical trials should be specifically trained and monitored to minimize variability. This article discusses the different scales that have been/are being used to assess polyneuropathy in patients with hATTR amyloidosis, their correlation with other disease assessments, and reflects on how and why scales have evolved to the latest iteration of mNIS + 7

Social and physical environmental correlates of adults\u27 weekend sitting time and moderating effects of retirement status and physical health

Emerging research suggests that prolonged sedentary behaviour (SB) is detrimental to health. Changes in SB patterns are likely to occur during particular life stages, for example at retirement age (55-65-year-old). Evidence on socio-ecological SB correlates is scarce and inconsistent in this age group. Moreover, the influence of socio-ecological correlates may vary depending on health and retirement status. This study examined social and environment correlates of overall weekend day sitting among adults at or approaching retirement age, and moderating effects of perceived physical health and retirement status. Baseline data from the Wellbeing, Eating and Exercise for a Long Life study in 2839 Australian adults (55-65-year-old) were analysed. Participants self-reported proximal social factors, neighbourhood social and physical environment, physical health and retirement status. MLwiN multilevel regression analyses were conducted. In the multivariable model, only social support from friends/colleagues to discourage sitting (B = -0.891; p = 0.036) was associated with overall weekend day sitting. No moderation of retirement status, nor physical health were found in the multivariable results. Results from this study suggest the importance of social factors in relation to weekend day sitting among 55-65-year-old adults. Health promotion initiatives in this age group should pay special attention to enhancing social interaction opportunities. Moreover, findings suggest that SB-specific correlates may need to be examined in future research

Quantum Logic with a Single Trapped Electron

We propose the use of a trapped electron to implement quantum logic operations. The fundamental controlled-NOT gate is shown to be feasible. The two quantum bits are stored in the internal and external (motional) degrees of freedom.Comment: 7 Pages, REVTeX, No Figures, To appear in Phys. Rev.

The Challenges of Living with and Caring for a Child or Children Affected by Neuronal Ceroid Lipofuscinosis Type 2 Disease: In-Depth Family Surveys in the United Kingdom and Germany

Limited research has investigated the challenges faced by families caring for children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Face-to-face, mixed-method, in-depth surveys were conducted with 19 families (23 children) in the UK (n=9) and Germany (n=10) to assess the impact of caring for children with CLN2 disease, using national wellbeing and quality of life (QoL) measures. Primary (n=19) and secondary (n=10) caregivers, adult siblings (n=2), and child siblings (n=2) were included. Caregivers reported reduced health-related QoL compared with age and gender-matched controls (mean utility scores 0.08 and 0.11 lower in Germany and the UK, respectively). Hours of caregiving were significantly higher relative to that provided to a child of normal health, with stress, back pain, and reductions in sleep being recorded. Lower life satisfaction and happiness with partners were also reported, along with significant financial burden. Those caring for children in the late stage of disease were more greatly impacted than those with children in the rapidly progressive stage, or who were bereaved. The results of this study make clear the importance of emotional and practical support for caregivers and siblings coping with CLN2 disease

Electron diffraction and high-resolution transmission electron microscopy of the high temperature crystal structures of GexSb2Te3+x (x=1,2,3) phase change material

The crystal structures of GeSb2Te4, Ge2Sb2Te5, and Ge3Sb2Te6 were determined using electron diffraction and high-resolution transmission electron microscopy. The structure determined for the former two crystals deviates from the ones proposed in the literature. These crystal structures were developed jointly upon cooling of liquid Ge2Sb2Te5. A stacking disorder parallel to the basal plane was observed that increases with increasing cooling rates. For the GexSb2Te3+x (x=1,2,3) crystals it is shown that an a,b,c stacking holds with an alternating stacking of x GeTe double layers identically present in binary GeTe and one Te-Sb-Te-Te-Sb- repeat unit also present in binary Sb2Te3. A stacking disorder is a logical consequence of building crystals with these two principal units. On the other hand, it is likely that all stable crystals of the Ge-Sb-Te systems are an ordered sequence of these two units. Some of the implications of these findings of the stable and metastable crystal structures that develop from amorphous Ge2Sb2Te5 are presented so as to understand the crucial crystallization process in Ge2Sb2Te5 phase change material

A List of Bright Interferometric Calibrators measured at the ESO VLTI

In a previous publication (Richichi & Percheron 2005) we described a program of observations of candidate calibrator stars at the ESO Very Large Telescope Interferometer (VLTI), and presented the main results from a statistical point of view. In the present paper, we concentrate on establishing a new homogeneous group of bright interferometric calibrators, based entirely on publicly available K-band VLTI observations carried out with the VINCI instrument up to July 2004. For this, we have defined a number of selection criteria for the quality and volume of the observations, and we have accordingly selected a list of 17 primary and 47 secondary calibrators. We have developed an approach to a robust global fit for the angular diameters using the whole volume of quality-controlled data, largely independent of a priori assumptions. Our results have been compared with direct measurements, and indirect estimates based on spectrophotometric methods, and general agreement is found within the combined uncertainties. The stars in our list cover the range K=-2.9 to +3.0 mag in brightness, and 1.3 to 20.5 milliarcseconds in uniform-disk diameter. The relative accuracy of the angular diameter values is on average 0.4% and 2% for the primary and secondary calibrators respectively. Our calibrators are well suited for interferometric observations in the near-infrared on baselines between ~20m and ~200m, and their accuracy is superior, at least for the primary calibrators, to other similar catalogues. Therefore, the present list of calibrators has the potential to lead to significantly improved interferometric scientific results

International Public Health Research Involving Interpreters: a Case Study from Bangladesh

Background: Cross-cultural and international research are important components of public health research, but the challenges of language barriers and working with interpreters are often overlooked, particularly in the case of qualitative research. Methods: A case-study approach was used to explore experiences of working with an interpreter in Bangladesh as part of a research project investigating women's experiences of emergency obstetric care. The case study: Data from the researcher's field notes provided evidence of experiences in working with an interpreter and show how the model of interviewing was adapted over time to give a more active role to the interpreter. The advantages of a more active role were increased rapport and "flow" in interviews. The disadvantages included reduced control from the researcher's perspective. Some tensions between the researcher and interpreter remained hard to overcome, irrespective of the model used. Independent transcription and translation of the interviews also raised questions around accuracy in translation. Conclusion: The issues examined in this case study have broader implications for public health research. Further work is needed in three areas: 1) developing effective relationships with interpreters; 2) the impact of the interpreter on the research process; and 3) the accuracy of the translation and level of analysis needed in any specific public health research. Finally, this paper highlights the importance to authors of reflecting on the potential impact of translation and interpretation on the research process when disseminating their research

Childcare, choice and social class: Caring for young children in the UK

This paper draws on the results of two qualitative research projects examining parental engagements with the childcare market in the UK. Both projects are located in the same two London localities. One project focuses on professional middle class parents, and the other on working class families, and we discuss the key importance of social class in shaping parents' differential engagement with the childcare market, and their understandings of the role childcare plays in their children's lives. We identify and discuss the different "circuits" of care (Ball et al 1995) available to and used by families living physically close to each other, but in social class terms living in different worlds. We also consider parents' relationships with carers, and their social networks. We conclude that in order to fully understand childcare policies and practices and families' experiences of care, an analysis which encompasses social class and the workings of the childcare market is needed

Signals for CPT and Lorentz Violation in Neutral-Meson Oscillations

Experimental signals for indirect CPT violation in the neutral-meson systems are studied in the context of a general CPT- and Lorentz-violating standard-model extension. In this explicit theory, some CPT observables depend on the meson momentum and exhibit diurnal variations. The consequences for CPT tests vary significantly with the specific experimental scenario. The wide range of possible effects is illustrated for two types of CPT experiment presently underway, one involving boosted uncorrelated kaons and the other involving unboosted correlated kaon pairs.Comment: Accepted in Physical Review D, scheduled for December 1999 issu

Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma