In this cross-sectional study, the relationship between noninvasively measured neurocardiovascular signal entropy and physical frailty was explored in a sample of community-dwelling older adults from The Irish Longitudinal Study on Ageing (TILDA). The hypothesis under investigation was that dysfunction in the neurovascular and cardiovascular systems, as quantified by short-length signal complexity during a lying-to-stand test (active stand), could provide a marker for frailty. Frailty status (i.e., “non-frail”, “pre-frail”, and “frail”) was based on Fried’s criteria (i.e., exhaustion, unexplained weight loss, weakness, slowness, and low physical activity). Approximate entropy (ApEn) and sample entropy (SampEn) were calculated during resting (lying down), active standing, and recovery phases. There was continuously measured blood pressure/heart rate data from 2645 individuals (53.0% female) and frontal lobe tissue oxygenation data from 2225 participants (52.3% female); both samples had a mean (SD) age of 64.3 (7.7) years. Results revealed statistically significant associations between neurocardiovascular signal entropy and frailty status. Entropy differences between non-frail and pre-frail/frail were greater during resting state compared with standing and recovery phases. Compared with ApEn, SampEn seemed to have better discriminating power between non-frail and pre-frail/frail individuals. The quantification of entropy in short length neurocardiovascular signals could provide a clinically useful marker of the multiple physiological dysregulations that underlie physical frailty.

Objective. To biologically optimise proton therapy, models which can accurately predict variations in proton relative biological effectiveness (RBE) are essential. Current phenomenological models show large disagreements in RBE predictions, due to different model assumptions and differences in the data to which they were fit. In this work, thirteen RBE models were benchmarked against a comprehensive proton RBE dataset to evaluate predictions when all models are fit using the same data and fitting techniques, and to assess the statistical robustness of the models. Approach. Model performance was initially evaluated by fitting to the full dataset, and then a cross-validation approach was applied to assess model generalisability and robustness. The impact of weighting the fit and the choice of biological endpoint (either single or multiple survival levels) was also evaluated. Main results. Fitting the models to a common dataset reduced differences between their predictions, however significant disagreements remained due to different underlying assumptions. All models performed poorly under cross-validation in the weighted fits, suggesting that some uncertainties on the experimental data were significantly underestimated, resulting in over-fitting and poor performance on unseen data. The simplest model, which depends linearly on the LET but has no tissue or dose dependence, performed best for a single survival level. However, when fitting to multiple survival levels simultaneously, more complex models with tissue dependence performed better. All models had significant residual uncertainty in their predictions compared to experimental data. Significance. This analysis highlights that poor quality of error estimation on the dose response parameters introduces substantial uncertainty in model fitting. The significant residual error present in all approaches illustrates the challenges inherent in fitting to large, heterogeneous datasets and the importance of robust statistical validation of RBE models.

The cerebrovascular effects of supine hypertension (SH) are still poorly understood. With aging and atherosclerosis of the vascular system, it is not uncommon for SH and non-neurogenic orthostatic hypotension to co-occur. Given evidence for end organ damage and more extreme cerebral dysfunction in those with SH-orthostatic hypotension, we hypothesized that SH would be associated with impaired cerebral autoregulation. The aim of this study was to characterize the cerebrovascular response to orthostasis. Near-infrared spectroscopy was used to quantify the cerebrovascular response. We analyzed data from Wave 3 of TILDA (The Irish Longitudinal Study on Ageing; n=2750). Cerebral oxygenation and blood pressure (BP) were monitored continuously during an active stand. Responses were modeled using multilevel mixed-effects models and adjusted for important covariates such as age, sex, education, antihypertensive medications, and comorbidities. Forty-nine percent of the sample had SH. Those with SH demonstrated an impaired BP response and a slower recovery of BP after standing, graded by severity of SH. The cerebral oxygenation response was similar for both groups, but when standardized to mean arterial BP, the response was impaired in those with SH. A deficit of −0.83% (95% CI, −0.93 to −0.74) remained after 3 minutes of standing. Our study determined that cerebral oxygenation and cerebral autoregulation are impaired in those with SH. In older patients, consideration should be given to measuring SH and screening for orthostatic hypotension. Therapeutic studies are needed to better understand the relationship between cerebral oxygenation, medications, supine BP, and orthostatic hypotension.

In this study, the relationship between non-invasively measured cardiovascular signal entropy and global cognitive performance was explored in a sample of community-dwelling older adults from The Irish Longitudinal Study on Ageing (TILDA), both cross-sectionally at baseline (n = 4525; mean (SD) age: 61.9 (8.4) years; 54.1% female) and longitudinally. We hypothesised that signal disorder in the cardiovascular system, as quantified by short-length signal entropy during rest, could provide a marker for cognitive function. Global cognitive function was assessed via Mini Mental State Examination (MMSE) across five longitudinal waves (8 year period; n = 4316; mean (SD) age: 61.9 (8.4) years; 54.4% female) and the Montreal Cognitive Assessment (MOCA) across two longitudinal waves (4 year period; n = 3600; mean (SD) age: 61.7 (8.2) years; 54.1% female). Blood pressure (BP) was continuously monitored during supine rest at baseline, and sample entropy values were calculated for one-minute and five-minute sections of this data, both for time-series data interpolated at 5 Hz and beat-to-beat data. Results revealed significant associations between BP signal entropy and cognitive performance, both cross-sectionally and longitudinally. Results also suggested that as regards associations with cognitive performance, the entropy analysis approach used herein potentially outperformed more traditional cardiovascular measures such as resting heart rate and heart rate variability. The quantification of entropy in short-length BP signals could provide a clinically useful marker of the cardiovascular dysregulations that potentially underlie cognitive decline.

Cerebral autoregulation (CAR) systems maintain blood flow to the brain across a wide range of blood pressures. Deficits in CAR have been linked to gait speed (GS) but previous studies had small sample sizes and used specialized equipment which impede clinical translation. The purpose of this work was to assess the association between GS and orthostatic cerebral oxygenation in a large, community-dwelling sample of older adults. Data for this study came from the Irish Longitudinal Study on Ageing. A near-infrared spectroscopy (NIRS) device attached to the forehead of each participant (n = 2 708) was used to track tissue saturation index (TSI; the ratio of oxygenated to total hemoglobin) during standing. GS was assessed using a portable walkway. Recovery was impaired in slower GS participants with a TSI value at 20 seconds (after standing) of −0.55% (95% CI: −0.67, −0.42) below baseline in the slowest GS quartile versus −0.14% (95% CI: −0.25, −0.04) in the fastest quartile. Slower GS predicted a lower TSI throughout the 3-minute monitoring period. Results were not substantially altered by adjusting for orthostatic hypotension. Adjustment for clinical and demographic covariates attenuated the association between but differences remained between GS quartiles from 20 seconds to 3 minutes after standing. This study reported evidence for impaired recovery of orthostatic cerebral oxygenation depending on GS in community-dwelling older adults. Future work assessing NIRS as a clinical tool for monitoring the relationship between GS and cerebral regulation is warranted.

Variation in hip joint contact forces directly influences the performance of total hip replacements (THRs). Measurement and calculation of contact forces in THR patients has been limited by small sample sizes, wide variation in patient and surgical factors, and short-term follow-up. This study hypothesised that, at long-term follow-up, unilateral THR patients have similar calculated hip contact forces compared to controls walking at similar (self-selected) speeds and, in contrast, THR patients walking at slower (self-selected) speeds have reduced hip contact forces. It was further hypothesised that there is no difference in calculated hip contact forces between operated and non-operated limbs at long-term follow-up for both faster and slower patients. Gait analysis data for THR patients walking at faster (walking speed: 1.29 ± 0.12 m/s; n = 11) and slower (walking speed: 0.72 ± 0.09 m/s; n = 11) speeds were used. Healthy subjects constituted the control group (walking speed: 1.36 ± 0.12 m/s; n = 10). Hip contact forces were calculated using static optimisation. There was no significant difference (p>0.31) in hip contact forces between faster and control groups. Conversely, force was reduced at heel strike by 19% (p=0.002), toe-off by 31% (p<0.001) and increased at mid-stance by 15% (p=0.02) for the slower group compared to controls. There were no differences between operated and non-operated limbs for the slower group or the faster group, suggesting good biomechanical recovery at long-term follow-up. Loading, at different walking speeds, presented here can improve the relevance of preclinical testing methods.