Pharmacogenetics of tamoxifen in breast cancer patients of African descent: Lack of data.

Tamoxifen, a selective estrogen receptor modulator, is used to treat hormone receptor-positive breast cancer. Tamoxifen acts as a prodrug, with its primary therapeutic effect mediated by its principal metabolite, endoxifen. However, tamoxifen has complex pharmacokinetics involving several drug-metabolizing enzymes and transporters influencing its disposition. Genes encoding enzymes involved in tamoxifen disposition exhibit genetic polymorphisms which vary widely across world populations. This review highlights the lack of data on tamoxifen pharmacogenetics among African populations. Gaps in data are described in this study with the purpose that future research can address this dearth of research on the pharmacogenetics of tamoxifen among African breast cancer patients. Initiatives such as the African Pharmacogenomics Network (APN) are crucial in promoting comprehensive pharmacogenetics studies to pinpoint important variants in pharmacogenes that could be used to reduce toxicity and improve efficacy.

Towards Evidence-Based Implementation of Pharmacogenomics in Southern Africa: Comorbidities and Polypharmacy Profiles across Diseases.

Pharmacogenomics may improve patient care by guiding drug selection and dosing; however, this requires prior knowledge of the pharmacogenomics of drugs commonly used in a specific setting. The aim of this study was to identify a preliminary set of pharmacogenetic variants important in Southern Africa. We describe comorbidities in 3997 patients from Malawi, South Africa, and Zimbabwe. These patient cohorts were included in pharmacogenomic studies of anticoagulation, dyslipidemia, hypertension, HIV and breast cancer. The 20 topmost prescribed drugs in this population were identified. Using the literature, a list of pharmacogenes vital in the response to the top 20 drugs was constructed leading to drug-gene pairs potentially informative in translation of pharmacogenomics. The most reported morbidity was hypertension (58.4%), making antihypertensives the most prescribed drugs, particularly amlodipine. Dyslipidemia occurred in 31.5% of the participants, and statins were the most frequently prescribed as cholesterol-lowering drugs. HIV was reported in 20.3% of the study participants, with lamivudine/stavudine/efavirenz being the most prescribed antiretroviral combination. Based on these data, pharmacogenes of immediate interest in Southern African populations include ABCB1, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLC22A1, SLCO1B1 and UGT1A1. Variants in these genes are a good starting point for pharmacogenomic translation programs in Southern Africa.

ABCB1 and OPRM1 single-nucleotide polymorphisms collectively modulate chronic shoulder pain and dysfunction in South African breast cancer survivors.

Background: Chronic shoulder pain/disability is a well-recognized side effect of treatment for breast cancer, with ∼40% of patients experiencing this, despite receiving pain management. To manage acute and chronic pain, several opioids are commonly prescribed. Pharmacogenomics have implicated genes within the opioid signaling pathway, including ABCB1 and OPRM1, to contribute to an individual's variable response to opioids. Aim: To evaluate ABCB1 (rs1045642 G>A, rs1128503 G>A) and OPRM1 (rs1799971 A>G, rs540825 T>A) single-nucleotide polymorphisms (SNPs) in chronic shoulder pain/disability in BCS. Materials & methods: TaqManTM assays were used to genotype ABCB1 and OPRM1 SNPs within the BCS (N = 252) cohort. The Shoulder Pain and Disability Index was used to evaluate pain and disability features associated with shoulder pathologies. Participants end scores for each feature (pain, disability and combined [pain and disability]) were categorized into no-low (>30%) and moderate-high (≥30%) scores. Statistical analysis was applied, and significance was accepted at p < 0.05. Results: Of participants, 27.0, 19.0 and 22.0% reported moderate-high pain, disability and combined (pain and disability) scores, respectively. ABCB1:rs1045642-(A/A) genotype was significantly associated with disability (p = 0.028: no-low [14.9%] vs mod-high [4.3%]) and combined (pain and disability) (p = 0.011: no-low [15.9%] vs mod-high [5.7%]). The ABCB1:rs1045642-(A) allele was significantly associated with disability (p = 0.015: no-low [37.9%] vs mod-high [23.9%]) and combined (pain and disability) (p = 0.003: no-low [38.5%] vs mod-high [23.6%]). The inferred ABCB1 (rs1045642 G>A - rs1128503 G>A): A-G (p = 0.029; odds ratio [OR]: 0.0; 95% CI: 0.0-0.0) and the OPRM1 (rs1799971 A>G - rs540825 T>A): G-T (p = 0.019; OR: 0.33; 95% CI: 0.14-0.75) haplotypes were associated with disability and pain, respectively. Gene-gene interactions showed the ABCB1 (rs1045642 G>A) - OPRM1 (rs540825 T>A) combinations, (A-T) (p = 0.019; OR: 0.62; 95% CI: 0.33-1.16) and (G-A) (p = 0.021; OR: 1.57; 95% CI: 0.30-3.10) were associated with disability. Conclusion: The study implicated ABCB1 with shoulder pain and disability; and haplotype analyses identified specific genetic intervals within ABCB1 and OPRM1 to associate with chronic shoulder pain and disability. Evidence suggests that potentially gene-gene interactions between ABCB1 and OPRM1 contribute to chronic shoulder pain and disability experienced in this SA cohort.

Strategies to Increase Participation of African Populations in Clinical Trials.

Conducting clinical research in low- and middle-income countries is essential to address the global impact of cancer. In 2017, ASCO convened an Academic Global Oncology Task Force that recommended an increase in global oncology research to enhance the field of oncology through research and education. The emerging crisis of cancer in Africa demands a similar global commitment to workforce development, infrastructure building, and access to care that will provide a platform for impactful and relevant research efforts. In the words of the African Organisation for Research and Training in Cancer, it is time to "transform cancer control in Africa through collaboration in education, research, (and) delivery of equitable and timely interventions to minimize the impact of cancer." Although there are some initiatives aimed at developing research capacity to host trials in Africa, there is now a need to establish strategic partnerships with the aim of achieving harmonized, accredited clinical trial units capable of running trials according to Good Clinical Practice standards.

A scoping review examining the integration of exercise services in clinical oncology settings.

BACKGROUND: Addressing questions surrounding the feasibility of embedding exercise service units in clinical oncology settings is imperative for developing a sustainable exercise-oncology clinical pathway. We examined available literature and offered practical recommendations to support evidence-based practice, policymaking, and further investigations. METHODS: Four thousand eight hundred sixty-three unique records identified in Embase, CINAHL, MEDLINE, Web of Science Core Collection, and ProQuest (Health and Medicine) were screened for studies that recruited cancer patients, assessed the co-location of exercise service and cancer treatment units, and reported findings on service implementation. Evidence from six studies providing data from over 30 programs was integrated using narrative synthesis. RESULTS: Service implementation was relatively modest across the included studies. Exercise services were delivered by physiotherapists, exercise physiologists, and kinesiologists and funded mainly through grants and private donations, with staff salaries accruing as the major expense. Service penetration, adoption, and acceptability were generally low. However, studies recorded high clinician/patient satisfaction. Major barriers to service integration were limited funding, lack of detailed implementation plan, and low organizational buy-in. Common reasons for non-utilization, missed sessions, and dropouts were lack of interest, unwellness, hospital readmission, disease progression, and adverse skeletal events. CONCLUSION: Implementing exercise services in clinical oncology settings seems an effective approach for increasing access to exercise-based rehabilitation for individuals on cancer treatment. While this model appears feasible for patients/clinicians, efforts are required to optimize service integration both in the short and long term. Key priorities include seeking [local] actions to address issues relating to funding and organizational buy-in. Important considerations may include developing an implementation plan to guide the implementation process, expanding the patient core management team to include staff from the exercise rehabilitation unit, and exploring the role of patient feedback in increasing clinician participation (e.g., treating oncologists and nurses) in the referral process. Future research should consider effective strategies to promote patients' sense of self-efficacy and behavioral control and, further, the place of audit and feedback in improving exercise service delivery and overall service implementation.

Plausible conditions and mechanisms for increasing physical activity behavior in men with prostate cancer using patient education interventions: sequential explanatory mixed studies synthesis.

PURPOSE: This mixed studies synthesis sought to evaluate structured patient education interventions (PEIs) to elucidate relevant conditions and mechanisms for increasing physical activity behavior in men with prostate cancer (PCa). METHODS: Studies that randomized men diagnosed with PCa, assessed PEIs, and reported (1) between-group changes in the outcome measures of exercise self-efficacy, PA level, or patient-centered outcomes (cancer-related fatigue, aerobic fitness, and quality of life) at baseline and post-intervention, and/or (2) men's perceptions of structured PEIs were synthesized. Results from five RCTs reporting data on 895 men and qualitative reports from four studies were respectively and sequentially analyzed with narrative and thematic syntheses. Findings from both syntheses were further integrated using the context-mechanism-outcome configuration (CMO) to elucidate potential "contextual factors" or "conditions" that may support plausible PEI mechanisms. RESULTS: Structured PEIs were associated with a beneficial increase in task self-efficacy, vigorous-intensity PA, minutes/week of resistance exercise, the proportion of men meeting ≥ 150 minutes/week of moderate-vigorous intensity aerobic exercise, and overall PA. No effects were found on patient-centered outcomes. Drawing upon the CMO configuration, the inclusion of a referral process, access to "credible influence" (e.g., involving former patients as program facilitators), and adopting hybrid service delivery are likely critical conditions that may explain the success of PEIs in men with PCa. CONCLUSION: PEIs can increase PA behavior in men with PCa. The likelihood of success is higher for multicomponent interventions that prioritized credible influence and exercise referral as critical components besides offering access to interventions within hospital settings, with home-based sessions in addition.

Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors'.

Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (<30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A > G), rs4633 (C > T), rs4818 (C > G) and the functional rs4680(G > A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele-allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p < 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33-7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47-9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03-2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07-2.71). For the inferred COMT (rs6269 A > G-rs4680 G > A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38-1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89-4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92-5.17) haplotype was also significantly associated with combined (pain and disability). Gene-gene interaction analyses further showed allele-allele combinations for COMT (rs4680 G > A)-OPRM1 (rs1799971 A > G) and COMT (rs4680 G > A)-OPRM1(rs540825 T > A) were associated with reporting pain and combined (pain and disability) symptoms, p < 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape.

Regulatory VCAN polymorphism is associated with shoulder pain and disability in breast cancer survivors.

BACKGROUND AND PURPOSE: Shoulder morbidity following breast cancer treatment is multifactorial. Despite several treatment- and patient-related factors being implicated, unexplained inter-individual variability exists in the development of such morbidity. Given the paucity of relavant genetic studies, we investigate the role of polymorphisms in candidate proteoglycan genes. PATIENTS AND METHODS: We conducted a cross-sectional study on 254 South African breast cancer survivors, to evaluate associations between shoulder pain/disability and ten single nucleotide polymorphisms (SNPs) within four proteoglycan genes: ACAN (rs1126823 G>A, rs1516797 G>T, rs2882676 A>C); BGN (rs1042103 G>A, rs743641 A>T, rs743642 G>T); DCN rs516115 C>T; and VCAN (rs11726 A>G, rs2287926 G>A, rs309559). Participants were grouped into no-low and moderate-high shoulder pain/disability based on total pain/disability scores: < 30 and ≥ 30, respectively using the Shoulder Pain and Disability Index (SPADI). RESULTS: The GG genotype of VCAN rs11726 was independently associated with an increased risk of being in the moderate-to-high shoulder pain (P = 0.005, OR = 2.326, 95% CI = 1.259-4.348) or disability (P = 0.011, OR = 2.439, 95% CI = 1.235-4.762) categories, after adjusting for participants' age. In addition, the T-T-G inferred allele combination of BGN (rs74364-rs743642)-VCAN rs11726 was associated with an increased risk of being in the moderate-to-high shoulder disability category (0 = 0.002, OR = 2.347, 95% CI = 1.215-4.534). CONCLUSION: Our study is first to report that VCAN rs11726, independently or interacting with BGN polymorphisms, is associated with shoulder pain or disability in breast cancer survivors. Whereas our findings suggest an involvement of proteoglycans in the etiology of shoulder pain/disability, further studies are recommended.

Oncology Clinical Trials in Africa: Partnering for Quality.

Oncology clinical trials are requisite for testing the safety and effectiveness of promising treatments and deciphering new knowledge into concrete benefits for patients. They present opportunities to innovate promising, novel cancer remedies. A dearth of local evidence to guide cancer treatment in Africans is creating an increased interest in oncology clinical trials to improve patient care. This is primarily because of limitations in pathology, surgery, medical oncology, radiation, and palliation that are leading to worse cancer outcomes on the continent.Investment in oversight of Human Research Ethics committees and Medicines Regulatory Authorities in Africa has improved the potential for many countries to host clinical trials. However, the distribution of cancer trials remains poor across the continent, resulting in inadequate treatment options for patients with cancer.There are some initiatives aimed at developing research capacity to host trials in Africa. However, there is now a need to establish strategic partnerships whose aim should be to achieve harmonized, accredited Clinical Trials Units capable of running trials to meet Good Clinical Practice standards. This article discusses what has been achieved and proposes a model for quality oversight of Clinical Trials Units in Africa.

Landscape of Oncology Clinical Trials in Africa.

PURPOSE: The burden of cancer in Africa is of significant concern for several reasons, including that incidence of cancer in Africa continues to rise while Africa is also dealing with communicable diseases. To combat cancer in Africa, oncology clinical trials are needed to develop innovative interventions for cancer prevention, screening, diagnosis, treatment, and survivorship. Unfortunately, there is a paucity of clinical trials in Africa and it is difficult for African clinicians to get information on open oncology clinical trials and impossible for African patients with cancer to access this information. The primary objective of this study was to identify open oncology clinical trials in Africa. METHODS: This project was part of a large-scale study to develop an African Virtual Platform for Oncology Clinical Trials Registry. The study was a quantitative, web-based, retrospective review of clinical trials registries. RESULTS: A total of 109 open oncology clinical trials were identified. Most of the trials were in Egypt, South Africa, Algeria, and Kenya. The top cancer types for oncology clinical trials in Africa were breast, cervical, and lung cancers. The top sponsor of oncology clinical trials in Africa was academic institutions, especially institutions in the United States. CONCLUSION: The paucity of clinical trials in Africa will continue to magnify the global disparities of cancer in the African population. Clinical trials are needed to ensure therapeutic interventions are safe and effective in the African population. In the era of personalized and precision health, it no longer suffices to assume that drugs developed in North America, Europe, or Asia will be effective in the African population.

Effectiveness of over-ground robotic locomotor training in improving walking performance, cardiovascular demands, secondary complications and user-satisfaction in individuals with spinal cord injuries: A systematic review.

OBJECTIVES: To evaluate the effectiveness of over-ground robotic locomotor training in individuals with spinal cord injuries with regard to walking performance, cardiovascular demands, secondary health complications and user-satisfaction. DATA SOURCES: PubMed, Cochrane, Web of Science, Scopus, EBSCOhost and Engineering Village. STUDY SELECTION: Trials in which robotic locomotor training was used for a minimum of 3 participants with spinal cord injury. DATA EXTRACTION: Independent extraction of data by 2 reviewers using a pre-established data abstraction table. Quality of evidence assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). DATA SYNTHESIS: Total of 27 non-controlled studies representing 308 participants. Most studies showed decreases in exertion ratings, pain and spasticity and reported positive well-being post-intervention. Seven studies were included in meta-analyses on walking performance, showing significant improvements post-intervention (p < 0.05), with pooled effects for the 6-min walking test and 10-metre walking test of-0.94 (95% confidence interval (95% CI) -1.53,-0.36) and -1.22 (95% CI -1.87,-0.57), respectively. The Timed Up and Go Test showed a positive pooled effect of 0.74 (95% CI 0.36, 1.11). Improvements in walking parameters were seen with an increase in session number; however, no significant cardiovascular changes were found over time. CONCLUSION: Robotic locomotor training shows promise as a tool for improving neurological rehabilitation; however, there is limited evidence regarding its training benefits. Further high-powered, randomized controlled trials, with homogenous samples, are required to investigate these effects.

KDR inferred haplotype is associated with upper limb dysfunction in breast cancer survivors of mixed ancestry.

Introduction: Shoulder pain and disability are well-documented sequelae of breast cancer treatment. Angiogenesis signaling may have a role in the development of shoulder pain or shoulder disability in breast cancer survivors. The aim of this study was to determine if polymorphisms in angiogenesis-related genes are associated with shoulder pain or disability following breast cancer treatment. Participants and methods: A cross-sectional study was conducted on 220 South African breast cancer survivors. The study aimed to evaluate associations between shoulder pain/disability and seven single nucleotide polymorphisms (SNPs) within five angiogenesis-associated genes: KDR (rs2305948 C>T; rs7667298 C>T), NOS3 (rs1549758 C>T), MMP2 (rs708269 A>T), THBS2 (rs9766678 A>G) and TIMP3 (rs5754312 T>A; rs715572 G>A). In addition, associations between shoulder pain/disability and inferred haplotypes for KDR and TIMP3 SNPs were evaluated. Participants were grouped into no-low and moderate-high shoulder pain/disability based on total pain/disability scores: ≤30 and >30, respectively using the shoulder pain and disability index (SPADI). Results: No independent associations with shoulder pain/disability categories were found for all SNPs. However, 1 inferred haplotype (KDR "TT") differed significantly (P=0.014) between the shoulder disability categories. After adjusting for participants' age, the differences in KDR inferred haplotype frequencies between shoulder disability categories became non-significant (P=0.052). Conclusion: Our findings provide a preliminary suggestion of a possible association between polymorphisms in genes involved in angiogenesis and the presence of moderate-high shoulder disability among South African breast cancer survivors. A larger prospective cohort study is currently being conducted by our group.

Prevalence of shoulder morbidity after treatment for breast Cancer in South Africa.

PURPOSE: Breast cancer is the most frequently diagnosed cancer and leading cause of cancer death among women, representing a considerable public health burden in South Africa and other low-middle income countries. Short- and long-term complications of these treatments include shoulder morbidities such as pain, decreased range of motion, tightness, weakness, pain, numbness and lymphoedema and may be present for up to 6 years post-treatment. An understanding of baseline demographic and clinical risk factors can guide rehabilitation and management strategies for high-risk patients. The aims of this study were to quantify the burden of shoulder pain and disability in a tertiary academic hospital in Cape Town, South Africa, and identify potential risk factors for the development of shoulder morbidity. METHODS: This study was a cross-sectional analysis of the prevalence of shoulder pain and dysfunction in women attending their post-treatment annual follow-up visit for unilateral breast carcinoma. RESULTS: Three in four patients reported a presence of any pain or disability while only 9% experienced severe pain and disability. Multivariable ordinal logistic regression analysis identified race, side, axillary surgery, chemotherapy and age as significant predictors of pain and chemotherapy a significant predictor of disability. CONCLUSION: The substantial burden of shoulder morbidity in this population represents a significant public health burden. The use of identified clinical and demographic characteristics may guide in the development of survivorship programmes incorporating surveillance and management of these high-risk patients.

The potential role of angiogenesis in the development of shoulder pain, shoulder dysfunction, and lymphedema after breast cancer treatment.

Shoulder morbidity is a well-documented sequela of breast cancer treatment, which includes various manifestations such as pain, reduced range of motion, and lymphedema, among others. The multifactorial nature of such morbidities has long been appreciated, and research on reliable risk predictors of development thereof still continues. Previous studies have demonstrated the potential of different types of physical therapy to treat such shoulder problems, and the integration of such interventions into routine care for breast cancer survivors is a requirement in most high-income countries. Although patients at risk for developing shoulder problems would most likely benefit from posttreatment physical therapy, currently, there is no gold standard for identifying this patient group. This is particularly important in low- and middle-income countries where scarce monetary resources need to be directed specifically to those most in need. Modulators of the angiogenesis pathway have been implicated in noncancer shoulder conditions such as rotator cuff disease, adhesive capsulitis, and tendon injuries. The present review summarizes the role of angiogenesis in the development of shoulder morbidity among breast cancer survivors and sets forth the rationale for our belief that angiogenesis signaling may help explain a proportion of the reported clinical variability noted in the development of shoulder pain and dysfunction and upper-limb lymphedema after breast cancer treatment.

Availability, effectiveness and safety of ART in sub-Saharan Africa: a systematic review.

STUDY QUESTION: What is the evidence pertaining to availability, effectiveness and safety of ART in sub-Saharan Africa? SUMMARY ANSWER: According to overall limited and heterogeneous evidence, availability and utilization of ART are very low, clinical pregnancy rates largely compare to other regions but are accompanied by high multiple pregnancy rates, and in the near absence of data on deliveries and live births the true degree of effectiveness and safety remains to be established. WHAT IS KNOWN ALREADY: In most world regions, availability, utilization and outcomes of ART are monitored and reported by national and regional ART registries. In sub-Saharan Africa there is only one national and no regional registry to date, raising the question what other evidence exists documenting the status of ART in this region. STUDY DESIGN SIZE DURATION: A systematic review was conducted searching Pubmed, Scopus, Africawide, Web Of Science and CINAHL databases from January 2000 to June 2017. A total of 29 studies were included in the review. The extracted data were not suitable for meta-analysis. PARTICIPANTS/MATERIALS SETTING METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. All peer-reviewed manuscripts irrespective of language or study design that presented original data pertaining to availability, effectiveness and safety of ART in sub-Saharan Africa were eligible for inclusion. Selection criteria were specified prior to the search. Two authors independently reviewed studies for possible inclusion and critically appraised selected manuscripts. Data were analysed descriptively, being unsuitable for statistical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The search yielded 810 references of which 29 were included based on the predefined selection and eligibility criteria. Extracted data came from 23 single centre observational studies, two global ART reports, two reviews, one national data registry and one community-based study. ART services were available in 10 countries and delivered by 80 centres in six of these. Data pertaining to number of procedures existed from three countries totalling 4619 fresh non-donor aspirations in 2010. The most prominent barrier to access was cost. Clinical pregnancy rates ranged between 21.2% and 43.9% per embryo transfer but information on deliveries and live births were lacking, seriously limiting evaluation of ART effectiveness. When documented, the rate of multiple pregnancy was high with information on outcomes similarly lacking. LIMITATIONS REASONS FOR CAUTION: The findings in this review are based on limited data from a limited number of countries, and are derived from heterogeneous studies, both in terms of study design and quality, many of which include small sample sizes. Although representing best available evidence, this requires careful interpretation regarding the degree of representativeness of the current status of ART in sub-Saharan Africa. WIDER IMPLICATIONS OF THE FINDINGS: The true extent and outcome of ART in sub-Saharan Africa could not be reliably documented as the relevant information was not available. Current efforts are underway to establish a regional ART data registry in order to report and monitor availability, effectiveness and safety of ART thus contributing to evidence-based practice and possible development strategies. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study. The authors had no competing interests. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016032336.

Myocardial blood flow reserve is impaired in patients with aortic valve calcification and unobstructed epicardial coronary arteries.

BACKGROUND: Although calcific aortic valve disease (CAVD) is associated with coronary atherosclerosis, it is not known whether early CAVD is associated with coronary microcirculatory dysfunction (CMD). We sought to investigate the relationship between myocardial blood flow reserve (MBFR) - a measure of CMD, and early CAVD in the absence of obstructive epicardial coronary artery disease. We also determined whether this relationship was independent of coronary artery disease (CAD) and hs-CRP, a marker of systemic inflammation. METHODS: 183 patients with chest pain and unobstructed coronary arteries were studied. Aortic valve calcification score (AVCS), coronary total plaque length (TPL), and coronary calcium score were quantified from multislice CT. MBFR was assessed using vasodilator myocardial contrast echocardiography. Hs-CRP was measured from venous blood using a particle-enhanced immunoassay. RESULTS: Mean (±SD) participant age was 59.8 (9.6) years. Mean AVCS was 68 (258) AU, TPL was 15.6 (22.2) mm, and median coronary calcification score was 43.5AU. Mean MBFR was 2.20 (0.52). Mean hs-CRP was 2.52 (3.86) mg/l. Multivariable linear regression modelling incorporating demographics, coronary plaque characteristics, MBFR, and inflammatory markers, demonstrated that age (ß=0.05, 95% CI: 0.02, 0.08, P=0.007), hs-CRP (ß=0.09, CI: 0.02, 0.16, P=0.010) and diabetes (ß=1.03, CI: 0.08, 1.98, P=0.033), were positively associated with AVCS. MBFR (ß=-0.87, CI: -1.44, -0.30, P=0.003), BMI (ß=-0.11, CI: -0.21, -0.01, P=0.033), and LDL (ß=-0.32, CI: -0.61, -0.03, P=0.029) were negatively associated with AVCS. TPL and coronary calcium score were not independently associated with AVCS when included in the regression model. CONCLUSION: Coronary microvascular function as determined by measurement of myocardial blood flow reserve is independently associated with early CAVD. This effect is independent of the presence of coronary artery disease and also systemic inflammation.

An Application of the Multivariate Linear Mixed Model to the Analysis of Shoulder Complexity in Breast Cancer Patients.

In this study, four major muscles acting on the scapula were investigated in patients who had been treated in the last six years for unilateral carcinoma of the breast. Muscle activity was assessed by electromyography during abduction and adduction of the affected and unaffected arms. The main principal aim of the study was to compare shoulder muscle activity in the affected and unaffected shoulder during elevation of the arm. A multivariate linear mixed model was introduced and applied to address the principal aims. The result of fitting this model to the data shows a huge improvement as compared to the alternatives.

An early warning surveillance programme for detecting upper limb deterioration after treatment for breast cancer: A novel technology supported system.

Upper limb morbidity is a well-recognised consequence of treatment for breast cancer that can develop for up to 6 years after treatment. However, the capacity to fully integrate evidence-based rehabilitation pathways into routine care for all patients is questionable due to limited resources. A long term surveillance programme must therefore be accessible to all patients, should identify those at risk of developing morbidity and target the interventions at the high risk population of patients. The proposed model uses a surrogate marker for assessing risk of morbidity, incorporated into an Early Warning System (EWS), to produce a technology-lead, prospective surveillance programme.

Clinical anatomy of the shoulder after treatment for breast cancer.

Normal painfree movement of the upper limb requires movement at the glenohumeral joint and movement of the scapula on the thorax. Co-ordinated movement of these joints is known as the scapulohumeral rhythm and is required during elevation of the arm. Coordinated movement is further achieved by timing of the many muscles acting across the joints. A pilot study from our laboratory has shown significant alterations to this scapulohumeral rhythm and its muscle control following treatment for breast cancer. The aims of this study were to: (1) correlate altered muscle activity from a larger sample with observed movement deviations; (2) compare movement and muscle deviations in survivors with a healthy population and (3) explore the impact of a mastectomy versus a wide local excision (WLE) on the observed deviations. Cross-sectional study. 155 women treated for unilateral carcinoma of the breast and 21 age-matched healthy women were included in the study. All patients filled out the Shoulder Pain and Disability Index (SPADI). Three-dimensional kinematic data and EMG muscle activity were recorded during scaption on the affected and unaffected side. Patients demonstrated a different movement dysfunction depending on whether the left or the right shoulder was affected. Left affected shoulders demonstrated the greatest degree of internal rotation of all shoulders studied. Compared to healthy shoulders patients following a mastectomy demonstrated increased activity in both the left and right affected shoulders in all the measured muscles. In patients having a WLE, such increases were not observed in serratus anterior and pectoralis major activity on the right affected shoulder, where a decrease was noted. Muscle dysfunction was also observed in the unaffected side of patients. Having received chemotherapy contributed significantly to the difference seen between the affected and unaffected shoulders in patients. Differences in scapular tilt between affected and unaffected shoulders in patients were significantly associated with pain and disability, and changes in serratus anterior activity. Patterns of movement deviation resemble those seen in known shoulder conditions. Anatomical and biomechanical evidence supports the need for integrated rehabilitation and surveillance systems for the shoulder in oncology units.

Generic learning skills in academically-at-risk medical students: a development programme bridges the gap.

BACKGROUND: Widening access to medical students from diverse educational backgrounds is a global educational mandate. The impact, on students' generic learning skills profiles, of development programmes designed for students at risk of attrition is unknown. AIMS: This study investigated the impact of a 12-month Intervention Programme (IP) on the generic learning skills profile of academically-at-risk students who, after failing at the end of the first semester, completed the IP before entering the second semester of a conventional medical training programme. METHODS: This prospective study surveyed medical students admitted in 2009 and 2010, on entry and on completion of first year, on their reported practice and confidence in information handling, managing own learning, technical and numeracy, computer, organisational and presentation skills. RESULTS: Of 414 first year students, 80 (19%) entered the IP. Levels of practice and confidence for five of the six skills categories were significantly poorer at entry for IP students compared to conventional stream students. In four categories these differences were no longer statistically significant after students had completed the IP; 62 IP students (77.5%) progressed to second year. CONCLUSIONS: A 12-month development programme, the IP, effectively addressed generic learning skills deficiencies present in academically-at-risk students entering medical school.