A review of the potential local mechanisms by which exercise improves functional outcomes in intermittent claudication

© 2016 Elsevier Inc. All rights reserved. Background Intermittent claudication (IC) is a common condition which is associated with significant quality of life limitation. National Institute for Health and Care Excellence guidelines recommend a group-based supervised exercise program as the primary treatment option for claudication, based on clinical and cost effectiveness. This review aims to assess the mechanisms by which exercise improves outcomes in patients with IC. Methods MEDLINE, EMBASE, and PubMed were searched using the search strategy "claudication" [AND] "exercise" [AND] "mechanisms." Searches were limited from 1947 to October 2014. Only full-text articles published in the English language in adults (over 18 years of age) were eligible for the review. Any trial involving a nonsupervised exercise program was excluded. Abstracts identified by the database search were interrogated for relevance and citations from the shortlisted papers were hand searched for relevant references. Results The search yielded a total of 112 studies, of which 42 were duplicates. Forty-seven of the remaining 70 were deemed appropriate for inclusion in the review. Exercise is the first-line treatment for IC. Supervised exercise programs improve walking distances, endothelial and mitochondrial function, muscle strength, and endurance. Furthermore, it leads to a generalized improvement in cardiovascular fitness and overall quality of life. Conclusions The mechanism by which exercise improves outcome in claudicants is complicated and multifactorial. Further research is required in this area to fully elucidate the precise and predominant mechanisms and to assess whether targeted exercise program modification maximizes mechanism efficacy and patient outcome

Presurgery conditioning interventions (prehabilitation) in adults undergoing lower limb surgery for peripheral arterial disease

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To assess the effectiveness of prehabilitation (preoperative exercise, either alone or in combination with nutritional or psychological interventions or both) on postoperative outcomes in adults with PAD undergoing open lower limb surgery

The BASES Expert Statement on Exercise Training for People with Intermittent Claudication due to Peripheral Arterial Disease

Lower-limb peripheral arterial disease (PAD) is a type of cardiovascular disease in which the blood vessels (arteries) that carry blood to the legs and feet are hardened and narrowed or blocked by the build-up of fatty plaques (called atheroma). It affects around 13% of adults over 50 years old, and major risk factors for its development include smoking, diabetes mellitus, and dyslipidaemia (Morley, Sharma, Horsch & Hinchliffe, 2018). The presence of PAD itself is also a risk factor for other cardiovascular problems, such as angina, heart attack and stroke. This is because the underlying disease process, atherosclerosis, is a systemic process, meaning that blood vessels elsewhere in the body may also be affected.The most common symptom of PAD is intermittent claudication (IC), which is muscle pain or discomfort in the legs and/or buttocks brought on by walking and relieved within minutes on rest (Figure 1). It occurs due to an inability to increase blood flow (and oxygen delivery) sufficiently to match the metabolic demands of the lower-limb muscles during exercise. The walking distance or speed at which symptoms occur depends on multiple factors including the severity and site of the arterial disease, walking pace, terrain, incline and footwear. Nevertheless, IC can cause marked reductions in functional capacity and quality of life (Morley et al., 2018).Treatments for IC, aimed at relieving symptoms and reducing the risk of further cardiovascular disease, include lifestyle changes (e.g., stopping smoking, exercising more), vasoactive drugs (e.g. naftidrofuryl oxalate), and revascularisation (i.e. angioplasty or bypass surgery). In 2012, the United Kingdom’s National Institute of Health and Care Excellence (NICE) published a clinical guideline on the management of PAD, which stated that a supervised exercise programme should be offered as a first-line therapy for IC (NICE, 2012). This statement provides an overview of the evidence on exercise training and recommendations for people delivering exercise programmes to this population

Preferred exercise modalities in patients with intermittent claudication

Conventional supervised exercise programs (SEPs) for claudicants are traditionally based on time-constrained, groupbased structured programs usually at a hospital site. Uptake of an SEP is poor, despite the high-level evidence demonstrating its clinical effectiveness; therefore, alternative forms of exercise programs are needed which are more acceptable to patients. This study aimed to explore a range of exercise modalities to determine patient preferences for exercise delivery on a national level. This was a questionnaire survey to identify and incorporate patient preferences when designing a multicenter nationwide health-service evaluation of patient preference to exercise in the United Kingdom’s National Health Service (the PREFER study). Patients with documented stable intermittent claudication who were suitable for an SEP were given a questionnaire to fill out at their clinic visit. Data were recorded using the Bristol Online Survey tool (http://www.survey.bris.ac.uk/) and analyzed descriptively. Thirty complete questionnaires were analyzed. Participants were generally unilateral claudicants (80%) with symptoms for over 1 year (64%). Only 6 of the 30 patients had engaged in a lifelong routine of exercise. Eighty-seven percent of patients indicated that they had not taken part in an exercise program, but 73% of those indicated that they would be willing to participate to improve their walking. Most patients expressed a preference for a home exercise program (50%) followed by a hospital SEP. The majority of patients (43%) were happy to exercise 3 days per week using a walking-based program (53%). There was however no consensus on the duration or intensity of the exercise program. The SEP is the recommended first-line treatment for intermittent claudication patients; however, the vast majority of patients fail to engage with or complete an exercise program. This study demonstrates that exercise therapy should be individualized and take a patient-centered approach. Commissioning groups should incentivize hospitals and clinicians to engage with their patient populations to understand their needs and deliver an appropriate servic

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Recognising aspiration: The AIME program\u27s effectiveness in inspiring Indigenous young people\u27s participation in schooling and opportunities for further education and employment

A strong feature of the widening participation agenda is improving the aspirations of groups that are underrepresented in higher education. This paper seeks to reposition the utility of this as a focal point of educational interventions by showcasing the success of a mentoring program that takes a different approach. The Australian Indigenous Mentoring Experience (AIME) significantly and positively impacts Australian Indigenous high school students\u27 aspirations to finish school and continue to further study, training or employment. AIME is not read as a classic intervention program for raising aspirations. Instead, AIME builds upon the cultural wealth of participants and adopts an approach that seeks to inspire individuals rather than remediate them. The paper draws on survey data and fieldwork to present an example case study for resisting the assumption that young people\u27s aspirations are deficit and in need of \u27improving\u27. The paper describes how AIME works within young people\u27s \u27windows of aspiration\u27 to positively impact their engagement in school and further education, training and employment

AIME and the University of Wollongong: The Australian Indigenous Mentoring Experience

The collaborative research partnership between the University of Wollongong and the Australian Indigenous Mentoring Experience (AIME), an Indigenous community organisation, has grown from internal university funding to national funding. This mutually beneficial partnership has resulted in: outputs to AIME for use in their program; funded educational opportunities for Indigenous students at both undergraduate and postgraduate levels; and the design of statistical tools for the collection of quantitative data on the program