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Background Historical data suggesting poor survival in patients with aortic stenosis (AS) who do not undergo treatment are largely confined to patients with severe AS. Objectives This study sought to determine the prognostic impact of all levels of native valvular AS. Methods Severity of AS was characterized by convention and by statistical distribution in 122,809 male patients (mean age 61 ± 17 years) and 118,494 female patients (mean age 62 ± 19 years), with measured aortic valve (AV) mean gradient, peak velocity, and/or area. The relationship between AS severity and survival was then examined during median 1,208 days (interquartile range: 598 to 2,177 days) of follow-up. Patients with previous aortic valve intervention were excluded. Results Overall, 16,129 (6.7%), 3,315 (1.4%), and 6,383 (2.6%) patients had mild, moderate, and severe AS, respectively. On an adjusted basis (vs. no AS; 5-year mortality 19%), patients with mild to severe AS had an increasing risk of long-term mortality (adjusted hazard ratio: 1.44 to 2.09; p 50%) and cardiovascular disease was evident from a mean AV gradient >20.0 mm Hg (moderate AS) after adjusting for age, sex, left ventricular systolic or diastolic dysfunction, and aortic regurgitation. Conclusions These data confirm that when left untreated, severe AS is associated with poor long-term survival. Moreover, they also suggest poor survival rates in patients with moderate AS. (National Echocardiographic Database of Australia [NEDA]; ACTRN12617001387314)

There is limited literature available on the long-term effect of bariatric surgery especially laparoscopic sleeve gastrectomy (LSG) on the incretin hormone response. Our primary aim was to investigate changes in glucose metabolism and incretin hormone responses in participants with impaired glucose regulation approximately 4 years after LSG. The secondary aim was to examine the long-term incretin hormone changes of biliopancreatic diversion (BPD). A non-randomised prospective study comprising of 10 participants undergoing LSG and 6 participants undergoing BPD. Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were performed during an oral glucose tolerance test pre-operatively and 1 month, 6 months and at approximately 4–7 years post-operatively. Area under the curve (AUC) was examined at 60 and 120 min. In the LSG group, a significant reduction in 2-h plasma glucose (2 h PG), HbA1c and HOMA-IR was observed at 4 years. Compared with pre-operative levels, significant increases in post-glucose GLP-1 secretion were observed at 1 and 6 months, but not maintained at 4 years. A linear increase was seen in post-glucose GIP response at 1 month and 6 months and 4 years. Within the BPD group, a reduction in HbA1c along with an increase GLP-1 response was observed at 7 years. An increase in GLP-1 response was not preserved at 4 years, but a significant increase in GIP response was observed along with improved glycaemic control following LSG.

Aims We investigated whether addition of diastolic dysfunction (DD) and longitudinal strain (LS) to Stage B heart failure (SBHF) criteria (structural or systolic abnormality) improves prediction of symptomatic HF in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self‐selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. Both American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) criteria and age‐specific Atherosclerosis Risk in Communities (ARIC) study criteria, for SBHF and DD, and ARIC criteria for abnormal LS, were examined. Methods and results Inclusion criteria were age ≥60 years with one or more of self‐reported ischaemic or other heart disease, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment, or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known HF, or ejection fraction mild valve abnormality detected on previous echocardiography or other imaging. Echocardiography was performed in 3190 participants who were followed for a median of 3.9 (interquartile range: 3.4, 4.5) years after echocardiography. Symptomatic HF was diagnosed in 139 participants at a median of 3.1 (interquartile range: 2.1, 3.9) years after echocardiography. ARIC structural, systolic, and diastolic abnormalities predicted HF in univariate and multivariable proportional hazards analyses, whereas ASE/EACVI structural and systolic, but not diastolic, abnormalities predicted HF. ARIC and ASE/EACVI SBHF criteria predicted HF with sensitivities of 81% and 55%, specificities of 39% and 76%, and C statistics of 0.60 (95% confidence interval: 0.57, 0.64) and 0.66 (0.61, 0.71), respectively. Adding ARIC DD to SBHF increased sensitivity to 94% with specificity of 24% and C statistic of 0.59 (0.57, 0.61), whereas addition of ASE/EACVI DD to SBHF increased sensitivity to 97% but reduced specificity to 9% and the C statistic to 0.52 (0.50, 0.54, P

BACKGROUND Previously developed in vitro cultures of the human retina have been solo or dual cell cultures. We developed a triple-cell culture in vitro model utilizing a membrane system to produce a better representation of a functional and morphological human retina. METHODS Retinal microvascular endothelial cells (HRMVEC/ACBRI181, cell systems), retinal pigment epithelium cells (RPE/ARPE-19, ATCC) and Muller glial cells (Moorfield Institute of Ophthalmology-Muller 1, UCL) were grown in a triple culture. Our optimized triple-culture media contained a mix of specific endothelial medium and high glucose Dulbecco's Modified Eagle's medium, where all three layers were viable for up to 5 days. Co-culture effect on morphological changes (cell staining) and gene expression of functional genes (pigment epithelium derived factor [PEDF] and vascular endothelial growth factor [VEGF]) were measured from RNA via real-time polymerase chain reaction. Expression of tight junction protein 1 (TJP1) was measured in RNA isolated from ARPE-19s, to assess barrier stability. RESULTS The triple-culture promotes certain cell functionality through up-regulation of TJP1, increasing PEDF and decreasing VEGF expression highlighting its importance for the assessment of disease mechanisms distinct from a solo culture which would not allow the true effect of the native microenvironment to be elucidated. CONCLUSIONS This model's novelty and reliability allows for the assessment of singular cellular function within the retinal microenvironment and overall assessment of retinal health, while eliminating the requirement of animal-based models.

Exercise capacity is frequently reduced in people with diabetes mellitus (DM), and the contribution of pulmonary microvascular dysfunction remains undefined. We hypothesized that pulmonary microvascular disease, measured by a novel exercise echocardiography technique termed pulmonary transit of agitated contrast (PTAC), would be greater in subjects with DM and that the use of pulmonary vasodilator agent sildenafil would improve exercise performance by reducing right ventricular afterload. Forty subjects with DM and 20 matched controls performed cardiopulmonary exercise testing and semisupine exercise echocardiography 1 h after placebo or sildenafil ingestion in a double-blind randomized crossover design. The primary efficacy end point was exercise capacity (V̇o2peak) while secondary measures included pulmonary vascular resistance, cardiac output, and change in PTAC. DM subjects were aged 44 ± 13 yr, 73% male, with 16 ± 10 yr DM history. Sildenafil caused marginal improvements in echocardiographic measures of biventricular systolic function in DM subjects. Exercise-induced increases in pulmonary artery systolic pressure and pulmonary vascular resistance were attenuated with sildenafil, while heart rate (+2.4 ±1.2 beats/min, P = 0.04) and cardiac output (+322 ± 21 ml, P = 0.03) improved. However, the degree of PTAC did not change ( P = 0.93) and V̇o2peak did not increase following sildenafil as compared with placebo (V̇o2peak: 31.8 ± 9.7 vs. 32.1 ± 9.5 ml·min−1·kg−1, P = 0.42). We conclude that sildenafil administration causes modest acute improvements in central hemodynamics but does not improve exercise capacity. This may be due to the mismatch in action of sildenafil on the pulmonary arteries rather than the distal pulmonary microvasculature and potential adverse effects on peripheral oxygen extraction. NEW & NOTEWORTHY This is one of the largest and most comprehensive studies of cardiopulmonary exercise performance in people with diabetes mellitus and to our knowledge the first to assess the effect of sildenafil using detailed echocardiographic measures during incremental exercise. Sildenafil attenuated the rise in pulmonary vascular resistance while augmenting cardiac output and intriguingly heart rate, without conferring any improvement in exercise capacity. The enhanced central hemodynamic indexes may have been offset by reduced peripheral O2 extraction.

There is increasing evidence that current thresholds for diagnosing pulmonary hypertension (PHT) underestimate the prognostic impact of PHT.The aim of this study was to determine the prognostic impact of increasing pulmonary pressures within the National Echocardiography Database of Australia cohort (n = 313,492).The distribution of estimated right ventricular systolic pressure (eRVSP) was examined in 157,842 men and women. All had data linkage to long-term survival during median follow-up of 4.2 years (interquartile range: 2.2 to 7.5 years).The cohort comprised 74,405 men and 83,437 women 65.6 ± 17.7 years of age. Overall, 17,955 (11.4%), 7,016 (4.4%), and 4,515 (2.9%) subjects had eRVSP levels indicative of mild (40 to 49 mm Hg), moderate (50 to 59 mm Hg), or severe (≥60 mm Hg) PHT, respectively, assuming a right atrial pressure of 5 mm Hg. These subjects were more likely to die during long-term follow up (for severe PHT, adjusted hazard ratio: 9.73; 95% confidence interval: 8.60 to 11.0; p 0.001). After adjustment for age, sex, and evidence of left heart disease, those subjects with eRVSP levels within the third (28.05 to 32.0 mm Hg; hazard ratio: 1.410; 95% confidence interval: 1.310 to 1.517) and fourth (32.05 to 38.83 mm Hg; hazard ratio: 1.979; 95% confidence interval: 1.853 to 2.114) quintiles had significantly higher mortality (p 0.001) than those in the lowest quintile. Accordingly, a clear and consistent threshold of increased mortality (including 1- and 5-year actuarial mortality) around an eRVSP of 30.0 mm Hg was evident.In this large and unique cohort, the prognostic impact of clinically accepted levels of PHT was confirmed. Moreover, a distinctly lower threshold for increased risk for mortality (eRVSP30.0 mm Hg) indicative of PHT was identified. (A Longitudinal Cohort Study of Echocardiograms From Public and Private Echocardiography Laboratories From Around Australia, Linked With the National Deaths Index; ACTRN12617001387314).

Background Burkholderia pseudomallei is a human pathogen causing severe infections in tropical and subtropical regions and is classified as a bio-threat agent. B. thailandensis strain E264 has been proposed as less pathogenic surrogate for understanding the interactions of B. pseudomallei with host cells. Results We show that, unlike B. thailandensis strain E264, the pattern of growth of B. thailandensis strain E555 in macrophages is similar to that of B. pseudomallei. We have genome sequenced B. thailandensis strain E555 and using the annotated sequence identified genes and proteins up-regulated during infection. Changes in gene expression identified more of the known B. pseudomallei virulence factors than changes in protein levels and used together we identified 16% of the currently known B. pseudomallei virulence factors. These findings demonstrate the utility of B. thailandensis strain E555 to study virulence of B. pseudomallei. Conclusions A weakness of studies using B. thailandensis as a surrogate for B. pseudomallei is that the strains used replicate at a slower rate in infected cells. We show that the pattern of growth of B. thailandensis strain E555 in macrophages closely mirrors that of B. pseudomallei. Using this infection model we have shown that virulence factors of B. pseudomallei can be identified as genes or proteins whose expression is elevated on the infection of macrophages. This finding confirms the utility of B. thailandensis strain E555 as a surrogate for B. pseudomallei and this strain should be used for future studies on virulence mechanisms. Electronic supplementary material The online version of this article (10.1186/s12866-019-1469-8) contains supplementary material, which is available to authorized users.

Background: Clinically evident primary heart involvement due to systemic sclerosis (SHI) is considered a poor prognostic factor and is a leading cause of systemic sclerosis (SSc) related death. Yet, there remains no consensus definition of SHI and poor understanding of the natural history and risk factors for the development of SHI. Methods: We performed a scoping literature review of published articles with a primary focus of SHI to capture previously used definitions of SHI and items used to measure SHI. Any factors reported to be associated with an increased risk of SHI were recorded. Results: Of the 2436 records identified in a search of MEDLINE, EMBASE and PubMed databases, 295 were included in the final scoping review. Analysis of the literature revealed studies of variable quality, generally low patient numbers and highly heterogeneous definitions of SHI within studies. There is no clear consensus from the literature as to the scope of SHI and the prognostic significance of sub-clinical investigation abnormalities commonly detected. Conclusion: The lack of a standardised definition of SHI remains a significant unmet need in SSc. The results of this review will assist in the development of consensus classification criteria to enable more accurate quantification of the burden of SHI, identification of factors associated with increased risk of developing SHI, and evaluation of the efficacy of any novel therapeutic strategies.

HIGHLIGHTS • A text message intervention was developed to support recovery from low back pain. • An iterative process with clinicians, researchers, and consumers was conducted. • This study offers scientific support for the elaboration of future interventions., Objective To develop a bank of text messages for a lifestyle-based self-management intervention for people with low back pain (LBP). Design Iterative development process. Setting Community and primary care. Participants Fifteen researchers, clinicians, and consumer representatives participated in the concept and initial content development phase. Twelve experts (researchers and clinicians) and 12 consumers participated in the experts and consumers review phase. Full study sample of participants was N=39. Interventions Not applicable. Main Outcome Measures We first conducted two 2-hour workshops to identify important domains for people with LBP, sources of content, appropriate volume, and timing of the messages. The messages were then drafted by a team of writers. Second, we invited expert researchers and clinicians to review and score the messages using a 5-item psychometric scale according to (1) the appropriateness of the content and (2) the likelihood of clinical effectiveness and to provide written feedback. Messages scoring ≤8 out of 10 points would be modified accordingly. Consumers were invited to review the messages and score them using a 5-item psychometric scale according to the utility of the content, the understanding of the content, and language acceptability and to provide feedback. Messages scoring ≤12 out of 15 points would be improved. Results Exercise, education, mood, sleep, use of care, and medication domains were identified and 82 domain-specific evidence-based messages were written. Messages received a mean score of 8.3 out of 10 points by experts. Twenty-nine messages were modified accordingly. The mean score of the messages based on consumers feedback was of 12.5 out of 15 points. Thirty-six messages were improved. Conclusions We developed a bank of text messages for an evidence-based self-management intervention using a theory-based, iterative, codesign process with researchers, consumers, and clinicians. This article provides scientific support for future development of text message interventions within the pain field.

Objective The authors sought to describe the protocol of a randomized controlled trial that will investigate the effects of the TEXT4myBACK self-management text message intervention compared with control in people with low back pain (LBP). Methods A single-blind (assessor and statistician), randomized controlled trial with economic analysis and process evaluation will be conducted. A total of 304 people with non-specific LBP of less than 12 weeks will be enrolled and randomly allocated either to TEXT4myBACK intervention or control groups. The TEXT4myBACK intervention group will receive 4 semi-personalized text messages per week providing advice, motivation, and information about LBP, physical activity, sleep, mood, use of care, and medication during 12 weeks. The control group will receive 1 text message with a link to a LBP and diet online information package. Outcomes will be assessed at baseline and 3, 6, and 12 months. The primary outcome will be function assessed with the Patient-Specific Functional Scale. Secondary outcomes will include pain intensity, physical activity participation, sedentary behavior, global impression of change, health-related quality of life, and eHealth literacy. Data on demographic characteristics, smallest worthwhile change (ie, smallest function scored needed to be achieved at the end of the intervention to consider it to be worthwhile), health care utilization, and adverse events (ie, any new health issue that occurs during participation in the study) will be collected. An economic and process evaluation will also be conducted. Impact This study will assess if a self-management text message intervention is effective and cost-effective in improving function of people with LBP. This study can inform clinical practice of a simple, scalable, and affordable intervention for managing LBP.

LS301 is a promising NIR fluorescence probe for targeting brain glioma cancer. The co-localization of LS31 and 5-ALA induced PpIX in vitro and in vivo enables LS301 to guide PpIX fluorescence image surgery. Moreover, LS301 showed no negative impact on 5-ALA-PpIX PDT outcome in brain glioma cells and mouse tumor model. Therefore, the implementation of LS301 and PpIX has potential to improve tumor resection surgery and PDT treatment for better tumor outcomes.

Background Given the age-related decline in glomerular filtration rate (GFR) in healthy individuals, we examined the association of all-cause death or cardiovascular event with the Kidney age - Chronological age Difference (KCD) score, whereby an individual’s kidney age is estimated from their estimated GFR (eGFR) and the age-dependent eGFR decline reported for healthy living potential kidney donors. Methods We examined the association between death or cardiovascular event and KCD score, age-dependent stepped eGFR criteria (eGFRstep), and eGFR 2 (eGFR60) in a community-based high cardiovascular risk cohort of 3837 individuals aged ≥60 (median 70, interquartile range 65, 75) years, followed for a median of 5.6 years. Results In proportional hazards analysis, KCD score ≥ 20 years (KCD20) was associated with increased risk of death or cardiovascular event in unadjusted analysis and after adjustment for age, sex and cardiovascular risk factors. Addition of KCD20, eGFRstep or eGFR60 to a cardiovascular risk factor model did not improve area under the curve for identification of individuals who experienced death or cardiovascular event in receiver operating characteristic curve analysis. However, addition of KCD20 or eGFR60, but not eGFRstep, to a cardiovascular risk factor model improved net reclassification and integrated discrimination. KCD20 identified individuals who experienced death or cardiovascular event with greater sensitivity than eGFRstep for all participants, and with greater sensitivity than eGFR60 for participants aged 60–69 years, with similar sensitivities for men and women. Conclusions In this high cardiovascular risk cohort aged ≥60 years, the KCD score provided an age-adapted measure of kidney function that may assist patient education, and KCD20 provided an age-adapted criterion of eGFR-related increased risk of death or cardiovascular event. Further studies that include the full age spectrum are required to examine the optimal KCD score cut point that identifies increased risk of death or cardiovascular event, and kidney events, associated with impaired kidney function, and whether the optimal KCD score cut point is similar for men and women. Trial registration ClinicalTrials.gov NCT00400257, NCT00604006, and NCT01581827.

BACKGROUND: This study examined the impact of mitral valve repair (MVRe) on survival of patients with moderate or severe (≥2+) MR and ischemic cardiomyopathy randomized to coronary artery bypass grafting (CABG) versus CABG+surgical ventricular reconstruction (SVR) in the STICH trial. METHODS: Among patients with moderate or severe MR and ischemic cardiomyopathy undergoing CABG or CABG+SVR, the impact of MVRe on mortality between the two treatment arms was compared. RESULTS: Among 867 patients with assessment of baseline MR severity, 211 had moderate or severe MR. After excluding 7 patients who underwent mitral valve replacement, 50, 44, 62, and 48 patients underwent CABG, CABG+MVRe, CABG+SVR, and CABG+SVR+MVRe, respectively. Four-year mortality rates were lower following CABG+MVRe than CABG alone (16% vs. 55%; adjusted hazard ratio [HR] 0.30; 95% CI 0.13–0.71). In contrast, the CABG+SVR+MVRe and CABG+SVR groups had similar 4-year mortality of 39% vs. 39% (adjusted HR 0.88; 95% CI 0.46–1.70). MVRe had a more favorable effect on survival in patients undergoing CABG alone compared to CABG+SVR (p=0.013). Baseline MR severity was similar between patients that received CABG+MVRe and those that underwent CABG+SVR+MVRe. A larger proportion of patients demonstrated a reduction in MR between 4 and 24 months after CABG+MVRe compared to CABG+SVR+MVRe (50.0% versus 25.0%, p=0.023). CONCLUSION: In patients with moderate or severe MR and ischemic cardiomyopathy undergoing CABG, MVRe appears to have a favorable effect on survival. The addition of SVR to CABG may attenuate the anticipated benefits of MVRe by limiting the long-term reduction of MR with MVRe.

Background Heart failure is increasing in prevalence, creating a greater public health and economic burden on our health care system. With a rising proportion of hospitalisations for heart failure with preserved ejection fraction (HFpEF) compared to heart failure with reduced ejection fraction (HFrEF) and lack of proven therapies for HFpEF, patient characterisation and defining clinical outcomes are important in determining optimal management of heart failure patients. There is scarce Australian-specific data with regards to the burden of disease of patients with HFpEF which further limits our ability to appropriately manage this syndrome. Aim To determine the characteristics, management practices and outcomes of patients with HFpEF compared to patients diagnosed with HFrEF. Method Data was sourced from the Victorian Cardiac Outcomes Registry-Heart Failure (VCOR-HF) snapshot of patients admitted with acute heart failure to one of 16 Victorian health services between 2014–2017 over one consecutive month annually. Outcomes measured were in-hospital mortality, and 30-day readmission and mortality. Results Of the 1,132 HF patients, 436 patients were diagnosed with HFpEF and were more likely to be female (59%) and older (81.5±9.8 vs 73.2±14.5 years). They were also more likely to have hypertension (80%), atrial fibrillation (59.9%), chronic obstructive airways disease (36.2%) and chronic kidney disease (68.8%). Patients with HFrEF were more likely to have ischaemic heart disease with a history of previous myocardial infarction (36.6%), percutaneous coronary intervention and cardiac bypass surgery (35.2%). There were no significant differences in 30-day mortality between HFpEF and HFrEF (10.2% vs 7.8%; p=0.19, respectively) and 30-day readmission rates (22.1% vs 25.9%; p=0.15, respectively). Conclusion VCOR-HF Snapshot data provides important insight into the burden of acute heart failure. Whilst patients with HFpEF and HFrEF have differing clinical profiles, morbidity, mortality and re-admission rates are similar.

Aims To examine the characteristics/prognostic impact of diastolic dysfunction (DD) according to 2016 American Society of Echocardiography (ASE) and European Society of Cardiovascular Imaging (ESCVI) guidelines, and individual parameters of DD. Methods and results Data were derived from a large multicentre mortality-linked echocardiographic registry comprising 436 360 adults with ≥1 diastolic function measurement linked to 100 597 deaths during 2.2 million person-years follow-up. ASE/European Association of Cardiovascular Imaging (EACVI) algorithms could be applied in 392 009 (89.8%) cases; comprising 11.4% of cases with ‘reduced’ left ventricular ejection fraction (LVEF Conclusion ASE/EACVI-classified DD is correlated with increased mortality. However, many cases remain ‘indeterminate’. Importantly, when analysed individually, mitral E velocity, septal e’ velocity, E:e’ ratio, and LAVi revealed clear pivot-points of increased risk of cardiovascular-related mortality.

During the 2013-2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods.

Glucuronide conjugates of soy isoflavone metabolites genistein, daidzein, glycitein and equol in urinary samples from women, female pigs and female rats were pretreated with methanol instead of solid phase extraction or liquid-liquid extraction after enzymatic digestion. The samples were analyzed using an LC-ESI-MS/MS ion trap system. Analysis of rat liver sample using this procedure was also attempted. By comparison the elution sequences with results from previous studies, glucuronide conjugates including 7-gluc-Dai, 7-gluc-Gly, 4'-gluc-Dai, 7-gluc-Gen, then 4'-gluc-Gen were identified sequentially in women urine. However, 5-gluc-Gen was also observed in female porcine urine. In rat urine, sul-Dai was observed after 7-gluc-Dai, while 7-gluc-Equ and 4'-gluc-Equ were observed after 7-gluc-Gen. The metabolite profiles in rat liver tissue samples were found with 7-gluc-Dai and 7-gluc-Gen. However, glucuronide conjugates of equol and sulfate conjugate of daidzein were only found in rat urine. Interestingly, quantification studies performed by LC-APCI/MS and LC-ECD showed that the aglycone and conjugated glycitein were both found in porcine and rat urine, but only conjugated glycitein was found in woman urine.

Burkholderia pseudomallei is a Gram-negative bacterium that causes melioidosis, an infectious disease endemic to south-east Asia. As B. pseudomallei is antibiotic-resistant, the need for cell-based vaccines and therapies is crucial to managing melioidosis. Dendritic cells (DC) provide the first line of defense to infection and direct downstream immune responses. Using practical volumes of fresh healthy donor blood, we show that heat-killed B. pseudomallei activated and stimulated expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 from both myeloid and plasmacytoid DC. Furthermore, B. pseudomallei-pulsed DC induced activation and proliferation of CD4+ T-cells. Thus, both DC subsets are important for driving primary T helper cell responses to B. pseudomallei in healthy individuals and have the potential to be targeted for future therapies and vaccines.Author SummaryMelioidosis is an infectious disease endemic to south-east Asia and northern Australia caused by the bacterium Burkholderia pseudomallei. Melioidosis presents a significant public health threat because it has no effective vaccine or cure, leading to a high mortality rate of between 10-50%. We highlight the possibility of immune-based strategies targeting Burkholderia pseudomallei to better treat and prevent melioidosis. Specifically, we show that dendritic cells-the sentinel cells of the immune system-respond to B. pseudomallei in healthy individuals and in turn can orchestrate downstream protective immune responses. Thus, dendritic cells may be key players in the development of both vaccines and therapeutics for melioidosis as well as other bacteria-driven diseases.

Nanogels are attractive biocompatible materials that enable local delivery of multiple drugs. In this study, we demonstrated that 3D printing technology could be used to precisely construct nanogel discs carrying paclitaxel and rapamycin. 3D-printed nanogel disc rounds (12 mm diameter × 1 mm thickness) carrying paclitaxel and rapamycin evaded premature gelation during storage and the initial burst release of the drugs in the dissolution medium. In vivo 3D-printed nanogel discs permitted successful intraperitoneal delivery of paclitaxel and rapamycin in ES-2-luc ovarian-cancer-bearing xenograft mice. They were also shown to be therapeutically effective and capable of preventing postsurgical peritoneal adhesions in the treated xenograft mice.

Rapid liver and spleen opsonization of systemically administered nanoparticles (NPs) for in vivo applications remains the Achilles’ heel of nanomedicine, allowing only a small fraction of the materials to reach the intended target tissue. Although focusing on diseases that reside in the natural disposal organs for nanoparticles is a viable option, it limits the plurality of lesions that could benefit from nanomedical interventions. Here we designed a theranostic nanoplatform consisting of reactive oxygen (ROS)-generating titanium dioxide (TiO(2)) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide ((89)Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO(2) NPs with (89)Zr afforded thermodynamically and kinetically stable chelate-free (89)Zr-TiO(2)-Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with (89)Zr-TiO(2)-Tf generated cytotoxic ROS to induce cancer cell killing via apoptosis pathway. Positron emission tomography/X-ray computed tomography (PET/CT) imaging and tissue biodistribution studies revealed that in vivo administration of (89)Zr-TiO(2)-Tf in mice leveraged the osteotropic effect of (89)Zr to selectively localize about 70% of the injected radioactivity in mouse bone tissue. A combination of small animal PET/CT imaging of NP distribution and bioluminescence imaging of cancer progression showed that a single dose (89)Zr-TiO(2)-Tf treatment in a disseminated MM mouse model completely inhibited cancer growth at euthanasia of untreated mice and at least doubled the survival of treated mice. Treatment of the mice with cold Zr-TiO(2)-Tf, (89)Zr-oxalate, or (89)Zr-Tf had no therapeutic benefit compared to untreated controls. This study reveals an effective radionuclide sensitizing nanophototherapy paradigm for the treatment of MM and possibly other bone-associated malignancies.

Aims We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods and results The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A 1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke. Conclusions Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Significance: The blood–brain barrier (BBB) is a major obstacle to detecting and treating brain tumors. Overcoming this challenge will facilitate the early and accurate detection of brain lesions and guide surgical resection of tumors. Aim: We generated an orthotopic brain tumor model that simulates the pathophysiology of gliomas at early stages; determine the BBB integrity and breakdown over the time course of tumor progression using generic and cancer-targeted near-infrared (NIR) fluorescent molecular probes. Approach: We developed an intracranial tumor xenograft model that rapidly reestablished BBB integrity and monitored tumor progression by bioluminescence imaging. Sham control mice were injected with phosphate-buffered saline only. Fluorescence molecular tomography (FMT) was used to quantify the uptake of tumor-targeted and passive NIR fluorescent imaging agents in orthotopic glioma (U87-GL-GFP PDE7B H217Q cells) tumor model. Cancer-induced and transient (with focused ultrasound, FUS) disruption of BBB integrity was monitored with NIR fluorescent dyes. Results: Stereotactic injection of 50,000 cells into mouse brain allowed rapid reestablishment of BBB integrity within a week, as determined by the inability of both tumor-targeted and generic NIR imaging agents to extravasate into the brain. Tumor-induced BBB disruption was observed 7 weeks after tumor implantation. FUS achieved a similar effect at any time point after reestablishing BBB integrity. While tumor uptake and retention of the passive NIR dye, indocyanine green, was negligible, both actively tumor-targeting agents exhibited selective accumulation in the tumor region. The tumor-targeting molecular probe that clears rapidly from nontumor brain tissue exhibits higher contrast than the analogous vascular-targeting agent and helps delineate tumors from sham control. Conclusions: We highlight the utility of FMT imaging for longitudinal assessment of brain tumors and the interplay between the stages of BBB disruption and molecular probe retention in tumors, with potential application to other neurological diseases.

Introduction Community pharmacies are well-placed to provide public health interventions, yet they are underutilised for services of this nature (1), which are needed to achieve public health policy goals. Previous qualitative studies have explored public perceptions of the role of community pharmacy in delivering public health services (2). However, to date, these views have not been captured quantitatively, which means it is not clear if the general public shares these views. Aim The aim was to design a questionnaire to obtain public perceptions of the role of community pharmacy in public health interventions and to establish any barriers and facilitators that exist regarding community pharmacy utilisation. Methods A questionnaire was developed based on published literature and semi-structured interviews. Following initial piloting of a paper-based then online format (by ten individuals) a 42-item questionnaire was completed digitally via Qualtrics by a self-selecting sample of the general public recruited through social media (i.e., Twitter, Instagram and Facebook) in May and June 2021. Principal component analysis with Varimax rotation was used to identify the underlying factors (scales) of the questionnaire. Cronbach’s alpha analysis was undertaken to ensure good internal consistency. Information on frequency of community pharmacy use and for what reason was collected. Content and thematic analysis were conducted on the free text qualitative comments. Content analysis was conducted first to observe which aspects of the questionnaire were mentioned the most. Further to this, thematic analysis was conducted as there were responses which did not fit into the content analysis. Results There were 306 valid questionnaire responses, where 235 (76.8%) were females. The mean age was 34.5 years (SD=15.09). Factor analysis identified four scales with a total of 18-items, all demonstrating good internal consistency. Scales were labelled as (n=number of items; ἀ =Cronbach’s alpha value): Expertise (n=3, ἀ =0.815); Role (n=4, ἀ =0.745); Privacy (n=3, ἀ =0.770) and Relationship (n=8, ἀ =0.862). Scale scores indicated that a lack of awareness of their role and expertise was a barrier and adequate privacy was an important facilitator in delivering public health services. In support of the quantitative findings, content analysis identified lack of privacy as a dominant theme, and further thematic analysis uncovered lack of knowledge of community pharmacy’s role in public health as an important barrier to uptake of services. Thematic analysis uncovered the themes ‘lack of knowledge of services’ and ‘accessibility’. Conclusion The outcome of this study was the development of a four scale, 18-item questionnaire to capture public perceptions of the community pharmacy’s role in public health. This can, therefore, be used in future studies aiming to explore public perceptions of community pharmacy. Strengths include being the first questionnaire to explore perceptions of community pharmacy. Weaknesses include the possibility of bias using social media in recruitment. This could be tackled using paper versions of the questionnaire in different settings. Further research is needed to continue testing the psychometric properties of the questionnaire with consideration given to the addition of a fifth scale to measure perceptions of Accessibility. References (1) Kember, J., Hodson, K., & James, D. H. (2018). The public’s perception of the role of community pharmacists in Wales. International Journal of Pharmacy Practice (26), 120-128. (2) Gidman, W., & Cowley, J. (2013). A qualitative exploration of opinions on the community pharmacists’ role amongst the general public in Scotland, International Journal of Pharmacy Practice, (21), 288-296.

The National Echocardiography Database Australia (NEDA) is a new echocardiography database collecting digital measurements on both a retrospective and prospective basis. To date, echocardiographic data from 435,133 individuals (aged 61.6 ± 17.9 years) with linkage to 59,725 all-cause deaths during a median of 40 months follow-up have been collected. These data will inform a number of initial analyses focusing on pulmonary hypertension, aortic stenosis and the role of artificial intelligence to facilitate accurate diagnoses of cardiac abnormalities.

Objective Clinical perfectionism is involved in the etiology and maintenance of eating disorders. Limited research has examined the factor structure of the Clinical Perfectionism Questionnaire (CPQ) in clinical eating disorder samples. The aim of this research was to examine the validity and reliability of the CPQ in a mixed eating disorder sample. Method Patients (N = 211) with an eating disorder completed the CPQ at pretreatment. A bifactor model was tested that included a general clinical perfectionism factor and two group factors; overevaluation of striving and concern over mistakes. The unique contributions that general and group factors make to the prediction of eating disorder symptoms were also investigated. Unidimensional, correlated two-factor, and bifactor models were tested using confirmatory factor analysis. Results A bifactor structure for a revised 10-item version of the CPQ provided the best fit, with a strong and reliable general clinical perfectionism factor. The general clinical perfectionism factor and the overevaluation of striving group factor explained reliable variance in the CPQ, and but only the general factor predicted eating disorder symptoms. Discussion The results suggested that a total score is generally appropriate for assessing clinical perfectionism in a clinical eating disorder sample.

Graphical abstract, Highlights • DSS is generally an acquired and progressive condition. • Subaortic stenosis often takes the form of a discrete crescentic fibromuscular ridge in the LVOT. • DSS should be considered when an elevated aortic Doppler gradient is seen in the presence of normal aortic leaflet mobility. • Surgery is considered when the peak instantaneous gradient is >50 to 60 mm Hg. • DSS has a high rate of recurrence following surgical intervention.

A decade after the alarming association of cabergoline-associated valvulopathy (CAV) in Parkinson disease, only two confirmed cases have occurred in patients with prolactinoma. Routine screening for CAV by echocardiography has not proved to be of diagnostic utility, has several limitations, and is not widely practiced. We have previously highlighted the value of annual cardiovascular examination as a screening tool for CAV in patients with prolactinoma. We present a case, now the third confirmed case of CAV, to highlight the value of the cardiovascular examination. A 52-year-old woman with a 25-year history of macroprolactinoma had received multimodal treatment, including surgery, radiosurgery, and medical therapy. Her medical therapy initially consisted of bromocriptine, followed by cabergoline. The cabergoline dose was 6 mg weekly. In 2009, the cumulative dose was 3272 mg when an echocardiogram showed no evidence of valvular disease. A routine cardiovascular examination in the clinic detected a new murmur in 2016. The echocardiogram demonstrated new-onset mild to moderate aortic regurgitation, with a thickened and restricted valve consistent with CAV. The cumulative dose of cabergoline at that point was 4192 mg. Follow-up echocardiography at 6-month intervals showed progression to moderate to severe aortic regurgitation, which has since stabilized. Cabergoline therapy was weaned and stopped completely in April 2017. An annual cardiovascular examination is the best screening test for CAV and can change the course of a patient’s treatment. Echocardiograms should be reserved for patients with a new-onset cardiac murmur or a high cumulative dose of cabergoline., Screening for cabergoline-associated valvulopathy by echocardiography has not been shown to be useful for patients with prolactinoma. The cardiovascular examination is, however, a useful screening tool.

BACKGROUND: Effective management of cardiovascular and chronic kidney disease risk factors offers longer, healthier lives and savings in healthcare. AIM: To examine risk factor management in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. METHODS: Inclusion criteria were age ≥ 60 years with one or more self-reported ischaemic or other heart diseases, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known heart failure or cardiac abnormality on echocardiography or other imaging. Medical history, clinical examination, full blood examination and biochemistry (without lipids and glycated haemoglobin (HbA1c)) were performed for 3847 participants on enrolment, and blood pressure, lipids and HbA1c were measured 1-2 years after enrolment for 3203 participants. RESULTS: Despite 99% of 3294 participants with hypertension receiving antihypertensive medication, half had blood pressures >140/90 mmHg. Approximately 77% of participants were overweight or obese, with one third being obese. Additionally, 74% of participants at high cardiovascular disease risk had low-density lipoprotein cholesterol levels ≥2 mmol/L, one third of diabetic participants had HbA1c >7%, 22% had an estimated glomerular filtration rate < 60 mL/min/1.73m2 , and substantial proportions had under-utilisation of antiplatelet therapy and anticoagulation for atrial fibrillation and were physically inactive. CONCLUSIONS: This population demonstrated substantial potential to reduce cardiovascular and renal morbidity and mortality and healthcare costs through more effective management of modifiable risk factors.

We review evidence concerning exercise for stroke prevention. Plausible biological reasons suggest that exercise would be important in preventing stroke. While definitive randomised controlled trials evaluating the impact of physical activity (PA) and exercise on preventing stroke and mortality are lacking, observational studies, small randomised controlled trials and meta-analyses have provided evidence that PA and exercise favourably modify stroke risk factors, including hypertension, dyslipidaemia, diabetes, sedentary lifestyle, obesity, excessive alcohol consumption and tobacco use. It is, therefore, important to understand the factors associated with poststroke PA/exercise and cardiorespiratory fitness. Positively associated factors include self-efficacy, social support and quality of patients’ relationships with health professionals. Negatively associated factors include logistical barriers, medical comorbidities, stroke-related deficits, negative exercise beliefs, fear of falling, poststroke fatigue, arthropathy/pain and depression. Definitive research is needed to specify efficacious behavioural approaches to increase poststroke exercise. Effective techniques probably include physician endorsement of exercise programmesto patients, enhancement of patient–professional relationships, providing patients an exercise rationale, motivational interviewing, collaborative goal-setting with patients, addressing logistical concerns, social support in programsmes, structured exercise programming, individualised behavioural instruction, behavioural diary recording, reviewing behavioural consequences of exercise efforts, reinforcing successful exercise performance. Exercise programming without counselling may increase short-term activity; simple advice or information-giving is probably ineffective. Older patients or those with cognitive impairment may need increased structure, with emphasis on behaviour per se, versus self-regulation skills. We support the latest American Heart Association/American Stroke Association guidelines (2014) recommending PA and exercise for stroke prevention, and referral to behaviourally oriented programmes to improve PA and exercise.

American cranberry (Vaccinium macrocarpon) is native to Eastern North America. Recent studies have suggested that the A-type proanthocyanidins (PACs) in cranberries are effective in preventing urinary tract infection. To meet the growing interest in the cranberry market, an accurate, reliable, and simple method to determine PAC concentration is needed. In this study, a modified method using 4-dimethylaminocinnamaldehyde to quantify total PACs in cranberry products was validated. Cranberry juice extract powder, cranberry capsules containing juice extract, and cranberry juice concentrate were used as the samples in this study. With the modified method, the calibration curves for proanthocyanidin A2 had correlation coefficients (r2) of >0.99. The recoveries of two different concentrations after spiking were 97.1 and 99.1%, and the RSDs for repeatability and reproducibility were

This paper presents the initial conceptual study of integration of reflectometry antennas and waveguides (WGs) in DEMO. The antennas are located at several poloidal angular positions covering a full poloidal section of the helium-cooled lithium lead breading blanket. The concept of slim cassette (SC) is presented which allows for possible side attachment to the blanket sector and offers compatibility with remote handling (RH) operations. The proposed concepts for WGs sectors relative motion decoupling, vacuum boundary breaking, and RH are presented. Monte Carlo neutronic simulations have been done in order to evaluate the heat loads and shielding capabilities of the system. The first results indicate that the cooling for the EUROFER diagnostic components (antennas and WGs) can in principle be provided by the blanket cooling services (He is considered) via connection to the main back supporting structure and routed via the main diagnostic structure body. The first results on the SC thermal analysis indicate that for the first wall (FW), an increase of He speed is required (or a higher cooling volume) as temperatures are above blanket FW temperature. As for the inner components (shielding and wave guides), the cooling requires localized optimization (hot spots in module corners and front antennas) but respects average temperature limit requirements.

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease., Most of the systemic cancer therapies lack spatiotemporal control. Here, the authors show targeted activation of a light-sensitive drug by radiopharmaceuticals in disseminated cancer cells as potential in vivo treatment of metastatic diseases with reduced off-target toxicity.

Background Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity and associated metabolic complications. Obesity and type 2 diabetes are associated with increased oxidative stress. Previous studies have examined changes in plasma oxidative stress after laparoscopic Roux-en-Y gastric bypass, but there is limited evidence of the effects of LSG. Objectives To examine the effects of LSG on plasma thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAOS) at 1 and 6 months after LSG in patients with obesity and impaired glucose regulation. Setting University hospital, United Kingdom. Methods Twenty-two participants with impaired glucose homeostasis undergoing LSG (body mass index 50.1 kg/m 2 , glycated hemoglobin 53 mmol/mol) were studied. Measurements of fasting and 120-minute TBARS and TAOS were performed during an oral glucose tolerance test preoperatively and postoperatively. Results Compared with preoperative levels, significant decreases were seen 6 months postoperatively in fasting TBARS (61.0±17.9 versus 39.4±13.8 ng/mL, P = .04) and 120-minute TBARS (76.0±29.5 versus 46.5±16.3 ng/mL, P = .02). No significant changes were observed in plasma TAOS. No significant association was observed between changes in TBARS and other clinical or biochemical measures. Conclusion We observed a significant reduction in TBARS, a global measure of lipid peroxidation 6 months after LSG in participants with obesity and impaired glucose regulation.

Background Pregnancy associated breast cancer (PABC) is defined as breast cancer (BC) diagnosed during the gestational period (GP) or in the first year postpartum (PP). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first combined prospective and retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments and maternal outcomes. We present the retrospective findings to date. Methods We performed a retrospective multicentre observational study of patients (pts) with PABC treated in the eight Irish cancer centres from August 2001 to March 2017. Data extracted included information on pt demographics, tumour biology, staging, treatment administered and maternal outcomes. Standard biostatistical methods were used for analysis. Results 111 PABC patients were identified. Sixty pts (54%) were diagnosed during the GP and 51 (46%) within 1 year PP. Median age at diagnosis was 36 years (yrs). Table 1 illustrates baseline characteristics. Two thirds of pts were node positive and a similar proportion had grade 3 pathology. Seventy pts (63%) were estrogen receptor (ER) positive, 36 (32%) HER2 positive, 25 (22%) triple negative. Twenty-two pts (20%) were metastatic at presentation. Seven pts (6%) had a known BRCA 1/2 mutation. The median OS (overall survival) and DFS (disease free survival) for the entire cohort was 107.4 and 94.2 months respectively (resp). There was no survival difference between those diagnosed during the GP versus PP. 5 yr DFS and OS was 68.6% and 69.2% resp. This compares unfavourably to results reported by the National Cancer Registry of Ireland in a similar age-matched BC population between 2000-2012 where the 5 yr OS was 86.5%. Variables in our study associated with poorer outcomes included younger age, tumour size, node positivity and lack of estrogen expression. Baseline characteristics PABC patients (n=11) %(n)Diagnosed in GP (n=60) %(n)Diagnosed 1yr PP (n=51) %(n)p valueDemographic Age at diagnosis3636(25-49)36(21-44)0.31Stage I-II54(60)55(33)53(27)0.85III23(26)23(14)23(12)1IV20(22)18(11)22(11)0.81Unknown3(3)3(2)2(1)1Pathology Grade 366(74)70(42)63(32)0.43Node positive66(73)68(41)63(32)0.55ER+/HER2-41(45)38(23)43(22)0.69ER+/HER2+23(25)28(17)16(8)0.17ER-/HER2+14(16)17(10)12(6)0.59Triple negative22(25)17(10)29(15)0.11Surgery Breast conservation23(26)25(15)21(11)0.82Mastectomy56(63)57(34)59(30)0.84Adjuavnt/Neoadjuvant treatment Chemotherapy73(81)77(46)69(35)0.39Anthracycline68(55)78(36)54(19)0.03Taxane89(72)93(43)83(29)0.16Anti HER2 agent21(23)18(11)24(12)0.63Endocrine therapy64(52)63(29)66(23)0.84Radiotherapy79(64)74(34)86(30)0.85Relapse in Stage I-III Local relapse15(13)12(6)18(7)0.55Distant relapse24(21)22(11)25(10)0.80 Conclusions PABC patients may have a poorer outcome. Our study reported higher rates of triple negative and HER2 positive breast cancer which are associated with more aggressive biology. Prospective evaluation of clinicopathological features, pharmacokinetics of treatments selected and maternal and fetal outcomes is imperative in this distinct pt group. Citation Format: Prior L, Teo M, Greally M, Ward C, O'Leary C, Aslam R, Darwish W, Ahmed N, Watson G, Kelly D, Kiely L, Hassan A, Gleeson J, Featherstone H, Lim M, Murray H, Gallagher D, Westrup J, Hennessy B, Leonard G, Grogan L, Breathnach O, Horgan A, Coate L, O'Mahony D, Coate L, O'Reilly S, Gupta R, Keane M, Duffy K, O'Connor M, Kennedy J, McCaffrey J, Higgins M, Kelly C, Carney D, Gullo G, Crown J, Walshe J. Pregnancy associated breast cancer: Evaluating maternal outcomes. A multicentre study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-17.

BACKGROUND AND OBJECTIVE It has been suggested that pelvic floor dysfunction may contribute to the development of lumbopelvic pain as a result of changes in trunk muscle control. However, there is limited evidence that pelvic floor muscle training (PFMT) can improve clinical outcomes in women with lumbopelvic pain. DATABASES AND DATA TREATMENT Six databases were searched for randomized controlled trials (RCTs) comparing the effectiveness of PFMT to other conservative interventions (usual physiotherapy care or minimal intervention), no treatment or placebo interventions on pain and disability in women with lumbopelvic pain. RESULTS We included eight RCTs totalling 469 participants. PFMT was more effective than minimal intervention for lumbopelvic pain [mean difference (MD) 15.9/100 (95% confidential interval (CI), 8.2 to 23.6; p = 0.00; I2 = 3.92%)] and disability [standardized mean difference (SMD) 0.5 (95% CI 0.1-0.9; p = 0.00; I2 = 0%)] during pregnancy. PFMT was more effective than usual physiotherapy care for pain (MD 11.7/100 [95% CI 7.5-15.9; p = 0.00; I2 = 94.14%]) and disability (SMD 0.3 (95% CI 0.0-0.6; p = 0.01; I2 = 82.54%]) in non-pregnant women. Effect sizes were in general of arguable clinical relevance. CONCLUSIONS Overall, the certainty of the evidence was very low to low. There is no conclusive evidence that the addition of PFMT to usual physiotherapy care or minimal intervention is superior to minimal intervention and usual care alone given the small number of studies and high levels of heterogeneity of included studies. Further well-designed trials are needed to establish the effectiveness of PFMT for lumbopelvic pain in women.

Most stroke survivors have very low levels of cardiovascular fitness, which limits mobility and leads to further physical deconditioning, increased sedentary behavior, and heightened risk of recurrent stroke. Although clinical guidelines recommend that aerobic exercise be a part of routine stroke rehabilitation, clinical uptake has been suboptimal. In 2013, an international group of stroke rehabilitation experts developed a user-friendly set of recommendations to guide screening and prescription—the Aerobic Exercise Recommendations to Optimize Best Practices in Care after Stroke (AEROBICS 2013). The objective of this project was to update AEROBICS 2013 using the highest quality of evidence currently available. The first step was to conduct a comprehensive review of literature from 2012 to 2018 related to aerobic exercise poststroke. A working group of the original consensus panel members drafted revisions based on synthesis. An iterative process was used to achieve agreement among all panel members. Final revisions included: (1) addition of 115 new references to replace or augment those in the original AEROBICS document, (2) rewording of the original recommendations and supporting material, and (3) addition of 2 new recommendations regarding prescription. The quality of evidence from which these recommendations were derived ranged from low to high. The AEROBICS 2019 Update should make it easier for clinicians to screen for, and prescribe, aerobic exercise in stroke rehabilitation. Clinical implementation will not only help to narrow the gap between evidence and practice but also reduce current variability and uncertainty regarding the role of aerobic exercise in recovery after stroke.

Background Patients admitted to hospital with acute heart failure (AHF) are at increased risk of readmission and mortality post-discharge. The aim of the study was to examine health service utilisation within 30 days post-discharge from an AHF hospitalisation. Methods This was a prospective, observational, non-randomised study of consecutive patients hospitalised with acute HF to one of 16 Victorian hospitals over a 30-day period each year and followed up for 30 days post-discharge. The project was conducted annually over three consecutive years from 2015 to 2017. Results Of the 1,197 patients, 56.3% were male with an average age of 77±13.23 years. Over half of the patients (711, 62.5%) were referred to an outpatient clinic and a third (391, 34.4%) to a HF disease management program. In-hospital mortality was 5.1% with 30 day-mortality of 9% and readmission rate of 24.4%. Patients who experienced a subsequent readmission less than 10 days post-discharge and between 11 and 20 days post-discharge had a five- to six-fold increase in risk of mortality (adjusted OR 5.02, 95% CI 2.11–11.97; OR 6.45, 95% CI 2.69–15.42; respectively) compared to patients who were not readmitted to hospital. An outpatient appointment within 30 days post-discharge significantly reduced the risk of 30-day mortality by 81% (95% CI 0.09–0.43). Conclusion Patients admitted to hospital with AHF who experience a subsequent readmission within 20 days post-discharge are at increased risk of dying. However, early follow-up post-discharge may reduce this risk. Early post-discharge follow-up is vital to address this vulnerable period after a HF admission.

Background Exercise capacity is frequently reduced in people with diabetes mellitus (DM) and may be due to subclinical cardiac dysfunction. Speckle-tracking echocardiography is now widely available; however, the clinical utility and significance of left ventricular (LV) strain and twist parameters remain uncertain. We hypothesized that LV strain and twist would be reduced in DM subjects during exercise. Methods Adults with type 1 or type 2 DM and age- and sex-matched controls performed cardiopulmonary exercise testing (VO2 peak) and supine bicycle exercise echocardiography. Detailed echocardiographic assessment of biventricular function was performed at baseline and repeated during incremental exercise to maximal intensity. Results Of the 60 participants completing the study protocol, 51 (34 DM, 17 controls; mean age, 42 ± 13 years; 69% male; DM duration, 16 ± 10 years) had sufficient image quality to assess LV deformation and twist mechanics at rest. Of these, 38 (25 DM, 13 controls) were able to be assessed immediately after exercise. Baseline LV systolic and diastolic function using standard echocardiography measurements were similar between groups. Resting LV global longitudinal strain, twist, twist rate and untwist rate, and the corresponding peak exercise and reserve measures did not differ significantly. As compared with the control subjects, exercise capacity was reduced in the DM cohort (VO2 peak 33 ± 10 vs 41 ± 12 mL/minute/kg; P = .02); however, no correlation was observed between VO2 peak and LV twist reserve (R = 0.28, P = .09), LV twist rate reserve (R = 0.14, P = .39), or LV untwist rate reserve (R = 0.24, P = .14). Conclusions Despite reduced VO2 peak, LV twist mechanics at rest and after maximal intensity exercise did not differ significantly in a cohort of asymptomatic DM subjects with normal resting LV systolic and diastolic function compared with age- and sex-matched controls. This would suggest that exercise capacity can be reduced in the absence of subclinical cardiac dysfunction and that noncardiac factors should be considered as alternative explanations.

Background Body mass index †Deceased. (BMI) is a risk factor for heart failure with preserved ejection fraction (HFpEF). Design We investigated the threshold BMI and sex-specific waist circumference associated with increased HFpEF incidence in the SCReening Evaluation of the Evolution of New Heart Failure (SCREEN-HF) study, a cohort study of a community-based population at increased cardiovascular disease risk. Methods Inclusion criteria were age ≥60 years with one or more of self-reported hypertension, diabetes, heart disease, abnormal heart rhythm, cerebrovascular disease or renal impairment. Exclusion criteria were known heart failure, ejection fraction Results HFpEF incidence rates were higher for BMI ≥27.5 kg/m2 than for BMI 2, and for waist circumference >100 cm (men) or > 90 cm (women) than for waist circumference ≤94 cm (men) or ≤ 83 cm (women) in Poisson regression analysis. Semiparametric proportional hazards analyses confirmed these BMI and waist circumference thresholds, and exceeding these thresholds was associated with an attributable risk of HFpEF of 44–49%. Conclusions Both central obesity and overweight were associated with increased HFpEF incidence. Although a randomised trial of weight control would be necessary to establish a causal relationship between obesity/overweight and HFpEF incidence, these data suggest that maintenance of BMI and waist circumference below these thresholds in a community similar to that of the SCREEN-HF cohort may reduce the HFpEF incidence rate by as much as 50%.

Background In the ICD Sports Safety Registry, death, arrhythmia- or shock-related physical injury did not occur in athletes who continue competitive sports after implantable cardioverter-defibrillator (ICD) implantation. However, data from non-competitive ICD recipients is lacking. This report describes arrhythmic events and lead performance in intensive recreational athletes with ICDs enrolled in the European recreational arm of the Registry, and compares their outcome with those of the competitive athletes in the Registry. Methods The Registry recruited 317 competitive athletes ≥ 18 years old, receiving an ICD for primary or secondary prevention (234 US; 83 non-US). In Europe, Israel and Australia only, an additional cohort of 80 ‘auto-competitive’ recreational athletes was also included, engaged in intense physical activity on a regular basis (≥2×/week and/or ≥ 2 h/week) with the explicit aim to improve their physical performance limits. Athletes were followed for a median of 44 and 49 months, respectively. ICD shock data and clinical outcomes were adjudicated by three electrophysiologists. Results Compared with competitive athletes, recreational athletes were older (median 44 vs. 37 years; p = 0.0004), more frequently men (79% vs. 68%; p = 0.06), with less idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia (1.3% vs. 15.4%), less congenital heart disease (1.3% vs. 6.9%) and more arrhythmogenic right ventricular cardiomyopathy (23.8% vs. 13.6%) ( p Conclusions Participants in recreational sports had less frequent appropriate and inappropriate shocks during physical activity than participants in competitive sports. Shocks did not cause death or injury. Recreational athletes with ICDs can engage in sports without severe adverse outcomes unless other reasons preclude continuation.