Assessment of Exercise Capacity and Oxygen Consumption Using a 6 min Stepper Test in Older Adults

It is often necessary to assess physical function in older adults to monitor disease progression, rehabilitation or decline in function with age. However, increasing frailty and poor balance that accompany aging are common barriers to exercise testing protocols. We investigated whether a 6-min stepper test (6MST) was acceptable to older adults and provided a measure of exercise capacity and a predicted value for peak aerobic capacity (VO2max). 635 older adults from a tri-ethnic UK population-based cohort were screened to undertake a self-paced 6MST. Expired gas analysis, heart rate and blood pressure monitoring were carried out. A sub-set of 20 participants performed a second 6MST for assessment of reproducibility and a further sub-set of 10 performed the 6-min walk test as verification against a well-recognized and accepted self-paced exercise test. 518 (82%) participants met inclusion criteria and undertook the 6MST (299 men, mean age 71.2 ± 6.4). Step rate showed a strong positive correlation with measured VO2 (r = 0.75, p < 0.001) and VO2 was lower in women (male-female difference in VO2 = 2.61 (95% confidence interval -3.6, -1.7) ml/min/kg; p < 0.001). 20 participants repeated a 6MST, step rate was higher in the second test but the predicted VO2max showed good agreement (mean difference = 0.1 [3.72, 3.95] ml/min/kg). In 10 participants who completed a 6MST and a 6-min walk test there was a strong positive correlation between walking rate and step rate (r = 0.77; p < 0.009) and weaker positive correlations between the tests for measured VO2 and peak heart rate. In conclusion, the 6MST is a convenient, acceptable method of assessing exercise capacity in older adults that allows VO2max to be predicted reproducibly. The test shows good correlation between performance and measured physiological markers of performance and can detect the expected gender differences in measured VO2. Furthermore, the 6MST results correlate with a previously verified and established self-paced exercise test

Characteristics and racial variations of polypoidal choroidal vasculopathy in tertiary centers in the United States and United Kingdom

PURPOSE: To evaluate the characteristics and racial variations amongst patients with polypoidal choroidal vasculopathy (PCV) in the United States and the United Kingdom. METHODS: Fundus photos and indocyanine green angiography images were evaluated in a multicenter retrospective study to establish the diagnosis of PCV. Visual acuity (VA) was recorded in ETDRS letter count. RESULTS: Eighty eyes of 71 PCV patients (average age of 69.4 ± 10.4 years) were included in the analysis. Of the total 71 subjects, 46 (65%) were women, 33 (46.5%) were Blacks, 16 (22.5%) were Whites, 19 (26.8%) were Asians and 3 (4.2%) belonged to other races. The Black subgroup had vision gain of 3.5 letters. The White and Asian subgroups had vision loss of 13.1 and 3.5 letters, respectively. There was female predominance in Blacks (67%), Whites (69%), and Asians (58%). PCV was found to be a bilateral disease in 14 patients (20%). There was significant decrease of 7 letters with every decade increase in age (p = 0.005). Final VA was worse in males when compared to females (p = 0.042), and worse in Whites when compared to Blacks (p = 0.005). For every 10 letters worse in initial VA upon diagnosis with PCV, the final VA was worse by 6 letters (p < 0.001). The location of the polypoidal lesion within the macula was associated with significant decrease of 14 letters in BCVA (p = 0.02). The length of follow up was significantly associated with worse visual outcome (p = 0.012). Final VA had no significant correlation with the lens status, or the different treatment modalities. CONCLUSIONS: Based on our cohort from tertiary centers in the United States and United Kingdom, PCV is a bilateral disease in one-fifth of patients. It features a variable female predominance based on ethnicity. Increased age, worse vision upon initial presentation, longer follow up and macular location of the polyp were associated with worse visual outcome

Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the MAPT gene, encoding the tau protein that accumulates in intraneuronal lesions in a number of neurodegenerative diseases. Several FTDP-17 mutations affect alternative splicing and result in excess exon 10 (E10) inclusion in tau mRNA. RNA reprogramming using spliceosome-mediated RNA trans-splicing (SMaRT) could be a method of choice to correct aberrant E10 splicing resulting from FTDP-17 mutations. SMaRT creates a hybrid mRNA through a trans-splicing reaction between an endogenous target pre-mRNA and a pre-trans-splicing RNA molecule (PTM). However, FTDP-17 mutations affect the strength of cis-splicing elements and could favor cis-splicing over trans-splicing. Excess E10 inclusion in FTDP-17 can be caused by intronic mutations destabilizing a stem-loop protecting the 5′ splice site at the E10/intron 10 junction. COS cells transfected with a minigene containing the intronic +14 mutation produce exclusively E10+ RNA. Generation of E10− RNA was restored after co-transfection with a PTM designed to exclude E10. Similar results were obtained with a target containing the exonic N279K mutation which strengthens a splicing enhancer within E10. Conversely, increase or decrease in E10 content was achieved by trans-splicing from a target carrying the Δ280K mutation, which weakens the same splicing enhancer. Thus E10 inclusion can be modulated by trans-splicing irrespective of the strength of the cis-splicing elements affected by FTDP-17 mutations. In conclusion, RNA trans-splicing could provide the basis of therapeutic strategies for impaired alternative splicing caused by pathogenic mutations in cis-acting splicing elements

Development of a Single Vector System that Enhances Trans-Splicing of SMN2 Transcripts

RNA modalities are developing as a powerful means to re-direct pathogenic pre-mRNA splicing events. Improving the efficiency of these molecules in vivo is critical as they move towards clinical applications. Spinal muscular atrophy (SMA) is caused by loss of SMN1. A nearly identical copy gene called SMN2 produces low levels of functional protein due to alternative splicing. We previously reported a trans-splicing RNA (tsRNA) that re-directed SMN2 splicing. Now we show that reducing the competition between endogenous splices sites enhanced the efficiency of trans-splicing. A single vector system was developed that expressed the SMN tsRNA and a splice-site blocking antisense (ASO-tsRNA). The ASO-tsRNA vector significantly elevated SMN levels in primary SMA patient fibroblasts, within the central nervous system of SMA mice and increased SMN-dependent in vitro snRNP assembly. These results demonstrate that the ASO-tsRNA strategy provides insight into the trans-splicing mechanism and a means of significantly enhancing trans-splicing activity in vivo

Sailing into the wind : new disciplines in Australian higher education

Much is made of the potential of lifelong learning for individuals and organisations. In this article we tend to make much less of it, certainly with respect to its use in universities to discipline academics. Nevertheless, we argue that academics now need to re-learn the positions they occupy and the stances they take in response to the marketisation of Australian universities. In particular, we suggest that the position of (pure) critique no longer commands attention in Australian contexts of higher education, although the paper does not suggest a disregard for a critical stance purely for the sake of participation. It is in understanding the interconnections between position and stance , and how they might be strategically performed during the everyday practices of academics, that a more promising way of engaging with the venalities of the market is envisaged; a strategy that could be described as \u27sailing into the wind\u27. In discussing these matters, the paper draws on semi-structured interviews with academics located in university faculties/departments/schools of education along Australia\u27s eastern seaboard

Researching the use of force: The background to the international project

This article provides the background to an international project on use of force by the police that was carried out in eight countries. Force is often considered to be the defining characteristic of policing and much research has been conducted on the determinants, prevalence and control of the use of force, particularly in the United States. However, little work has looked at police officers’ own views on the use of force, in particular the way in which they justify it. Using a hypothetical encounter developed for this project, researchers in each country conducted focus groups with police officers in which they were encouraged to talk about the use of force. The results show interesting similarities and differences across countries and demonstrate the value of using this kind of research focus and methodology

Ethnicity and prediction of cardiovascular disease: performance of QRISK2 and Framingham scores in a U.K. tri-ethnic prospective cohort study (SABRE--Southall And Brent REvisited).

OBJECTIVE: To evaluate QRISK2 and Framingham cardiovascular disease (CVD) risk scores in a tri-ethnic U.K. population. DESIGN: Cohort study. SETTING: West London. PARTICIPANTS: Randomly selected from primary care lists. Follow-up data were available for 87% of traced participants, comprising 1866 white Europeans, 1377 South Asians, and 578 African Caribbeans, aged 40-69 years at baseline (1998-1991). MAIN OUTCOME MEASURES: First CVD events: myocardial infarction, coronary revascularisation, angina, transient ischaemic attack or stroke reported by participant, primary care or hospital records or death certificate. RESULTS: During follow-up, 387 CVD events occurred in men (14%) and 78 in women (8%). Both scores underestimated risk in European and South Asian women (ratio of predicted to observed risk: European women: QRISK2: 0.73, Framingham: 0.73; South Asian women: QRISK2: 0.52, Framingham: 0.43). In African Caribbeans, Framingham over-predicted in men and women and QRISK2 over-predicted in women. Framingham classified 28% of participants as high risk, predicting 54% of all such events. QRISK2 classified 19% as high risk, predicting 42% of all such events. Both scores performed poorly in identifying high risk African Caribbeans; QRISK2 and Framingham identified as high risk only 10% and 24% of those who experienced events. CONCLUSIONS: Neither score performed consistently well in all ethnic groups. Further validation of QRISK2 in other multi-ethnic datasets, and better methods for identifying high risk African Caribbeans and South Asian women, are required

Exon Exchange Approach to Repair Duchenne Dystrophin Transcripts

Background: Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 59 or the 39 part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. Methodology/Principal Findings: As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23). This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25–45 % of repair depending on the construction in use. Conclusions/Significance: These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations

Word forms are structured for efficient use

Zipf famously stated that, if natural language lexicons are structured for efficient communication, the words that are used the most frequently should require the least effort. This observation explains the famous finding that the most frequent words in a language tend to be short. A related prediction is that, even within words of the same length, the most frequent word forms should be the ones that are easiest to produce and understand. Using orthographics as a proxy for phonetics, we test this hypothesis using corpora of 96 languages from Wikipedia. We find that, across a variety of languages and language families and controlling for length, the most frequent forms in a language tend to be more orthographically well‐formed and have more orthographic neighbors than less frequent forms. We interpret this result as evidence that lexicons are structured by language usage pressures to facilitate efficient communication. Keywords: Lexicon; Word frequency; Phonology; Communication; EfficiencyNational Science Foundation (Grant ES/N0174041/1