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Aims Risk factors for asymptomatic echocardiographic abnormalities that predict symptomatic heart failure (HF) may provide insight into early mechanisms of HF pathogenesis. We examined risk factors associated with asymptomatic echocardiographic structural, systolic, and diastolic abnormalities, separately and in combination, and interactions between risk factors, in the prospective community‐based SCReening Evaluation of the Evolution of New HF (SCREEN‐HF) Study cohort of 3190 participants at increased risk of cardiovascular disease. Methods and results Inclusion criteria were age ≥ 60 years with one or more of hypertension, diabetes, ischaemic heart disease, valvular heart disease, abnormal heart rhythm, cerebrovascular disease, or renal impairment. Exclusion criteria were known HF, ejection fraction mild valve abnormality. Structural, systolic, and diastolic echocardiographic abnormalities were defined according to the Atherosclerosis Risk in Communities study criteria, and risk factors for asymptomatic structural, systolic, and diastolic abnormalities were identified using logistic regression analysis. In multivariable analysis, increased body mass index (BMI), non‐steroidal anti‐inflammatory drug therapy, and alcohol intake were risk factors for isolated structural abnormality, whereas male gender, increased heart rate, atrial fibrillation (AF), angiotensin‐converting enzyme inhibitor therapy, and obstructive sleep apnoea were associated with a lower risk. Moreover, male gender, smoking, increased systolic blood pressure, and physical inactivity were risk factors for isolated systolic abnormality, whereas increased pulse pressure and antihypertensive therapy were associated with a lower risk. Furthermore, increased age, blood pressure, amino‐terminal pro‐B‐type natriuretic peptide level, and warfarin therapy (associated with AF) were risk factors for isolated diastolic abnormality, whereas increased heart rate and triglyceride level (associated with BMI) were associated with a lower risk. The association of increased heart rate with lower risk of structural and diastolic abnormalities was independent of β‐blocker therapy. Interactions between risk factors differed for structural, systolic, and diastolic abnormalities. Conclusions The different risk factors for asymptomatic structural, systolic, and diastolic abnormalities that predict symptomatic HF, and the interactions between risk factors, illustrate how these structural, systolic, and diastolic abnormalities represent unique trajectories that lead to symptomatic HF. Improved understanding of these trajectories may assist in the design of HF prevention strategies.

Aims We investigated long-term mortality associated with changes in left ventricular ejection fraction (LVEF) in a large, real-world patient cohort. Methods and results A total of 117 275 adults (63 ± 16 years, 46% women) had LVEF quantified by the same method ≥6 months apart. This included 17 343 cases (66 ± 15 years, 48% women) being initially investigated for heart failure (HF). During 3.3 [interquartile range (IQR) 1.7–6.0] years from first to last echocardiogram, median change in LVEF was −1 (IQR −8 to +5) units from a baseline of 62% (IQR 54–69%). During subsequent 7.6 (IQR 4.3–10.1) years of follow-up, 11 397 (9.7%) and 34 101 (29.1%) cases died from cardiovascular disease and all causes, respectively. Actual 5-year, all-cause mortality increased from 12% to 29% among those with the smallest to the largest decrease in LVEF (from 30 units); the adjusted risk of cardiovascular-related mortality increased two- to eightfold beyond a >10-unit decline in LVEF (vs. minimal change; P 30-unit increase to >30-unit decline in LVEF (vs. minimal change; P

Purpose To examine: (1) the rate of clinical events precluding cardiac rehabilitation (CR) continuation, (2) CR attendance by component in those without events, and (3) the association between disease severity (eg, tobacco use, diabetes, and depression) and component attendance (eg, exercise, diet, stress management, and tobacco cessation). Methods Retrospective analysis of electronic records of the CR program in London, Ontario, from 1999 to 2017. Patients in the supervised program are offered exercise sessions 2 times/wk with a minimum of 48 prescribed sessions tailored to patient need. Patients attending ≥1 session without major factors that would limit their exercise ability were included. Intervening events were recorded, as was component attendance. Results Of 5508 enrolled, supervised patients, 3696 did not have a condition that could preclude exercise. Of those enrolled, one-sixth (n = 912) had an intervening event; these patients were less likely to work, more likely to have medical risk factors, had more severe angina and depression, and lower functional capacity. The remaining cohort attended a mean of 26.5 ± 21.3 sessions overall (median = 27; 19% attending ≥48 sessions), including 20.5 ± 17.4 exercise sessions (median = 21). After exercise, the most common components attended were individual dietary and psychological counseling. Patients with more severe angina and depressive symptoms as well as tobacco users attended significantly fewer total sessions, but more of some specific components. Conclusions In one-sixth of patients, CR attendance and completion are impacted by clinical factors beyond their control. Many patients are taking advantage of components specific to their risk factors, buttressing the value of individually tailored, menu-based programming.

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the “vicious cycle” of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.

AIMS We investigated the sex-based risk of mortality across the spectrum of left ventricular ejection fraction (LVEF) in a large cohort of patients in Australia. METHODS AND RESULTS Quantified levels of LVEF from 237 046 women (48.1%) and 256 109 men undergoing first-time, routine echocardiography (2000-2019) were linked to 119 232 deaths (median 5.6 years of follow-up). Overall, 17.6% of men vs. 8.3% of women had an LVEF

Musculoskeletal pain is the greatest cause of disability worldwide. Owing to its increasing prevalence and burden, the importance of affordable treatments has been highlighted. Text message interventions are accessible, low cost, and effective in promoting healthy behaviour and managing chronic diseases. However, little is known about their role in musculoskeletal pain. This systematic review was conducted to appraise the literature on the effects of text messages (as an intervention or a component of an intervention) compared with any control on pain and function in people with musculoskeletal pain (PROSPERO: CRD42018117371). MEDLINE, EMBASE, CINAHL, Cochrane, and PEDro databases were searched from inception to April 2020. Keywords relating to musculoskeletal pain, text messages, and randomised controlled trials were combined. Methodological quality was assessed using the PEDro score. Of the 12,022 studies identified, 11 were included, with a mean PEDro score of 5.4/10 points (SD 1.3). Pooled analyses were not performed because of heterogeneity of interventions and clinical characteristics. When text messages were added to and compared with usual care, some positive effects were found only on treatment adherence. Although small and inconsistent, some positive effects were reported for pain intensity, function, care-seeking behaviour, adherence, and quality of life when text messages were added to multicomponent interventions. Moreover, text message and telephone counselling interventions had similar effects on function. Overall included studies were of limited methodological quality and heterogeneous. However, our results indicate potential benefits of text messages in the treatment of musculoskeletal pain, which need to be confirmed in future trials.

Aim Heart failure (HF) incidence increases markedly with age. We examined age‐associated longitudinal change in cardiac structure and function, and their prediction by age and cardiovascular disease (CVD) risk factors, in a community‐based cohort aged ≥60 years at increased CVD risk but without HF. Methods and results CVD risk factors were recorded in 3065 participants who underwent a baseline echocardiographic examination, of whom 2358 attended a follow‐up examination 3.8 [median, inter‐quartile range (IQR) 3.5, 4.2] years later. Median age was 71 (IQR 67, 76) years and 55% of participants were male. Age was associated with longitudinal increase in left ventricular (LV) mass index (LVMI); decrease in LV volumes; increase in LV ejection fraction; decrease in mitral annular systolic velocity; decrease in diastolic function (decreased mitral early diastolic annular velocity (e′); and increase in left atrial volume index, mitral peak early diastolic flow velocity (E)/e′ ratio, and tricuspid regurgitant velocity (TRVmax) in men and women, except for TRVmax in men). In multivariable analysis, longitudinal increase in LVMI was explained by CVD risk factors alone, whereas age, together with CVD risk factors, independently predicted longitudinal change in all other echocardiographic parameters. CVD risk factors were differentially associated with longitudinal change in different echocardiographic parameters. Conclusions Whereas the increase in LVMI with age was explained by CVD risk factors alone, age, together with risk factors, independently predicted longitudinal change in all other echocardiographic parameters, providing evidence for age‐specific mechanisms of change in cardiac structure and function as people age. Age‐associated change in LVMI, LV volumes, and diastolic function resembled what might be expected for the evolution of HF with preserved ejection fraction. Given the differential association of different CVD risk factors with longitudinal change in different echocardiographic parameters, therapies aimed at attenuation of age‐associated change in cardiac structure and function, and HF evolution, will likely need to address multiple CVD risk factors.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a group of cardiomyopathies associated with ventricular arrhythmias predominantly arising from the right ventricle, sudden cardiac death and right ventricular failure, caused largely due to inherited mutations in proteins of the desmosomal complex. Whilst long recognised as a cause of sudden cardiac death (SCD) during exercise, it has recently been recognised that intense and prolonged exercise can worsen the disease resulting in earlier and more severe phenotypic expression. Changes in cardiac structure and function as a result of exercise training also pose challenges with diagnosis as enlargement of the right ventricle is commonly seen in endurance athletes. Advice regarding restriction of exercise is an important part of patient management, not only of those with established disease, but also in individuals known to carry gene mutations associated with development of ARVC.

Background Bariatric surgery is an effective treatment for morbid obesity and glycaemic dysfunction. Objectives The aim of the work was to examine both the static and dynamic changes of glucose-insulin homeostasis and incretin hormone response following sleeve gastrectomy (SG) in a sample of 55 participants preoperatively and 1 month and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes (T2D). Setting Morriston Hospital, UK. Methods Prospective study comprising of 55 participants with impaired glucose homeostasis and T2D undergoing SG (mean body mass index [BMI] 50.4 kg/m2, mean glycated haemoglobin [A1C] 7.4%). Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 min. Results We observed significant improvements in measures of obesity, as well as static and dynamic measures of glucose, insulin, C-peptide and HOMA. Furthermore, significant increases in GLP-1 response as early as 6 months postoperatively were also seen. Conclusions To our knowledge, no study has examined the detailed dynamic changes in glucose and insulin homeostasis in this number of participants undergoing SG in relation to incretin hormones GIP and GLP-1. This current study supports the role of SG for the treatment of obesity-related glucose dysregulation.

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains – the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models.

Congestive Heart Failure (CHF) is an emerging epidemic. Within one generation, the medical community has learned much of CHF syndromes. It has two distinct mechanisms, systolic and diastolic abnormalities, to account for the common CHF presentation. It is complex as it challenges the available health care services, resource, and funding models in providing an equitable service across the health continuum. Despite the improvement in many cardiovascular diseases, some CHF outcomes like readmissions and costs have increased. The reinvigoration of evidence- based medicine, the development of health services models of care, and standardisation of disease processes with taxonomies have also occurred within the same time span. These processes, however, need to be linked with health policy as presented in white papers. In this paper, we explore achieving optimal CHF guideline-recommended outcomes as the science approaches realworld translation.

Background Previous studies have examined changes in plasma markers of inflammation and oxidative stress up to 24 months following bariatric surgery, but there is limited evidence on the long-term effects of bariatric surgery. Objectives To examine the effects of bariatric surgery on adipokines (adiponectin, leptin), inflammatory cytokines [C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10(IL-10)] and global plasma measures of oxidative stress [thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAOS) 1 and 6 months, and 4 years post-surgery in subjects with obesity and impaired glucose regulation. Methods A prospective study comprising of 19 participants (13 females, mean age 50.4 ± 6.2 years, mean body mass index (BMI) 54 ± 14 kg/m2, 17 type 2 diabetes) undergoing bariatric surgery (10 sleeve gastrectomy, 6 biliopancreatic diversion, 2 Roux-en-Y gastric bypass and 1 laparoscopic adjustable gastric banding). Serial measurements of the above markers were made pre-operatively, 1 and 6 months and 4 years post-operatively. Results Compared to pre-operative levels, significant decreases were seen 4 years post-operatively in CRP (11.4 vs 2.8 ng/mL, p p p = 0.001). At 4 years, both fasting and 120 min TAOS significantly increased by 35% and 19% respectively. However, fasting and 120 min TBARS did not show any significant changes. Conclusion To our knowledge, no other studies have described changes in inflammation and oxidative stress at 4 years following bariatric surgery. This study contributes to the current literature supporting the longer-term beneficial effect of bariatric surgery on chronic inflammation and oxidative stress.

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.

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: 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.

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.

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 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.

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.

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.

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.

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.

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 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%.

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 (V̇o(2peak)) 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 V̇o(2peak) did not increase following sildenafil as compared with placebo (V̇o(2peak): 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 O(2) extraction.

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.

Aim: CaCO3 nanoparticles (nano-CaCO3) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO3 to noninvasively monitor pH modulation and subsequent tumor response. Materials & methods: We synthesized ferromagnetic core coated with CaCO3 (magnetite CaCO3). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models. Results: Magnetite CaCO3-MRI imaging showed that nano-CaCO3 rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO3 infusion could inhibit metastasis. Conclusion: Nano-CaCO3 exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.

// Zhi Hong Lu 1, 2 , Sergey Kaliberov 2, 3, 4 , Rebecca E. Sohn 1, 2 , Lyudmila Kaliberova 2, 3, 4 , Yingqiu Du 1, 2 , Julie L. Prior 5 , Daniel J. Leib 6 , Anne Chauchereau 7 , Jennifer K. Sehn 2, 8 , David T. Curiel 2, 3, 4 , Jeffrey M. Arbeit 1, 2 1 Urology Division and Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 2 Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 3 Biologic Therapeutics Center, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 4 Department of Radiation Oncology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 5 Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 6 Department of Orthopedic Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 7 Prostate Cancer Group, INSERM U981, Gustave Roussy, Villejuif, F-94805, France 8 Department of Anatomic and Molecular Pathology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA Correspondence to: Jeffrey M. Arbeit, email: arbeitj@wudosis.wustl.edu David T. Curiel, email: dcuriel@radonc.wustl.edu Keywords: prostate, metastasis, endothelial, niche, adenovirus Received: August 12, 2016 Accepted: December 26, 2016 Published: January 17, 2017 ABSTRACT While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg -/- (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.

Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis if not treated. Pharmacological treatment options for PAH have increased significantly over the past 10 years, with availability of intravenous, oral and inhaled drugs targeting the nitric oxide, endothelin and prostacyclin pathways. Treatment with these therapies in specialised pulmonary hypertension centres has resulted in reductions in patient symptoms, disease progression and mortality, and improved exercise capacity. Recognition of chronic thromboembolic pulmonary hypertension is important, as this cause of pulmonary hypertension may be amenable to surgical treatment. Several new oral drugs, including macitentan, riociguat and selexipag, some of which have novel modes of action, and the use of combinations of PAH drugs have recently been shown to be beneficial in treating PAH and are likely to change treatment for this condition in the future.

There are limited data to describe the relationship between the transvalvular gradient and mortality among patients who undergo aortic valve replacement.Using the National Echo Database Australia, valvular hemodynamics were characterized in 3,943 men (mean age, 62 ± 18 years) and 2,107 women (mean age, 62 ± 19 years) who underwent aortic valve replacement (median follow-up duration, 770 days; interquartile range, 381-1,584 days). The degree of impaired valvular hemodynamics (IVH) was categorized as mild (mean gradient 10.0-19.9 mm Hg, peak velocity 2.0-2.9 m/sec), moderate (mean gradient 20.0-39.9 mm Hg, peak velocity 3.0-3.9 m/sec), or severe (mean gradient ≥ 40.0 mm Hg, peak velocity ≥ 4 m/sec or effective orifice area0.8 cmOverall, 2,175 (36.0%), 2,598 (42.9%), 698 (11.5%), and 579 (9.6%) patients had no, mild, moderate, and severe IVH, respectively. Those with residual moderate or severe IVH had 5-year mortality of 45.5% and 57.3%, respectively, and higher adjusted long-term all-cause mortality (adjusted hazard ratios, 1.44 and 2.02; P .001) compared with "no IVH." Patients with mild IVH had similar mortality rates to those without IVH. A mortality threshold was evident above a mean transvalvular gradient22.5 mm Hg after adjusting for age, sex, stroke volume index, aortic regurgitation, and effective orifice area.After aortic valve replacement, most patients displayed an acceptable aortic valve hemodynamic profile. Moderate to severe IVH, however, was associated with poor long-term survival, with a threshold for increased mortality similar to that of native valvular aortic stenosis evident.

Assessment of right ventricular (RV) structure and function by echocardiography has largely been qualitative in the past. More recent approaches emphasise the quantification of RV structure from multiple echocardiographic views and quantification of multiple parameters of RV function. Current echocardiographic examinations should include at least two quantitative measures of RV function. This paper will highlight commonly used measures along with their strengths and weaknesses. With further technical developments in three-dimensional and myocardial deformation imaging and as more outcome data become available it is likely that further quantitative assessment will become routine and be used to guide diagnosis and treatment choices.

Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue. Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRβ expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFα) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts. Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D.

Background Bariatric surgery is an effective treatment for morbid obesity and metabolic dysfunction. Objectives The aim of this work was to examine the early temporal effects of laparoscopic sleeve gastrectomy (LSG) on adipokines (adiponectin, leptin), inflammatory cytokines (interleukin-6, C-reactive protein, interleukin-10), and global plasma measures of oxidative stress (thiobarbituric acid reactive substances and total antioxidant status) in a sample of 55 participants preoperatively, and 1 and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes, which is associated with increased low-grade systemic inflammation and oxidative stress. Setting University hospital, United Kingdom. Methods This was a prospective study comprising 55 participants with impaired glucose homeostasis and type 2 diabetes undergoing LSG (mean body mass index 50.4 kg/m2, mean glycated hemoglobin 7.4%). Serial measurements of the above markers were made preoperatively, 1 and 6 months postoperatively (43 had measurable cytokines and oxidative stress at 1- and 6-mo follow-up). Results We observed a significant reduction in interleukin-6, C-reactive protein, leptin, and thiobarbituric acid reactive substances, along with an increase in adiponectin 6 months postoperatively. Conclusions To our knowledge the effects of LSG on inflammatory cytokines and plasma markers of oxidative stress have not been examined temporally in a sizeable sample of participants who have undergone LSG. This present study supports the role of LSG for the treatment of the proinflammatory and pro-oxidant status associated with obesity-related glucose dysregulation.

OBJECTIVES: This study sought to compare electrocardiogram (ECG) variants in athletic and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts matched for the confounders of age, sex, and ethnicity.BACKGROUND: Anterior T-wave inversion (TWIV1-V4) is a common electrocardiographic finding in both athletes and patients with ARVC, and is a frequent conundrum in the setting of pre-participation screening. J-point elevation (JPE) has been proposed as an accurate means of identifying athletes, whereas disease markers, including premature ventricular contractions (PVCs) and low-voltage signals, have been associated with ARVC.METHODS: This study examined 200 subjects with TWI V1-V4, including 100 healthy athletes and 100 ARVC patients matched 1:1 for age, sex, and ethnicity (age: 21 ± 5 years for athletes vs. 22 ± 5 years for ARVC patients; 47% male; 97% Caucasian). The presence of TWI, JPE, PVCs, and left ventricular hypertrophy (LVH) were assessed.RESULTS: JPE was observed in 27% of athletes versus 16% of ARVC patients (p = 0.09). Thus, JPE had poor specificity (27%) and accuracy (60%) in identifying healthy athletes. In contrast, ARVC patients demonstrated a greater prevalence of precordial TWI beyond lead V3 (34% vs. 8%; p < 0.001), inferior TWI (31% vs. 3%; p < 0.001), PVCs (18% vs. 0%; p < 0.001), and lower LVH scores (SV1 + RV5; 19 ± 1 mm vs. 30 ± 1 mm; p < 0.001). These combined factors provided more reliable differentiation between health and disease (specificity 82%, accuracy 81%).CONCLUSIONS: PVCs and low QRS voltages are more prevalent among ARVC patients than athletes, whereas JPE is a relatively poor discriminator of health and disease when the confounders of age, sex, and ethnicity are considered.

There is a requirement for an efficacious vaccine to protect people against infection fromFrancisella tularensis, the etiological agent of tularemia. The lipopolysaccharide (LPS) ofF. tularensisis suboptimally protective against a parenteral lethal challenge in mice. To develop a more efficacious subunit vaccine, we have used a novel biosynthetic technique of protein glycan coupling technology (PGCT) that exploits bacterial N-linked glycosylation to recombinantly conjugateF. tularensisO-antigen glycans to the immunogenic carrier proteinPseudomonas aeruginosaexoprotein A (ExoA). Previously, we demonstrated that an ExoA glycoconjugate with two glycosylation sequons was capable of providing significant protection to mice against a challenge with a low-virulence strain ofF. tularensis. Here, we have generated a more heavily glycosylated conjugate vaccine and evaluated its efficacy in a Fischer 344 rat model of tularemia. We demonstrate that this glycoconjugate vaccine protected rats against disease and the lethality of an inhalational challenge withF. tularensisSchu S4. Our data highlights the potential of this biosynthetic approach for the creation of next-generation tularemia subunit vaccines.

Berry consumption has been associated with cardiovascular disease prevention in recent years. Atherosclerosis is one of the major causes of cardiovascular diseases. However, research on the prevention of atherosclerosis through consuming individual whole berries, specifically direct evidence, remains scarce. Therefore, further elucidating the role that berries play in the prevention of atherosclerosis is warranted. In this perspective, blueberries were selected to articulate research strategies for studying atheroprotective effects of berries. Studies from human subjects and various animal models are summarized. The mechanisms by which blueberries may act, through reducing oxidative stress, decreasing inflammation, improving endothelial dysfunction, regulating cholesterol accumulation and trafficking, along with potentially influencing gut microbiota, are also discussed. Blueberries contain high levels of polyphenolic compounds, which were widely indicated as major bioactive compounds. Nonetheless, the metabolites/catabolites after blueberry consumption, such as simple phenolic acids, rather than original compounds in berries, may be the actual in vivo bioactive compounds. Future research should focus on obtaining more direct evidence, preferably in humans, understanding of the mechanisms of action at the molecular level, and identifying bioactive compounds as well as which compounds act synergistically to convey health benefits. The research strategy discussed here may also be applied to the studies of other fruits and berries.

Aims We investigated which serum amino-terminal pro-B-type-natriuretic peptide (NT-proBNP) levels inform heart failure (HF) risk in a community-based population at increased cardiovascular disease (CVD) risk. Methods and results 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 HF, ejection fraction (EF) 76% and specificities of 47–69% for 5-year prediction of total HF in men and women in all three age groups. Sensitivities were ≥ 75% in most subgroups according to body mass index, estimated glomerular filtration rate, and the presence or absence of atrial fibrillation, pacemaker, or CVD, and for the prediction of HFpEF, HFrEF and VHF. Conclusion Age-specific serum NT-proBNP levels inform prognosis, and hence therapeutic decisions, regarding HF risk in individuals at increased CVD risk.

Key Points Question What is the variability in left ventricular ejection fraction (LVEF) as measured by different cardiac imaging modalities? Findings In this multicenter diagnostic study of 2032 patients with coronary artery disease and LVEF of 35% or less with imaging interpreted by core laboratories, correlation of LVEF between modalities ranged from r = 0.493 (for biplane echocardiography and cardiovascular magnetic resonance) to r = 0.660 (for cardiovascular magnetic resonance and gated single-photon emission computed tomography). There was no systematic overestimation or underestimation of LVEF for any modality. Meaning There is substantial variability in LVEF assessment between modalities, which should be considered in trial design and clinical management., Importance Clinical decisions are frequently based on measurement of left ventricular ejection fraction (LVEF). Limited information exists regarding inconsistencies in LVEF measurements when determined by various imaging modalities and the potential impact of such variability. Objective To determine the intermodality variability of LVEF measured by echocardiography, gated single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR) in patients with left ventricular dysfunction. Design, Setting, and Participants International multicenter diagnostic study with LVEF imaging performed at 127 clinical sites in 26 countries from July 24, 2002, to May 5, 2007, and measured by core laboratories. Secondary study of clinical diagnostic measurements of LVEF in the Surgical Treatment for Ischemic Heart Failure (STICH), a randomized trial to identify the optimal treatment strategy for patients with LVEF of 35% or less and coronary artery disease. Data analysis was conducted from March 19, 2016, to May 29, 2018. Main Outcomes and Measures At baseline, most patients had an echocardiogram and subsets of patients underwent SPECT and/or CMR. Left ventricular ejection fraction was measured by a core laboratory for each modality independent of the results of other modalities, and measurements were compared among imaging methods using correlation, Bland-Altman plots, and coverage probability methods. Association of LVEF by each method and death was assessed. Results A total of 2032 patients (mean [SD] age, 60.9 [9.6] years; 1759 [86.6%] male) with baseline LVEF data were included. Correlation of LVEF between modalities was r = 0.601 (for biplane echocardiography and SPECT [n = 385]), r = 0.493 (for biplane echocardiography and CMR [n = 204]), and r = 0.660 (for CMR and SPECT [n = 134]). Bland-Altman plots showed only moderate agreement in LVEF measurements from all 3 core laboratories with no substantial overestimation or underestimation of LVEF by any modality. The percentage of observations that fell within a range of 5% ranged from 43% to 54% between different imaging modalities. Conclusions and Relevance In this international multicenter study of patients with coronary artery disease and reduced LVEF, there was substantial variation between modalities in LVEF determination by core laboratories. This variability should be considered in clinical management and trial design. Trial Registration Clinicaltrials.gov Identifier: NCT00023595, This multicenter diagnostic study determines the intermodality variability of left ventricular ejection fraction (LVEF) measured by echocardiography, gated single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR) in patients with coronary artery disease and left ventricular dysfunction.