Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial.

PURPOSE: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D). METHODS: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months. RESULTS: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months. CONCLUSIONS: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549.

Treatment patterns in women with postmenopausal osteoporosis using abaloparatide: a real-world observational study.

Review of medical records from 173 women with osteoporosis who received abaloparatide treatment revealed that 96.0% had at least one visit for osteoporosis management and 55.5% had medication support group access. The most common reasons for discontinuing treatment were financial (31.2%) and tolerability (22.8%). Most patients (64.8%) completed treatment as prescribed. PURPOSE: Abaloparatide is approved for the treatment of women with postmenopausal osteoporosis at high risk for fracture. This study evaluated real-world treatment patterns for patients new to abaloparatide, regardless of osteoporosis treatment history. METHODS: Data for patients with ≥ 1 prescription for abaloparatide were collected retrospectively from six academic and clinical practice settings across the US. RESULTS: A total of 173 patients were enrolled (mean [SD] age, 69.8 [7.4] years). At the time of abaloparatide treatment initiation, 78.6% had received other osteoporosis medications. Mean (SD) time from discontinuation of osteoporosis medications prior to initiation of abaloparatide was 1.7 (3.2) years. Twenty-four months of follow-up data from the initiation date of abaloparatide was collected from 94.0% of patients and 6.0% of patients had 12-24 months of follow-up. During the follow-up period, 96.0% of patients had at least one visit for osteoporosis management and 55.5% had access to a medication support program. The median duration of therapy was 18.6 months and 105/162 (64.8%) completed abaloparatide treatment as prescribed. The most common reasons for treatment discontinuation were financial (31.2%) and tolerability (22.8%). Following completion of a course of treatment with abaloparatide, 82/162 (50.6%) patients transitioned to another osteoporosis medication. The median time between abaloparatide treatment course completion and the initiation of follow-on medication was 21 days. CONCLUSION: Most patients completed treatment with abaloparatide as prescribed, and over half continued with an antiresorptive agent. This favorable conduct may be the result of regular follow-up visits and accessibility to both medication and patient support services.

Multiplex genetic manipulations in Clostridium butyricum and Clostridium sporogenes to secrete recombinant antigen proteins for oral-spore vaccination.

BACKGROUND: Clostridium spp. has demonstrated therapeutic potential in cancer treatment through intravenous or intratumoral administration. This approach has expanded to include non-pathogenic clostridia for the treatment of various diseases, underscoring the innovative concept of oral-spore vaccination using clostridia. Recent advancements in the field of synthetic biology have significantly enhanced the development of Clostridium-based bio-therapeutics. These advancements are particularly notable in the areas of efficient protein overexpression and secretion, which are crucial for the feasibility of oral vaccination strategies. Here, we present two examples of genetically engineered Clostridium candidates: one as an oral cancer vaccine and the other as an antiviral oral vaccine against SARS-CoV-2. RESULTS: Using five validated promoters and a signal peptide derived from Clostridium sporogenes, a series of full-length NY-ESO-1/CTAG1, a promising cancer vaccine candidate, expression vectors were constructed and transformed into C. sporogenes and Clostridium butyricum. Western blotting analysis confirmed efficient expression and secretion of NY-ESO-1 in clostridia, with specific promoters leading to enhanced detection signals. Additionally, the fusion of a reported bacterial adjuvant to NY-ESO-1 for improved immune recognition led to the cloning difficulties in E. coli. The use of an AUU start codon successfully mitigated potential toxicity issues in E. coli, enabling the secretion of recombinant proteins in C. sporogenes and C. butyricum. We further demonstrate the successful replacement of PyrE loci with high-expression cassettes carrying NY-ESO-1 and adjuvant-fused NY-ESO-1, achieving plasmid-free clostridia capable of secreting the antigens. Lastly, the study successfully extends its multiplex genetic manipulations to engineer clostridia for the secretion of SARS-CoV-2-related Spike_S1 antigens. CONCLUSIONS: This study successfully demonstrated that C. butyricum and C. sporogenes can produce the two recombinant antigen proteins (NY-ESO-1 and SARS-CoV-2-related Spike_S1 antigens) through genetic manipulations, utilizing the AUU start codon. This approach overcomes challenges in cloning difficult proteins in E. coli. These findings underscore the feasibility of harnessing commensal clostridia for antigen protein secretion, emphasizing the applicability of non-canonical translation initiation across diverse species with broad implications for medical or industrial biotechnology.

Development of a CRISPR-Cas12a system for efficient genome engineering in clostridia.

IMPORTANCE: Continued efforts in developing the CRISPR-Cas systems will further enhance our understanding and utilization of Clostridium species. This study demonstrates the development and application of a genome-engineering tool in two Clostridium strains, Clostridium butyricum and Clostridium sporogenes, which have promising potential as probiotics and oncolytic agents. Particular attention was given to the folding of precursor crRNA and the role of this process in off-target DNA cleavage by Cas12a. The results provide the guidelines necessary for efficient genome engineering using this system in clostridia. Our findings not only expand our fundamental understanding of genome-engineering tools in clostridia but also improve this technology to allow use of its full potential in a plethora of biotechnological applications.

Refined control of CRISPR-Cas9 gene editing in Clostridium sporogenes: the creation of recombinant strains for therapeutic applications.

Despite considerable clinical success, the potential of cancer immunotherapy is restricted by a lack of tumour-targeting strategies. Treatment requires systemic delivery of cytokines or antibodies at high levels to achieve clinically effective doses at malignant sites. This is exacerbated by poor penetration of tumour tissue by therapeutic antibodies. High-grade immune-related adverse events (irAEs) occur in a significant number of patients (5-15%, cancer- and therapeutic-dependent) that can lead to lifelong issues and can exclude from treatment patients with pre-existing autoimmune diseases. Tumour-homing bacteria, genetically engineered to produce therapeutics, is one of the approaches that seeks to mitigate these drawbacks. The ability of Clostridium sporogenes to form spores that are unable to germinate in the presence of oxygen (typical of healthy tissue) offers a unique advantage over other vectors. However, the limited utility of existing gene editing tools hinders the development of therapeutic strains. To overcome the limitations of previous systems, expression of the Cas9 protein and the gRNA was controlled using tetracycline inducible promoters. Furthermore, the components of the system were divided across two plasmids, improving the efficiency of cloning and conjugation. Genome integrated therapeutic genes were assayed biochemically and in cell-based functional assays. The potency of these strains was further improved through rationally-conceived gene knock-outs. The new system was validated by demonstrating the efficient addition and deletion of large sequences from the genome. This included the creation of recombinant strains expressing two pro-inflammatory cytokines, interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF), and a pro-drug converting enzyme (PCE). A comparative, temporal in vitro analysis of the integrant strains and their plasmid-based equivalents revealed a substantial reduction of cytokine activity in chromosome-based constructs. To compensate for this loss, a 7.6 kb operon of proteolytic genes was deleted from the genome. The resultant knock-out strains showed an 8- to 10-fold increase in cytokine activity compared to parental strains.

Streamlined assembly of cloning and genome editing vectors for genus Clostridium.

Reported herein is a new set of vectors designed to streamline molecular cloning and genome editing by exploiting modern cloning methods. The new vectors build on the existing pMTL8000 vectors that have been a staple of Clostridium research for more than a decade. The introduction of two pairs of type IIS restriction sites flanking an insulated multiple cloning site in both a cloning vector and a CRISPR-Cas9 gene editing vector enables plasmid construction in a "one-pot" reaction, avoiding the more laborious steps of conventional cloning. A synthetic lacZα expression cassette introduced between the cloning sites enables visual detection of background colonies. In addition, distinct selection markers on each vector permit selection of the desired clones according to antibiotic resistance. An example of strain development using the new vectors is demonstrated.

Agreement between left and right middle cerebral artery blood velocity responses to incremental and constant work-rate exercise in healthy males and females.

Objective.To quantify the agreement between left and right middle cerebral artery blood velocity (MCAv) responses to incremental and constant work-rate exercise in adults.ApproachSeventeen healthy adults (23.8 ± 2.4 years, 9 females) completed a ramp incremental test to exhaustion on a cycle ergometer, three 6-minute transitions at a moderate-intensity, and three at a heavy-intensity, all on separate days. Bilateral MCAv was measured throughout using transcranial Doppler ultrasonography, with left and right MCAv data analysed separately. Data were analysed at baseline, gas exchange threshold, respiratory compensation point and exhaustion during ramp incremental exercise. MCAv responses to constant work-rate exercise were analysed using a mono-exponential model, to determine time- and amplitude-based kinetic response parameters.Main ResultsLeft and right MCAv responses to incremental and constant work-rate exercise were significantly, strongly and positively correlated (r≥ 0.61,P< 0.01). Coefficient of variation (left versus right) ranged from 7.3%-20.7%, 6.4%-26.2% and 5.9%-22.5% for ramp, moderate and heavy-intensity exercise, respectively. The relative change in MCAv from baseline was higher in the right compared to left MCAv during ramp, moderate and heavy-intensity exercise (allP< 0.05), but the effect sizes were small (d≤ 0.4). Small mean left-right differences were present during ramp incremental exercise at all time-points (<6 cm s-1; <4%), and for all kinetic parameters during moderate and heavy-intensity exercise (<3 cm s-1, <3%, <4 s).SignificanceThese findings demonstrate similarities between left and right MCAv responses to incremental and constant-work rate exercise in adults on a group-level, but also highlight individual variation in the agreement between left and right MCAv exercise responses.

Cardiorespiratory Fitness and Muscular Strength Do Not Predict Social Cognitive Capacity in Older Age.

OBJECTIVES: Social cognitive function often declines in older age but the mechanisms underlying these declines are not completely clear. Cardiorespiratory fitness (CRF) and muscular strength are positively associated with broader cognitive function in older adults, yet surprisingly, no study has examined whether a similar relationship exists between CRF or muscular strength and social cognition in older age. METHODS: We assessed whether higher CRF and muscular strength were associated with enhanced social cognitive function in a sample of fifty older adults (Mage = 70.08, standard deviation = 3.93). Participants completed a gold-standard cardiopulmonary exercise test to assess CRF, an isometric handgrip strength test to index muscular strength, and validated measures of social cognition to index emotion perception and theory of mind (ToM). RESULTS: The results showed that CRF and muscular strength did not explain any unique variance in older adults' social cognitive performance. Bayesian analyses confirmed that the evidence for the null hypothesis was moderate for all tested relationships, except for the relationship between CRF and cognitive ToM where the evidence for the null was anecdotal. DISCUSSION: This study has provided the first evidence to suggest that CRF and muscular strength-two important modifiable lifestyle factors-are not associated with social cognition in healthy older adults. However, replication studies are now needed to cross-validate these findings and to clarify whether any moderating variables may be important for understanding the relationship between fitness and social cognition in older age.

Gradient Boosted Machine Learning Model to Predict H2, CH4, and CO2 Uptake in Metal-Organic Frameworks Using Experimental Data.

Predictive screening of metal-organic framework (MOF) materials for their gas uptake properties has been previously limited by using data from a range of simulated sources, meaning the final predictions are dependent on the performance of these original models. In this work, experimental gas uptake data has been used to create a Gradient Boosted Tree model for the prediction of H2, CH4, and CO2 uptake over a range of temperatures and pressures in MOF materials. The descriptors used in this database were obtained from the literature, with no computational modeling needed. This model was repeated 10 times, showing an average R2 of 0.86 and a mean absolute error (MAE) of ±2.88 wt % across the runs. This model will provide gas uptake predictions for a range of gases, temperatures, and pressures as a one-stop solution, with the data provided being based on previous experimental observations in the literature, rather than simulations, which may differ from their real-world results. The objective of this work is to create a machine learning model for the inference of gas uptake in MOFs. The basis of model development is experimental as opposed to simulated data to realize its applications by practitioners. The real-world nature of this research materializes in a focus on the application of algorithms as opposed to the detailed assessment of the algorithms.

Efficacy of two doses of external counterpulsation (ECP) on glycemic control in people with type 2 diabetes mellitus: A randomized SHAM-controlled trial.

AIMS: To determine the efficacy of two doses of external counterpulsation (ECP) on glycemic control in people with type 2 diabetes mellitus (T2D), and any persistent benefits 7 weeks following treatment. METHODS: 50 participants with T2D were randomly assigned to either 1) 20x45-minute ECP sessions over 7 weeks (ECP45), 2) 20x30-minute ECP sessions over 7 weeks (ECP30) or 3) SHAM control. Outcomes were assessed at baseline, after 7 weeks of the intervention and 7 weeks after the interventions finished. Efficacy was determined from changes in HbA1c. RESULTS: After 7 weeks, there were significant between-group differences, with ECP45 lowering HbA1c compared to SHAM (mean [95% CI] -0.7 [-0.1 to -1.3] %; -7 [-1 to -15] mmol/mol). Within group changes were; ECP45 (mean ± SD -0.8 ± 0.8%; -8 ± 8 mmol/mol), ECP30 (-0.2 ± 0.5%; -2 ± 6 mmol/mol) and SHAM (-0.1 ± 0.9%; -1 ± 10 mmol/mol). HbA1c in the ECP45 group remained lower 7 weeks after completing the intervention; ECP45 (7.0 ± 1.1%; 53 ± 26 mmol/mol), ECP30 (7.7 ± 1.4%; 60 ± 16 mmol/mol) and SHAM (7.7 ± 1.0%; 60 ± 10 mmol/mol). CONCLUSIONS: In people with T2D, ECP45 for 7 weeks improved glycemic control when compared to ECP30 and a SHAM control group.

Efficacy of exercise interventions for women during and after gynaecological cancer treatment - a systematic scoping review.

PURPOSE: To systematically synthesise evidence of exercise intervention efficacy for physical/psychosocial outcomes that matter to women during/following treatment for gynaecological cancer. METHODS: Five databases were searched (PubMed, EMBASE, CINAHL, PsychInfo, Scopus). Exercise-only intervention studies that included women during/ following treatment for any gynaecological cancer, with/ without control comparison, on any physical or psychosocial outcome(s), were included and qualitatively appraised using the Revised Cochrane Risk of Bias tool and a modified Newcastle-Ottawa Scale. RESULTS: Seven randomised controlled trials (RCTs), three single-arm pre-post studies, and one prospective cohort study satisfied were included (11 studies). Most studies were completed following treatment (91%), included combined (aerobic and resistance; 36%) and aerobic (36%) training, were fully/mostly (63%) unsupervised, and had a moderate-to-high risk of bias. Overall, 33 outcomes (64% objectively-measured) were assessed. Improvements were observed in aerobic capacity (V̇O2 Peak +1.6 mL/kg/min, 6-minute walk distance +20-27 m), lower- (30-second sit-to-stand +2-4 repetitions) and upper-limb strength (30-second arm curl +5 repetitions; 1RM grip strength/chest press +2.4-3.1 kg), and agility (timed up-and-go -0.6 seconds). However, changes in quality of life, anthropometry/body composition, balance and flexibility were inconsistent. There was no evidence to support worsening of outcomes. CONCLUSION: Preliminary research into the role of exercise post-gynaecological cancer suggests an improvement in exercise capacity, muscular strength, and agility which, in the absence of exercise, typically decline following gynaecological cancer. Future exercise trials involving larger and more diverse gynaecological cancer samples will improve understanding of the potential and magnitude of effect of guideline-recommended exercise on outcomes that matter to patients.

Antibody prevalence to avian influenza virus subtypes H5, H7 and H9 in falcons, captive and wild birds, United Arab Emirates, 2003-2006.

BACKGROUND: Avian influenza viruses (AIV) may cause enormous economic losses in the poultry industry and sporadically severe disease in humans. Falconry is a tradition of great importance in the Arabian Peninsula. Falcons may catch AIV through contact with infected quarry species. OBJECTIVES: Falcons together with other bird species are the focus of this seroprevalence study, carried out on sera collected in the United Arab Emirates (UAE). AIV with the haemagglutinin subtypes H5, H7 and possibly H9 may infect humans. METHODS: We investigated the antibody prevalence to these subtypes in falcons and other birds by haemagglutination inhibition test. 617 sera of falcons and 429 sera of 46 wild/captive bird species were tested. RESULTS: From the falcons, only one was positive for H5 antibodies (0.2%), none contained antibodies to H7, but 78 had antibodies to H9 (13.2%). Regarding other birds, eight were positive for antibodies to H5 (2.1%), none had antibodies to H7, but 55 sera from 17 species contained antibodies to H9 (14.4%). CONCLUSIONS: In contrast to H5 and H7 infections, H9N2 is widespread worldwide. Its ability to reassort, thereby creating possibly pathogenic strains for humans, should remind us of the potential risk that close contact with birds entails.

The Effect of Exercise on Pain in People with Cancer: A Systematic Review with Meta-analysis.

INTRODUCTION: Cancer-related pain is common and undertreated. Exercise is known to have a pain-relieving effect in non-cancer pain. OBJECTIVES: This systematic review aimed to evaluate (1) the effect of exercise on cancer-related pain in all cancers, and (2) whether the effect of exercise differed according to exercise mode, degree of supervision, intervention duration and timing (during or after cancer treatment), pain types, measurement tool and cancer type. METHODS: Electronic searches were undertaken in six databases to identify exercise studies evaluating pain in people with cancer, published prior to 11 January 2023. All stages of screening and data extraction were conducted independently by two authors. The Cochrane risk of bias tool for randomised trials (RoB 2) was used and overall strength of evidence was assessed using the GRADE approach. Meta-analyses were performed overall and by study design, exercise intervention and pain characteristics. RESULTS: In total, 71 studies reported in 74 papers were eligible for inclusion. The overall meta-analysis included 5877 participants and showed reductions in pain favouring exercise (standardised mean difference - 0.45; 95% confidence interval - 0.62, - 0.28). For most (> 82%) of the subgroup analyses, the direction of effect favoured exercise compared with usual care, with effect sizes ranging from small to large (median effect size - 0.35; range - 0.03 to - 1.17). The overall strength of evidence for the effect of exercise on cancer-related pain was very low. CONCLUSION: The findings provide support that exercise participation does not worsen cancer-related pain and that it may be beneficial. Better pain categorisation and inclusion of more diverse cancer populations in future research would improve understanding of the extent of benefit and to whom. PROSPERO REGISTRATION NUMBER: CRD42021266826.

Efficacy of exercise training for improving vascular dysfunction in people with cancer: a systematic review with meta-analyses.

PURPOSE: Cancer treatments exert vascular toxic effects that can lead to the development of cardiovascular disease. Exercise training has the potential to prevent or reduce cancer treatment-induced damage to vascular structure and function. This systematic review with meta-analyses aimed to determine the isolated effects of exercise training on vascular outcomes in people with cancer. METHODS: Seven electronic databases were searched on 20 September 2021 to identify randomised controlled trials, quasi-randomised trials, pilot and cohort studies. Included studies implemented a structured exercise intervention and assessed vascular structure and/or function in people during or following cancer treatment. Meta-analyses examined the effects of exercise training on endothelial function (via brachial artery flow-mediated dilation) and arterial stiffness (via pulse wave velocity). Methodological quality was assessed using the Cochrane Quality Assessment tool and modified Newcastle-Ottawa Quality Appraisal tool. Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the certainty of evidence. RESULTS: Ten studies (discussed across 11 articles) met the inclusion criteria. Methodological quality of the included studies was moderate (71% average). Exercise improved vascular function when compared to control (standardised mean difference = 0.34, 95% CI (0.01, 0.67); p = 0.044: studies = 5, participants = 171), but not pulse wave velocity (standardised mean difference = - 0.64, 95% CI (- 1.29, 0.02); p = 0.056: studies = 4, participants = 333). The certainty of evidence was moderate for flow-mediated dilation and low for pulse wave velocity. CONCLUSIONS: Compared to usual care, exercise training significantly improves flow-mediated dilation (endothelial function) but not pulse wave analysis, in people treated for cancer. IMPLICATIONS FOR CANCER SURVIVORS: Exercise may improve vascular health in individuals during and following cancer treatment.

Sex modifies the relationship between age and neurovascular coupling in healthy adults.

Neurovascular coupling (NVC) is the matching between local neuronal activity and regional cerebral blood flow (CBF), but little is known about the effects of age and sex on NVC. This study aimed to investigate the relationships and interaction between age and sex on NVC. Sixty-four healthy adults (18-85 years, N = 34 female) completed a visual stimulus evoked NVC assessment to a flashing checkerboard. NVC responses were measured in the posterior cerebral artery (PCAv) using transcranial Doppler ultrasound. A hierarchical multiple regression was used to determine the relationships between age, sex, and the age by sex interaction on NVC. There was a significant age by sex interaction for baseline (P = 0.001) and peak PCAv (P = 0.01), with a negative relationship with age in females (P < 0.005), and no relationship in males (P ≥ 0.17). NVC responses as a percent increase from baseline showed a significant age by sex interaction (P = 0.014), with a positive relationship with age in females (P = 0.04) and no relationship in males (P = 0.17), even after adjusting for baseline PCAv. These data highlight important sex differences, with an association between age and NVC only apparent in females but not males, and thus a need to account for sex dependent effects of ageing when investigating cerebrovascular regulation.

Economic evaluation of exercise interventions for individuals with cancer: A systematic review.

While there is good evidence that exercise is an effective adjunct therapy to cancer care, little is known about its value for money. The aim of this systematic review is to explore the available evidence pertaining to the cost-effectiveness of exercise interventions following cancer. A search of eight online databases (CINAHL, the Cochrane Library (NHSEED), Econlit, Embase, PsycInfo, PubMed, Scopus, Web of science) was first conducted on 26 March 2021 and updated on 8 March 2022. Only economic evaluations with results in the form of incremental cost-effectiveness ratio (ICER) were included. The Consolidated Health Economics Evaluation Reporting Standards (CHEERS) was used to appraise the quality of reporting in the studies. The study protocol was registered in PROSPERO. Sixteen studies comprising seven (44%) cost-utility analyses (CUA), one (6%) cost-effectiveness analyses (CEA) and eight (50%) combined CUA and CEA were identified. These studies explored exercise in five cancer types (breast, colon, lung, prostate, and blood), with half (50%) in breast cancer. Seven studies (44%) adopted societal perspectives. Exercise interventions were found to be cost-effective in five of ten (50%) trial-based economic evaluations and in five of the six (83%) model-based economic evaluations. Most exercise interventions included were supervised, while close supervision and individualized exercise sessions incurred higher costs. Exercise interventions in cancer care are cost-effective for various cancer types despite considerable heterogeneity in exercise delivery and the type of analysis used for economic evaluation. There is clear value in using decision-analytic modelling to account for the long-term benefits of exercise in cancer care.

Comparison of peripheral and cerebral vascular function between premenopausal, early and late postmenopausal females.

NEW FINDINGS: What is the central question of this study? We sought to investigate whether peripheral and cerebrovascular function are impaired in early and late postmenopausal females compared with premenopausal females, while also accounting for nitric oxide and estradiol levels. What is the main finding and its importance? We observed no differences in peripheral vascular and cerebrovascular function between healthy and physically active premenopausal females and early and late postmenopausal females. Our findings contradict previous cross-sectional observations of vascular and cerebrovascular dysfunction across menopause. Longitudinal studies assessing vascular and cerebrovascular outcomes across the menopausal transition are warranted. ABSTRACT: The risk of cardiovascular and cerebrovascular disease increases in ageing females, coinciding with the onset of menopause. Differences in peripheral and cerebrovascular function across menopausal stages, however, are poorly characterized. The aim of this study was to compare peripheral and cerebrovascular function between healthy premenopausal (PRE), early (1-6 years after final menstrual period; E-POST) and late (>6 years after final menstrual period; L-POST) postmenopausal females. We also explored the association between reproductive hormones, NO bioavailability and cerebrovascular function. In 39 females (40-65 years of age), we measured arterial stiffness, brachial artery flow-mediated dilatation, and cerebrovascular reactivity (CVR) to hypercapnia in the middle (MCAv) and internal (ICA) carotid arteries. Follicle-stimulating hormone, estradiol, progesterone and plasma nitrate and nitrite concentrations were also measured. Years since final menstrual period (PRE, 0 ± 0 years; E-POST, 3 ± 1 years; L-POST, 11 ± 4 years; P < 0.001) and estradiol levels (PRE, 145.5 ± 65.6 pg ml-1 ; E-POSTm 30.2 ± 81.2 pg ml-1 ; L-POST, 7.7 ± 11.3 pg ml-1 ; P < 0.001) were different between groups. All groups exceeded the guidelines for recommended physical activity. There were no group differences in blood pressure (P = 0.382), arterial stiffness (P = 0.129), flow-mediated dilatation (P = 0.696) or MCAv CVR (P = 0.442). The ICA CVR blood flow response was lower in PRE compared with L-POST (26.5 ± 19.2 vs. 47.8 ± 12.6%; P = 0.010), but after adjusting for age these differences were no longer present. Flow-mediated dilatation (r = 0.313, P = 0.105) and ICA CVR (r = -0.154, P = 0.495) were not associated with the estradiol concentration. There were no associations between the estradiol concentration and NO bioavailability. These results suggest that in healthy, physically active early and late postmenopausal females, vascular and cerebrovascular function is generally well preserved.

Challenging behaviour and its risk factors in children and young people in a special school setting: A four wave longitudinal study.

BACKGROUND: Longitudinal research is needed to strengthen evidence for risk factors for challenging behaviour in children with intellectual disabilities and to understand patterns of change over time. METHODS: Data on challenging behaviour were collected for 225 students in one school over four annual time points and a range of potential risk correlates. Data were analysed using Generalised Estimating Equations. RESULTS: Prevalence of challenging behaviour, aggression and self-injury did not vary significantly over time. Stereotyped behaviours increased over the 4-year period. Challenging behaviour was associated with lower levels of adaptive skills and autism. Stereotyped behaviour increased with age. Self-injurious behaviour was less likely to be shown in children with profound intellectual disabilities over time. CONCLUSIONS: These findings are consistent with previous research in terms of potential risk factors identified. Implications for schools include proactive interventions for children with intellectual disabilities at high risk; especially those with autism and poorer adaptive skills.

Usage of epidermal growth factor mutation testing and impact on treatment patterns in non-small cell lung cancer: An international observational study.

OBJECTIVES: Epidermal growth factor receptor (EGFR) mutations (EGFRm) are common oncogene drivers in non-small cell lung cancer (NSCLC). This real-world study explored treatment patterns and time to receive EGFRm test results in patients with advanced EGFRm NSCLC. METHODS: A cross-sectional medical chart review was completed May-August 2020 in Australia, Canada, Germany, Italy, South Korea, Taiwan, UK, and USA. Eligible patients had advanced NSCLC and a positive EGFRm test result January-December 2017. Data were abstracted from NSCLC diagnosis to end of follow-up (31 March 2020) or patient's death whichever occurred earlier. The index date was the date of EGFRm confirmation. RESULTS: 223 physicians provided data for 1,793 patients. Patients' mean age was 64.7 years, 54 % were male, 30.7 % had no history of smoking. Overall, 78 % of EGFRm test results were received ≤ 2 weeks after request (range of median 7-14 days across countries). Median time from advanced NSCLC diagnosis to EGFRm test result was 18 days (median range 10-22 days across countries). Over a third (37 %) of patients received a systemic treatment prior to EGFRm result; chemotherapy (25 %) and EGFR-TKI (15 %) were most commonly prescribed; post-EGFR test-result was EGFR-TKI (68 %); 80 % of patients initiated EGFR-TKI at any time point post-NSCLC diagnosis. Of those receiving a first-line EGFR-TKI post-EGFRm testing, 84 % received a TKI alone, 12 % in combination with chemotherapy, and 3 % with other treatments. Median time from first-line EGFR-TKI initiation post-EGFRm testing to first subsequent treatment was 19.8 months. CONCLUSION: Over one-fifth of patients wait >14 days for their EGFRm test results, affecting their likelihood of receiving first-line EGFR-TKI with 20 % of patients never receiving EGFR TKI treatment. There was significant inter-country variability in the proportion of patients receiving EGFR TKIs. Our study highlights the need to improve EGFRm testing turnaround times and treatment initiation across countries.