An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

Effects of immersive virtual reality training on balance, gait and mobility in older adults: A systematic review and meta-analysis.

OBJECTIVE: To examine whether immersive virtual reality (VR) can improve balance, gait, mobility and fear of falling in older people. DATA SOURCES: MEDLINE, EMBASE, CINAHL, PsycINFO, ProQuest Central (Engineering and Computer Science) and reference lists of included articles. STUDY SELECTION: Randomised controlled trials that administered immersive VR training and assessed balance, gait and mobility outcomes in older adults without neurological disorders (mean age ≥ 65). Primary outcomes were standing balance (e.g. postural sway), multi-item balance scales (e.g. Berg Balance Scale), gait (e.g. gait speed) and mobility (e.g. Timed Up and Go test). Secondary outcomes comprised measures of enjoyment, fear of falling, adherence (e.g. dropout rate), feasibility/usability and adverse effects (e.g. motion sickness). RESULTS: Meta-analyses showed that immersive VR training significantly improved standing balance (SMD: 0.51, 95% CI: .15, 0.86, p = 0.005, I2 = 28% - 3 studies, n = 79) and performance on the Berg Balance Scale (MD: 2.36, 95% CI: 1.17, 3.56, p=0.0001, I2=0% - 4 studies, n = 190). No significant improvement in gait, mobility or fear of falling was found. Subgroup analyses revealed higher training doses (≥4.5 total hours) and VR interventions using non-head mounted displays were more likely to improve standing balance. No meta-analyses were conducted for enjoyment, adherence, feasibility/usability and adverse events. CONCLUSIONS: The findings indicate immersive VR has beneficial effects on balance, but not gait, mobility or fear of falling. Further research is required to examine these outcomes in trials that also include quantitative measurements of enjoyment, adherence, clinical feasibility, usability and adverse effects.

The influence of fear of falling on the control of upright stance across the lifespan.

BACKGROUND: Standing at height, and subsequent changes in emotional state (e.g., fear of falling), lead to robust alterations in balance in adults. However, little is known about how height-induced postural threat affects balance performance in children. Children may lack the cognitive capability necessary to inhibit the processing of threat and fear-related stimuli, and as a result, may show more marked (and perhaps detrimental) changes in postural control compared to adults. This work explored the emotional and balance responses to standing at height in children, and compared responses to young and older adults. METHODS: Children (age: 9.7 ± 0.8 years, n = 38), young adults (age: 21.8 ± 4.0 years, n = 45) and older adults (age: 73.3 ± 5.0 years, n = 15) stood in bipedal stance in two conditions: at ground level and 80 cm above ground. Centre of pressure (COP) amplitude (RMS), frequency (MPF) and complexity (sample entropy) were calculated to infer postural performance and strategy. Emotional responses were quantified by assessing balance confidence, fear of falling and perceived instability. RESULTS: Young and older adults demonstrated a postural adaptation characterised by increased frequency and decreased amplitude of the COP, in conjunction with increased COP complexity (sample entropy). In contrast, children demonstrated opposite patterns of changes: they exhibited an increase in COP amplitude and decrease in both frequency and complexity when standing at height. SIGNIFICANCE: Children and adults adopted different postural control strategies when standing at height. Whilst young and older adults exhibited a potentially protective "stiffening" response to a height-induced threat, children demonstrated a potentially maladaptive and ineffective postural adaptation strategy. These observations expand upon existing postural threat related research in adults, providing important new insight into understanding how children respond to standing in a hazardous situation.

CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Effects of free versus restricted arm movements on postural control in normal and modified sensory conditions in young and older adults.

The purpose of this study was to explore the effects of arm movements on postural control when standing under different sensory conditions in healthy young and older adults. Fifteen young (mean ± SD age; 21.3 ± 4.2 years) and 15 older (mean ± SD age; 73.3 ± 5.0 years) adults completed the modified Romberg test, which uses four task manipulations (i.e. eyes open and eyes closed on a firm and foam surface) to compromise the fidelity of sensory feedback mechanisms. Each participant completed the tasks under two arm movement conditions: restricted and free arm movements. Centre of pressure (COP) range and frequency were calculated to characterise postural performance and strategy, respectively. Older adults showed greater COP range with restricted compared to free arm movements during all modified sensory conditions, with these effects most prominent in the medio-lateral (ML) plane (all p < .05, Cohen's d = 0.69-1.61). Compared to the free arm movement condition, there was an increase in ML displacement and frequency when arm movements were restricted during only the most challenging (i.e. vestibular dominant) task in young adults (all p < .05, d = 0.645-0.83). Finally, main age effects for the arm restriction cost (p < .05) indicates a greater reliance on an upper body strategy in older compared to young adults, independent of sensory availability/accuracy. These findings indicate that older adults compensate for the loss of accuracy in sensory input by increasing reliance on upper body movement strategies.

Exploring how arm movement moderates the effect of task difficulty on balance performance in young and older adults.

Emerging evidence highlights that arm movements exert a substantial and functionally relevant contribution on quiet standing balance control in young adults. Ageing is associated with "non-functional" compensatory postural control strategies (i.e., lower limb co-contraction), which in turn, may increase the reliance on an upper body strategy to control upright stance. Thus, the primary purpose of this study was to compare the effects of free versus restricted arm movements on balance performance in young and older adults, during tasks of different difficulty. Fifteen young (mean ± SD age; 21.3 ± 4.2 years) and fifteen older (mean ± SD age; 73.3 ± 5.0 years) adults performed bipedal, semi-tandem and tandem balance tasks under two arm position conditions: restricted arm movements and free arm movements. Centre of pressure (COP) amplitude and frequency were calculated as indices of postural performance and strategy, respectively. Especially in older adults, restriction of arm movement resulted in increased sway amplitude and frequency, which was primarily observed for the mediolateral direction. Further, increasing balance task difficulty raised the arm restriction cost (ARC; a new measure to quantify free vs. restricted arm movement differences in postural control) that was more prominent in older adults. These findings indicate the ARC provides a measure of reliance on the upper body for balance control and that arm movement is important for postural control in older adults, especially during tasks of greater difficulty.

Effects of arm movement strategies on emotional state and balance control during height-induced postural threat in young adults.

BACKGROUND: It is firmly established that postural threat seems to lead to an increased reliance on an ankle control ('stiffening') strategy. However, little is known about how postural threat affects performance in challenging tasks that require the use of upper body postural control strategies for stability. It is logical to assume that in such conditions, being able to utilise an upper body strategy may reduce the reliance on such ankle stiffening strategy. RESEARCH QUESTION: The objective of this study was to determine how arm movement influences balance control during a challenging balance task performed under conditions of postural threat. METHODS: Thirty young adults (mean ± SD age; 22.0 ± 4.0 years) balanced in tandem stance whilst standing at both ground-level (no threat) and 0.8 m above ground (threat). In both conditions, participants performed the task under two different arm positions: restricted arm movements and free arm movements. Postural sway amplitude and frequency were calculated to infer postural stiffening response. Self-reported emotional responses were quantified by assessing balance confidence, fear of falling, perceived stability, and conscious balance processing. RESULTS: Independent of arm movements, postural threat evoked an increase in fear of falling and conscious balance processing, and reductions in balance confidence and perceived stability. These threat-related changes in emotional state were further amplified when arm movements were restricted. Whilst significant increases in sway frequency during threat were observed in both arm conditions, reductions in sway amplitude were only observed during the restricted arm movement condition. SIGNIFICANCE: We propose that these responses likely reflect a fear-related cautious strategy intended to reduce the postural destabilisation associated with individuals being unable to use their arms to counter any destabilisation, as would normally be the case in daily life.

Occupational Fall Risk Assessment Tool for older workers.

BACKGROUND: No easy-to-use fall risk assessment tools have been devised to assess occupational fall risk in older workers. AIMS: To develop an Occupational Fall Risk Assessment Tool (OFRAT) and report its predictive validity and reliability in older workers. METHODS: The baseline fall risk assessment was completed by 1113 participants aged ≥60 years who worked ≥4 days/month in Saitama, Japan. Participants were followed up for falls during occupational activities for 1 year, and 30 participants were assessed twice for test-retest reliability. The following assessment measures were summed to form the OFRAT risk score: older age, male sex, history of falls, physical work participation, diabetes, use of medications increasing fall risk, reduced vision, poor hearing, executive dysfunction and slow stepping. The scores were then classified into four grades (0-2 points: very low, 3 points: low, 4 points: moderate and ≥5 points: high). RESULTS: During follow-up, 112 participants fell 214 times during work. The negative binomial regression model showed that participants with higher grades had a higher incidence rate ratio [95% confidence interval] for falls than those with very low grades (low: 1.64 [1.08-2.47], moderate: 4.23 [2.82-6.34] and high: 6.12 [3.83-9.76]). The intraclass correlation coefficient for risk score was 0.86 [0.72-0.93], and the weighted kappa coefficient for grade assessment was 0.74 [0.52-0.95]. CONCLUSIONS: The OFRAT is a valid and reliable tool for estimating the occupational fall risk in older workers. It may assist occupational physicians implement strategies to prevent falls in this group.

Cytotoxic Chemotherapy for Pancreatic Adenocarcinoma in England 2010-2017: Survival Outcomes.

AIMS: Cytotoxic chemotherapy is widely used in the management of pancreatic adenocarcinoma as adjuvant treatment after radical surgery and also in advanced disease. The results of randomised trials in selected patient groups provide reliable evidence of comparative treatment efficacy, but studies of population-based observational cohorts provide insight into survival outcomes in routine care. MATERIALS AND METHODS: We conducted a large population-based observational cohort study of patients, diagnosed during 2010-2017, who received chemotherapy within the National Health Service in England. We considered overall survival and 30-day all-cause mortality risk after chemotherapy. We conducted a literature search to compare these results to published studies. RESULTS: In total, 9390 patients were included in the cohort. For 1114 patients treated with radical surgery and chemotherapy with curative intent, overall survival from the start of chemotherapy was 75.8% (95% confidence interval 73.3-78.3) at 1 year and 22.0% (18.6-25.3) at 5 years. For 7468 patients treated with non-curative intent, overall survival was 29.6% (28.6-30.6) at 1 year and 2.0% (1.6-2.4) at 5 years. In both groups, poorer performance status at the start of chemotherapy was strongly associated with poorer survival. The risk of 30-day mortality in patients treated with non-curative intent was 13.6% (12.8-14.5). This was higher in younger patients and those with higher stage disease and a poorer performance status. CONCLUSIONS: Survival in this general population was poorer than that published in randomised trials. This study will aid informed discussion with patients regarding anticipated outcomes in routine clinical care.

Visuospatial working memory and obstacle crossing in young and older people.

Obstacle crossing requires visuospatial working memory to guide the trailing leg trajectory when vision in unavailable. Visuospatial working memory, as assessed with neuropsychological tests, declines with age, however, this remains to be investigated functionally in obstacle crossing. There is also evidence that visuospatial encoding during a secondary task interferes with balance control during stepping and walking in older people. Here, we studied the interaction effects of age by delay (study 1) and age by secondary visuospatial task (study 2) conditions on obstacle clearance in a visuospatial working memory -guided obstacle crossing task. Healthy young adults aged 19 to 36 years (n = 20 in study 1 and n = 17 in study 2) and healthy older adults aged 66 to 83 years (n = 29 in study 1 and n = 21 in study 2) were instructed to step over an obstacle with their leading leg and straddle it for a delay period before completing the crossing with their trailing leg. In study 1, two obstacle height conditions (12 cm, 18 cm) and two delay durations (20 s, 60 s) were presented in random order. In study 2, participants were required to attend to either no secondary task (control), a visuospatial secondary (star movement) task, or a nonspatial secondary (arithmetic) task, while straddling the obstacle for a delay duration of 20 s, at obstacle heights of 12 cm and 18 cm, randomly presented. Trailing leg kinematics (mean and variability of maximum toe clearance over the obstacle) were determined via motion capture. There were no statistically significant age by delay or age by secondary task interactions. In study 1, toe clearance variability was significantly greater in young adults and increased with increasing delay duration in both groups. In study 2, compared with the control condition, toe clearance variability was significantly greater in the non-spatial secondary task condition but not in the visuospatial condition. Contrary to our hypotheses, these findings suggest that young and older adults alike can store an obstacle representation via visuospatial working memory for durations of at least 60 s and use this information to safely scale their trailing leg over an obstacle. However, the increase in trailing leg toe clearance variability with delay duration suggests that obstacle representation starts to deteriorate even within the first 20 s regardless of age. The finding that undertaking a concurrent arithmetic task impaired visuospatial working memory-guided obstacle clearance suggests a potential increased risk of tripping during obstacle crossing while dual-tasking in both young and older people.

Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism.

BACKGROUND: PET imaging of 18F-fluorodeoxygucose (FDG) is used widely for tumour staging and assessment of treatment response, but the biology associated with FDG uptake is still not fully elucidated. We therefore carried out gene set enrichment analyses (GSEA) of RNA sequencing data to find KEGG pathways associated with FDG uptake in primary breast cancers. METHODS: Pre-treatment data were analysed from a window-of-opportunity study in which 30 patients underwent static and dynamic FDG-PET and tumour biopsy. Kinetic models were fitted to dynamic images, and GSEA was performed for enrichment scores reflecting Pearson and Spearman coefficients of correlations between gene expression and imaging. RESULTS: A total of 38 pathways were associated with kinetic model flux-constants or static measures of FDG uptake, all positively. The associated pathways included glycolysis/gluconeogenesis ('GLYC-GLUC') which mediates FDG uptake and was associated with model flux-constants but not with static uptake measures, and 28 pathways related to immune-response or inflammation. More pathways, 32, were associated with the flux-constant K of the simple Patlak model than with any other imaging index. Numbers of pathways categorised as being associated with individual micro-parameters of the kinetic models were substantially fewer than numbers associated with flux-constants, and lay around levels expected by chance. CONCLUSIONS: In pre-treatment images GLYC-GLUC was associated with FDG kinetic flux-constants including Patlak K, but not with static uptake measures. Immune-related pathways were associated with flux-constants and static uptake. Patlak K was associated with more pathways than were the flux-constants of more complex kinetic models. On the basis of these results Patlak analysis of dynamic FDG-PET scans is advantageous, compared to other kinetic analyses or static imaging, in studies seeking to infer tumour-to-tumour differences in biology from differences in imaging. Trial registration NCT01266486, December 24th 2010.

De novo and recurrent metastatic breast cancer - A systematic review of population-level changes in survival since 1995.

BACKGROUND: Advances in breast cancer (BC) care have reduced mortality, but their impact on survival once diagnosed with metastasis is less well described. This systematic review aimed to describe population-level survival since 1995 for de novo metastatic BC (dnMBC) and recurrent MBC (rMBC). METHODS: We searched MEDLINE 01/01/1995-12/04/2021 to identify population-based cohort studies of MBC reporting overall (OS) or BC-specific survival (BCSS) over time. We appraised risk-of-bias and summarised survival descriptively for MBC diagnoses in 5-year periods from 1995 until 2014; and for age, hormone receptor and HER2 subgroups. FINDINGS: We identified 20 eligible studies (14 dnMBC, 1 rMBC, 5 combined). Potential sources of bias in these studies were confounding and shorter follow-up for the latest diagnosis period.For dnMBC, 13 of 14 studies reported improved OS or BCSS since 1995. In 2005-2009, the median OS was 26 months (range 24-30), a median gain of 6 months since 1995-1999 (range 0-9, 4 studies). Median 5-year OS was 23% in 2005-2009, a median gain of 7% since 1995-1999 (range -2 to 14%, 4 studies). For women ≥70 years, the median and 5-year OS was unchanged (1 study) with no to modest difference in relative survival (range: -1·9% (p = 0.71) to +2·1% (p = 0.045), 3 studies). For rMBC, one study reported no change in survival between 1998 and 2006 and 2007-2013 (median OS 23 months). For combined MBC, 76-89% had rMBC. Three of four studies observed no change in median OS after 2000. Of these, one study reported median OS improved for women ≤60 years (1995-1999 19·1; 2000-2004 22·3 months) but not >60 years (12·7, 11·6 months). INTERPRETATION: Population-level improvements in OS for dnMBC have not been consistently observed in rMBC cohorts nor older women. These findings have implications for counselling patients about prognosis, planning cancer services and trial stratification. FUNDING: SL was funded in part by a National Health and Medical Research Council (NHMRC) Project Grant ID: 1125433. NH was funded by the NBCF Chair in Breast Cancer Prevention grant (EC-21-001) and a NHMRC Investigator (Leader) grant (194410). BD and SAP were funded in part by the NHMRC Centre of Research Excellence in Medicines Intelligence (1196900).

Impact of ageing, fall history and exercise on postural reflexes following unpredictable perturbations: A systematic review and meta-analyses.

INTRODUCTION: This review examined the impact of ageing, fall history and exercise on postural reflexes and adaptation to unpredictable perturbations. METHODS: MEDLINE, EMBASE, Scopus, SportDiscus and Web of Science were systematically searched for cross-sectional and intervention studies that assessed muscle onset latency following unpredictable postural perturbations in adults (CRD42020170861). RESULTS: Thirty-seven articles (n = 1257) were included in this review. Older adults had slower onset latencies compared to young adults (mean difference 14 ms, 95% CI: 10, 18, P < 0.001). Regular exercisers had faster onset latencies compared to sedentary/untrained participants (mean difference 11 ms, 95%CI: -19, -4, P = 0.002). Exercise interventions delivered in randomised control trials (RCTs) led to faster onset latencies (mean difference -4 ms, 95%CI: -9, 0, P = 0.04) compared to controls. Uncontrolled clinical trials of exercise (mainly short-term) did not show changes in onset latency in pre-post tests (mean difference -2 ms, 95%CI: -5, 1, P = 0.36). CONCLUSION: This review demonstrated that in response to postural perturbation, muscle activation is significantly delayed in older compared to young adults, and that adults who regularly exercised had faster muscle activation compared to their less active counterparts. No significant changes in onset latencies were evident in uncontrolled clinical trials of short duration, but longer-term RCTs indicated postural reflexes are responsive to training.

Non-cardiogenic pulmonary oedema complicating balloon valvuloplasty and stent angioplasty of severe pulmonary valve stenosis in four dogs.

In dogs, balloon valvuloplasty is considered the treatment of choice for severe pulmonary valve stenosis, and this technique is currently performed routinely in specialist referral practices with low morbidity and mortality. Stent angioplasty has also been recently proposed as a viable treatment option. The present case series describes the clinical course of four dogs with severe pulmonary valve stenosis, treated with balloon valvuloplasty or stent angioplasty at four different institutions, which developed non-cardiogenic pulmonary oedema perioperatively after apparently successful dilation of the pulmonary valve. In three cases, there was evidence of some degree of pulmonary hypertension before ballooning. Despite intensive care, the complication proved fatal in three cases. Clinicians should therefore be aware of this life-threatening complication, previously undescribed in dogs.

Cortical activation during gait adaptability in people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PD) have difficulties adapting their gait. While underlying neural mechanisms involving the prefrontal cortex (PFC) have been studied across various complex walking tasks, less is known about the premotor cortex (PMC) and supplementary motor area (SMA), key cortical regions for motor planning. This study compared frontal cortical regions activation patterns using functional near-infrared spectroscopy (fNIRS), between people with PD and healthy controls (HC) during gait adaptability tasks. METHODS: Forty-nine people with PD (mean (SD) age: 69.5 (7.9) years) and 21 HC (69.0 (5.9) years) completed a simple walk and three randomly presented gait adaptability tasks: (i) stepping on targets, (ii) avoiding obstacles and (iii) negotiating both targets and obstacles. Cortical activity in the dorsolateral PFC (DLPFC), SMA and PMC were recorded using fNIRS. Step length, velocity and accuracy and cortical activity were contrasted between the groups and walking conditions. RESULTS: Compared with the HC, the PD group exhibited greater PMC activation and walked significantly slower and took shorter steps in all conditions. A statistically significant group by condition interaction indicated an increase in DLPFC cortical activation in the HC participants when undertaking the obstacle avoidance task compared with the simple walk but no increase in cortical activation in the PD group when undergoing this more challenging gait task. CONCLUSIONS: Our findings suggest people with PD have little or no DLPFC, SMA and PMC capacity beyond what they need for simple walking and in consequence need to slow their gait velocity to meet the demands of target stepping and obstacle avoidance tasks. Such behavioral and neural patterns appear consistent with concepts of compensatory over-activation and capacity limitation.

Phonological complexity in intervention for Spanish-speaking children with speech sound disorder.

The efficiency of intervention for children with speech sound disorder may be influenced by linguistic complexity of the phonological intervention target. Complex targets, particularly, later-acquired, less-known consonants and consonant clusters, have been linked to greater post-intervention generalization to untargeted phonological structures. Yet there is little direct evidence to support target selection based on linguistic complexity for Spanish-speaking children with speech sound disorder. This intervention study utilizes an experimental single-case design to examine the efficacy of intervention in Spanish using different complex targets (i.e. /ɡɾ/, /bɾ/, and /l/). For each of the four Spanish-speaking children with speech sound disorder, sounds at 0% accuracy during baseline were monitored across the baseline period, during and post-intervention, and at one- and two-month follow-up visits. Over the course of intervention, only one participant achieved mastery of the targeted structure in practiced words. However, all participants demonstrated some amount of broad phonological generalization to untargeted consonants or clusters. Variable learning trajectories and broad phonological generalization are discussed as they relate to participant characteristics and linguistic complexity.

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging.

BACKGROUND: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION: NCT03036943.

Mobility performance predicts incident depression: A systematic review and meta-analysis.

Impaired mobility often co-occurs with depression. However, there is no systematic review evidence as to whether mobility impairments precede the onset of depression. The objective of this systematic review and meta-analysis was to evaluate whether mobility impairment could predict incident depression. A systematic search of cohort studies were performed in MEDLINE, EMBASE, CINAHL and PsycINFO. The target population was people with no depressive symptoms at baseline and follow-up for depression or depressive symptoms of at least three months. Of 1061 identified abstracts, 13 studies met the review eligibility criteria. The majority of included studies (8 out of 13) were of high methodological quality. Follow-up periods ranged from 12 months to 16 years. Gait speed was the most consistently reported mobility measure. Participants with slow gait speed were at higher risk of developing depressive symptoms (pooled OR = 1.93, 95%CI: 1.54 to 2.42, 11 studies). This review shows that slow gait speed is predictive of the onset of depressive symptoms. Systematic review registration number: CRD42020153791.

Prevalence of motor impairment in residents of New South Wales, Australia aged 55 years and over: cross-sectional survey of the 45 and Up cohort.

BACKGROUND: The population prevalence of many diseases is known. However, little is known of the population prevalence of motor impairments. METHODS: The aim of this study was to determine the point prevalence of specific motor impairments (weakness, fatigue, contracture, impaired balance and impaired coordination) in the population aged 55 years and older resident in New South Wales, Australia in 2018. 55,210 members of the 45 and Up cohort were invited to participate in a follow-up survey that included questions on motor impairment. Responses were received from 20,141 people (36%). Calibrated estimates of prevalence of specific motor impairments, and of having at least one motor impairment, were obtained using survey weights based on the known multivariate distributions of age, gender and geographical location (28 regions) in the population. RESULTS: More than one-third of adults aged over 55 residing in New South Wales have difficulty using their hands, arms or legs. The prevalence of each motor impairment (muscle weakness, fatigue, contracture, impaired balance or impaired coordination) in this population is between 4 and 12%. The prevalence of at least one of these impairments is 21%. The prevalence of at least one impairment in people aged 85 and over is 42%. Women consistently had more difficulty using hands, arms and legs, and more motor impairment, than men. Difficulty using hands, arms and legs and the prevalence of all motor impairments, especially poor balance, greatly increased with age. CONCLUSION: The prevalence of specific motor impairments in older Australian adults is high - comparable to that of the most prevalent diseases. There may be merit in considering motor impairment as a significant public health problem in its own right.

Mobility in Community Dwelling Older Adults: Predicting Successful Mobility Using an Instrumented Battery of Novel Measures.

Mobility in older adults is associated with better quality of life. However, evidence suggests that older people spend less time out-of-home than younger adults. Traditional methods for assessing mobility have serious limitations. Wearable technologies provide the possibility of objectively assessing mobility over extended periods enabling better estimates of levels of mobility to be made and possible predictors to be explored. Eighty-six community dwelling older adults (mean age 79.8 years) had their mobility assessed for one week using GPS, accelerometry and self-report. Outcomes were: number of steps, time spent in dynamic outdoor activity, total distance travelled and total number of journeys made over the week. Assessments were also made of personal, cognitive, psychological, physical and social variables. Four regression models were calculated (one for each outcome). The models predicted 32 to 43% of the variance in levels of mobility. The ability to balance on one leg significantly predicted all four outcomes. In addition, cognitive ability predicted number of journeys made per week and time spent engaged in dynamic outdoor activity, and age significantly predicted total distance travelled. Overall estimates of mobility indicated step counts that were similar to those shown by previous research but distances travelled, measured by GPS, were lower. These findings suggest that mobility in this sample of older adults is predicted by the ability to balance on one leg. Possible interventions to improve out-of-home mobility could target balance. The fact that participants travelled shorter distances than those reported in previous studies is interesting since this high-functioning subgroup would be expected to demonstrate the highest levels.