The relationships between age, sex and exercise intensity on cerebral artery haemodynamics during isometric handgrip exercise.

Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 years, N=42 female), cerebrovascular responses were assessed during two minute isometric exercise bouts at three intensities (15, 30, 45% maximal voluntary contraction). Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary haemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P<0.001) and PCAv (P=0.005). There were no effects of intensity on ICA and VA responses (P>0.05), despite intensity-dependent increases in MAP (P<0.001). The increased MCAv response to exercise was blunted with advancing age (P=0.01) with no influence of sex (P=0.86). The present study provides data on age, sex and intensity specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex dependent influence. Further, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress and velocity responses were similarly increased at all intensities during handgrip exercise.

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.

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.

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.

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.

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 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.

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.

Autonomic control of cerebral blood flow: fundamental comparisons between peripheral and cerebrovascular circulations in humans.

Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region-specific autonomic regulation of CBF. Compensatory chemo- and autoregulatory responses throughout the cerebral circulation, and interactions with parasympathetic nerve activity are unique features to the cerebral circulation. This crosstalk between sympathetic and parasympathetic reflexes acts to ensure adequate perfusion of CBF to rising and falling perfusion pressures, optimizing delivery of oxygen and nutrients to the brain, while attempting to maintain blood volume and intracranial pressure. Herein, we highlight the distinct similarities and differences between autonomic control of cerebral and peripheral blood flow, and the regional specificity of sympathetic and parasympathetic regulation within the cerebrovasculature. Future research directions are outlined with the goal to further our understanding of autonomic control of CBF in humans.

The relationships between age, sex, and cerebrovascular reactivity to hypercapnia using traditional and kinetic-based analyses in healthy adults.

The effect of age and sex on intracranial and extracranial cerebrovascular function is poorly understood. We investigated the relationships between age, sex, and cerebrovascular reactivity (CVR) to hypercapnia in 73 healthy adults (18-80 yr, n = 39 female). CVR to hypercapnia was assessed in the middle cerebral artery (MCA) using transcranial Doppler ultrasound and at the internal carotid artery (ICA) using duplex ultrasound. MCA CVR was characterized by peak MCA velocity (MCAv) response per mmHg increase in end-tidal CO2 and by using a monoexponential model to characterize the kinetics (time constant) of the MCAv response. ICA reactivity was assessed as the relative peak increase in artery diameter. Hierarchical multiple regression determined the relationships between age, sex, and the age-by-sex interaction on all baseline and CVR outcomes. There was no relationship between ICA reactivity (%) with age (P = 0.07), sex (P = 0.56), or a moderator effect of sex on the age effect (P = 0.24). MCAv CVR showed no relationship with age (P = 0.59), sex (P = 0.09), or an age-by-sex moderator effect (P = 0.90). We observed a positive relationship of MCAv CVR time constant with age (P = 0.013), such that the speed of the MCA response was slower with advancing age. The present study provides comprehensive data on age- and sex-specific relationships with intracranial and extracranial cerebrovascular responses to hypercapnia. Despite similar MCAv CVR and ICA reactivity between sexes, kinetic responses of the MCA revealed a slower rate of adjustment with advancing age.NEW & NOTEWORTHY We observed similar MCA CVR and ICA reactivity in males and females. However, kinetic responses of the MCA to hypercapnia suggest that advancing age slows down the rate at which MCA velocity increases in response to hypercapnia. These data indicate distinct regulatory differences, and an impaired vasomotor control of the cerebrovasculature with advancing age, not detected by traditional methods.

The physiological and clinical importance of cardiorespiratory fitness in people with abdominal aortic aneurysm.

NEW FINDINGS: What is the topic of this review? This review focuses on the physiological impact of abdominal aortic aneurysm (AAA) on cardiorespiratory fitness and the negative consequences of low fitness on clinical outcomes in AAA. We also discuss the efficacy of exercise training for improving cardiorespiratory fitness in AAA. What advances does it highlight? We demonstrate the negative impact of low fitness on disease progression and clinical outcomes in AAA. We highlight potential mechanistic determinants of low fitness in AAA and present evidence that exercise training can be an effective treatment strategy for improving cardiorespiratory fitness, postoperative mortality and disease progression. ABSTRACT: An abdominal aortic aneurysm (AAA) is an abnormal enlargement of the aorta, below the level of the renal arteries, where the aorta diameter increases by >50%. As an aneurysm increases in size, there is a progressive increase in the risk of rupture, which ranges from 25 to 40% for aneurysms >5.5 cm in diameter. People with AAA are also at a heightened risk of cardiovascular events and associated mortality. Cardiorespiratory fitness is impaired in people with AAA and is associated with poor (postoperative) clinical outcomes, including increased length of hospital stay and postoperative mortality after open surgical or endovascular AAA repair. Although cardiorespiratory fitness is a well-recognized prognostic marker of cardiovascular health and mortality, it is not assessed routinely, nor is it included in current clinical practice guidelines for the management of people with AAA. In this review, we discuss the physiological impact of AAA on cardiorespiratory fitness, in addition to the consequences of low cardiorespiratory fitness on clinical outcomes in people with AAA. Finally, we summarize current evidence for the effect of exercise training interventions on cardiorespiratory fitness in people with AAA, including the associated improvements in postoperative mortality, AAA growth and cardiovascular risk. Based on this review, we propose that cardiorespiratory fitness should be considered as part of the routine risk assessment and monitoring of people with AAA and that targeting improvements in cardiorespiratory fitness with exercise training might represent a viable adjunct treatment strategy for reducing postoperative mortality and disease progression.

The within- and between-day reliability of cerebrovascular reactivity using traditional and novel analytical approaches.

NEW FINDINGS: What is the central question of the study? What is the reliability of middle cerebral artery velocity cerebrovascular reactivity (CVR) when using traditional and novel outcomes, as measured by transcranial Doppler? What is the main finding and its importance? Traditional CVR approaches presented acceptable reproducibility but should be expressed as an absolute CVR. Large within- and between-individual differences in the middle cerebral artery velocity response profile support using a dynamic peak, rather than a set time point, for the most reliable interpretation. The study highlights the utility of novel kinetic CVR outcomes, but due to increased variability in time-based metrics, this analysis requires larger sample sizes than traditional methods. ABSTRACT: Cerebrovascular reactivity (CVR) of middle cerebral artery velocity (MCAv) to CO2 is a common method to assess cerebrovascular function. Yet, the approaches used to calculate CVR outcomes vary. The aim of this study was to explore the within- and between-day reliability of traditional CVR outcomes. The second aim was to explore the reliability of novel kinetic-based analyses. Healthy adults (n = 10, 22.3 ± 3.4 years) completed assessments of CVR over 4 min using a fixed fraction of inspired CO2 (6%). This was repeated across four separate visits (between-day), and on one visit measures were repeated 2.5 h later (within-day). No mean biases were present between assessments for traditional CVR metrics, expressed as absolute (cm/s/mmHg) or relative (%/mmHg) outcomes (minute 3, minute 4, peak 1 s, peak 30 s) (between-day: P > 0.14, ηp2 < 0.20; within-day: P > 0.22, d > 0.27). Absolute, rather than relative, CVR yielded the most reproducible parameters (coefficient of variation: 8.1-13.2% vs. 14-83%, respectively). There were significant differences between CVR outcomes (P < 0.001, ηp2 > 0.89) dependent on the time point used to determine CVR, as a steady state MCAv response was rarely observed. Furthermore, the MCAv response was not reproducible within an individual (κ = 0.15, P = 0.09). No mean differences were present for novel kinetic outcomes (amplitude, time-delay, time constant) (between-day: P > 0.05, d < 0.33; within-day: P > 0.38, d < 0.25). The results support the need for standardisation and indicate CVR should be defined as a dynamic peak, rather than a set time point for increased reliability. For novel kinetic outcomes variability was greater (CV: 8.7-120.9%) due to the nature of time-based metrics.

Burden of disease, treatment utilization, and the impact on education and employment in patients with sickle cell disease: A comparative analysis of high- and low- to middle-income countries for the international Sickle Cell World Assessment Survey.

The international Sickle Cell World Assessment Survey (SWAY) reported a high impact of sickle cell disease (SCD) on patients' daily lives globally. In this study, we analyzed whether the reported burden differed between patients from the USA (n = 384) and other high-income (HI; n = 820) or low- to middle-income (LMI; n = 941) countries. We assessed symptoms and complications, incidence/management of vaso-occlusive crises (VOCs), treatment utilization/satisfaction, and the impact of SCD on education/employment. Certain symptoms (bone aches, insomnia, and joint stiffness) and complications (swollen/painful fingers/toes, gallstones, vision problems, blood clots, and asthma) were reported proportionally more by patients in the USA than in the HI/LMI countries. Self-reported VOCs were more common (mean [SD]: 7.1 [5.7] vs. 5.5 [8.9] and 4.4 [4.6] in the previous 12 months) and were managed more often by hospitalization (52% vs. 24% and 32%) in the USA than the HI and LMI countries. A higher proportion of patients from the USA than the HI/LMI countries reported a negative impact of SCD on their employment/schooling. Although high overall satisfaction with current treatments was reported globally, most patients indicated a strong desire for alternative pain medications. There are likely several reasons for the relatively high patient-reported burden in the USA group compared with the HI/LMI countries, including an older population and differences in newborn screening programs and pediatric/adult transition of care. It is clear that there is an urgent need for improved understanding and management of SCD globally, not just in the USA.

Toward a Better Understanding of Muscle Microvascular Perfusion During Exercise in Patients With Peripheral Artery Disease: The Effect of Lower-Limb Revascularization.

PURPOSE: Leg muscle microvascular blood flow (perfusion) is impaired in response to maximal exercise in patients with peripheral artery disease (PAD); however, during submaximal exercise, microvascular perfusion is maintained due to a greater increase in microvascular blood volume compared with that seen in healthy adults. It is unclear whether this submaximal exercise response reflects a microvascular impairment, or whether it is a compensatory response for the limited conduit artery flow in PAD. Therefore, to clarify the role of conduit artery blood flow, we compared whole-limb blood flow and skeletal muscle microvascular perfusion responses with exercise in patients with PAD (n=9; 60±7 years) prior to, and following, lower-limb endovascular revascularization. MATERIALS AND METHODS: Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after a 5 minute bout of submaximal intermittent isometric plantar-flexion exercise using contrast-enhanced ultrasound imaging. Exercise contraction-by-contraction whole-leg blood flow and vascular conductance were measured using strain-gauge plethysmography. RESULTS: With revascularization there was a significant increase in whole-leg blood flow and conductance during exercise (p<0.05). Exercise-induced muscle microvascular perfusion response did not change with revascularization (pre-revascularization: 3.19±2.32; post-revascularization: 3.89±1.67 aU.s-1; p=0.38). However, the parameters that determine microvascular perfusion changed, with a reduction in the microvascular volume response to exercise (pre-revascularization: 6.76±3.56; post-revascularization: 2.42±0.69 aU; p<0.01) and an increase in microvascular flow velocity (pre-revascularization: 0.25±0.13; post-revascularization: 0.59±0.25 s-1; p=0.02). CONCLUSION: These findings suggest that patients with PAD compensate for the conduit artery blood flow impairment with an increase in microvascular blood volume to maintain muscle perfusion during submaximal exercise. CLINICAL IMPACT: The findings from this study support the notion that the impairment in conduit artery blood flow in patients with PAD leads to compensatory changes in microvascular blood volume and flow velocity to maintain muscle microvascular perfusion during submaximal leg exercise. Moreover, this study demonstrates that these microvascular changes are reversed and become normalized with successful lower-limb endovascular revascularization.

Comparison of high intensity interval training with standard cardiac rehabilitation on vascular function.

OBJECTIVES: To compare the short- and long-term effects of high-intensity interval training (HIIT) with usual care moderate intensity continuous training (MICT) on systemic vascular function and stiffness in patients with coronary artery disease undergoing a cardiac rehabilitation program. DESIGN: Randomized controlled trial. METHODS: Fifty-four patients (age = 63 ± 8 years, 93% male) were randomized to complete 3 sessions/week (2 supervised, 1 home-based) of either (1) 4 × 4-min HIIT or (2) 40-min MICT, for 4 weeks. Patients then continued 3 unsupervised home-based sessions/week of their allocated training for 11 months. Brachial artery flow-mediated dilation, pulse wave velocity, and blood pressure were measured at baseline, 4 weeks, 3 months, 6 months, and 12 months. Data were analyzed using linear mixed modeling and are presented as mean change from baseline (95% CI). RESULTS: HIIT showed a greater improvement in flow-mediated dilation compared to MICT after 4 weeks [1.5% (0.9, 2.1) vs 0.1% (-0.5, 0.8); p = 0.004) but not 12 months [1.2% (-0.2, 2.5) vs 0.4% (-0.8, 1.7); p = 0.153). There were no short- or long-term group differences for changes in pulse wave velocity, peripheral or central blood pressure between HIIT and MICT after 4 weeks, or over 12 months. CONCLUSIONS: A 4-week HIIT program was superior to MICT for improving vascular function, but not arterial stiffness or blood pressure. Over 12 months, changes in vascular function, blood pressure, and arterial stiffness were similar for HIIT and MICT.

Cerebrovascular function and its association with systemic artery function and stiffness in older adults with and without mild cognitive impairment.

PURPOSE: Our aim was to compare cerebrovascular and systemic vascular function between older adults with and without mild cognitive impairment (MCI), and to determine which measures of vascular function best predict the presence of MCI. METHODS: In 41 adults with MCI and 33 adults without MCI (control) we compared middle cerebral artery velocity (MCAv) and cerebrovascular pulsatility index (PI) at rest, cerebrovascular reactivity to CO2, and responsiveness to changes in blood pressure (%∆MCAv/%∆MAP). Systemic vascular function was assessed by flow-mediated dilation (FMD) and stiffness by pulse wave velocity (PWV). RESULTS: Cerebrovascular PI was higher in MCI compared with control (mean ± SD: 1.17 ± 0.27 vs. 1.04 ± 0.21), and MCI exhibited a lower %∆MCAv/%∆MAP (1.26 ± 0.44 vs. 1.50 ± 0.55%). Absolute (p = 0.76) and relative cerebrovascular reactivity to CO2 (p = 0.34) was similar between MCI and control. When age was included as a covariate the significant difference in cerebral PI between groups was lost. PWV was higher (13.2 ± 2.2 vs. 11.3 ± 2.5 m s-1) and FMD% (4.41 ± 1.70 vs. 5.43 ± 2.15%) was lower in MCI compared with control. FMD% was positively associated with PI across the cohort. Logistic regression analysis indicated that FMD and PWV significantly discriminated between MCI and controls, independent of age, whereas the inclusion of cerebrovascular measures did not improve the predictive accuracy of the model. CONCLUSION: These findings raise the possibility that early changes in systemic vascular stiffness and endothelial function may contribute to altered cerebrovascular haemodynamics and impaired cognitive function, and present potential targets for prevention and treatment strategies in people with MCI.

Modelling triadic relationships in families of children with intellectual disability.

BACKGROUND: Existing research has predominately focused on dyadic relationships in families of children with intellectual disabilities. The aim of this study was to build on emerging literature exploring triadic relationships between a mother, sibling, and child with intellectual disability, investigating how they influence each other's well-being. METHOD: An online survey was used to collect information regarding the mother's mental health and the emotional and behavioural problems of the sibling and the child with intellectual disability in 573 families. RESULTS: Using structural equation modelling, we found that maternal psychological distress was associated with higher levels of behaviour problems in the sibling, and the behaviour problems of the child with intellectual disability were associated with higher levels of maternal distress. CONCLUSIONS: Family member well-being is inter-related in families of children with intellectual disabilities. Clinical interventions that improve the behaviours of children with intellectual disabilities should be considered.

Effects of cardiorespiratory fitness and exercise training on cerebrovascular blood flow and reactivity: a systematic review with meta-analyses.

We address two aims: Aim 1 (Fitness Review) compares the effect of higher cardiorespiratory fitness (CRF) (e.g., endurance athletes) with lower CRF (e.g., sedentary adults) on cerebrovascular outcomes, including middle cerebral artery velocity (MCAv), cerebrovascular reactivity and resistance, and global cerebral blood flow, as assessed by transcranial Doppler (TCD) or magnetic resonance imaging (MRI). Aim 2 (Exercise Training Review) determines the effect of exercise training on cerebrovascular outcomes. Systematic review of studies with meta-analyses where appropriate. Certainty of evidence was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Twenty studies (18 using TCD) met the eligibility criteria for Aim 1, and 14 studies (8 by TCD) were included for Aim 2. There was a significant effect of higher CRF compared with lower CRF on cerebrovascular resistance (effect size = -0.54, 95% confidence interval = -0.91 to -0.16) and cerebrovascular reactivity (0.98, 0.41-1.55). Studies including males only demonstrated a greater effect of higher CRF on cerebrovascular resistance than mixed or female studies (male only: -0.69, -1.06 to -0.32; mixed and female studies: 0.10, -0.28 to 0.49). Exercise training did not increase MCAv (0.05, -0.21 to 0.31) but showed a small nonsignificant improvement in cerebrovascular reactivity (0.60, -0.08 to 1.28; P = 0.09). Exercise training showed heterogeneous effects on regional but little effect on global cerebral blood flow as measured by MRI. High CRF positively effects cerebrovascular function, including decreased cerebrovascular resistance and increased cerebrovascular reactivity; however, global cerebral blood flow and MCAv are primarily unchanged following an exercise intervention in healthy and clinical populations.NEW & NOTEWORTHY Higher cardiorespiratory fitness is associated with lower cerebrovascular resistance and elevated cerebrovascular reactivity at rest. Only adults with a true-high fitness based on normative data exhibited elevated middle cerebral artery velocity. The positive effect of higher compared with lower cardiorespiratory fitness on resting cerebrovascular resistance was more evident in male-only studies when compared with mixed or female-only studies. A period of exercise training resulted in negligible changes in middle cerebral artery velocity and global cerebral blood flow, with potential for improvements in cerebrovascular reactivity.

Real-world study of the impact of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) on quality of life and productivity in Europe.

BACKGROUND: Although current therapy for patients with early-stage squamous cell carcinoma of the head and neck (SCCHN) is potentially curative, the recurrence rate is high. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis and substantial disease burden, including impaired health-related quality of life (HRQoL), productivity loss and indirect costs, such as need for caregiver support. The aim of this study was to characterize the impact of R/M SCCHN and its first-line treatment on patient and caregiver quality of life, daily activities and work productivity using real-world evidence from Europe. METHODS: This was a multicentre retrospective study of patients with R/M SCCHN in France, Germany, Italy, Spain and the United Kingdom incorporating patient and caregiver surveys, and a physician-reported medical chart review, conducted between January and May 2019. Patients aged 18 or over with a physician confirmed diagnosis R/M SCCHN completed four validated measures of disease activity and its impact on quality of life and work productivity, while caregivers also completed questionnaire to assess the burden of providing care. Physicians provided data for clinical characteristics, patient management, testing history and treatment patterns. RESULTS: A total of 195 medical/clinical oncologists provided data for 937, predominantly male (72%) patients, with almost half of patients aged over 65 years. The most frequently reported symptoms were fatigue (43%), weight loss (40%), pain (35%) and difficulty swallowing (32%). The EXTREME regimen was the most common first line therapy in over half of patients, who reported moderate or extreme pain/discomfort, and anxiety/depression, and problems with self-care resulting in a diminished health status compared with the general population. Only 14% were employed with high absenteeism or presenteeism, and over half of patients had a caregiver for whom the burden of care was substantial. CONCLUSION: Our results provide real-world insight into the multi-faceted burden associated with R/M SCCHN. The combination of poor HRQoL and the impairment in daily activities, social life and employment illustrates the wider impact of R/M SCCHN on patients and their caregivers, and highlights a need for novel 1 L treatment regimens to improve the humanistic and productivity burdens of this cancer.