Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a "Pure" Patient Phenotype and the Generalizability of Trial Findings.

AIMS: To investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival. METHODS AND RESULTS: We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. CONCLUSIONS: Trial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality.

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI).

AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 µmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS: Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.

The Effect of Fatigue on Electromyographic Characteristics during Obstacle Crossing of Different Heights in Young Adults.

The aim of this study was to investigate the effect of fatigue on electromyographic (EMG) parameters of healthy young adults during obstacle crossing of two different heights. Twelve untrained male adults (23 ± 5 years of age) were fatigued running on a treadmill with increasing speed and inclination and walked over an obstacle with a height set at 10% and 20% of each individual's lower limb length. Maximal plantar flexor torque and EMG of the medial gastrocnemius, soleus, and tibialis anterior muscles of the trailing limb were assessed during obstacle crossing. Data were captured before, immediately after and 5 minutes after a fatigue session. Fatigue induced significant reduction on the plantar flexor torque output immediately after and 5 minutes after exhaustion. After fatigue gait speed was not affected, the minimum distance between the obstacle and the trailing or leading foot remained unchanged, and the trailing foot contacted the ground closer to the obstacle immediately after fatigue. Regarding the EMG, medial gastrocnemius became after fatigue more active during swing phase when increasing the obstacle height, whereas this was not the case before or 5 minutes after fatigue. No other significant difference was observed for any of the examined muscles. It is concluded that the assessed fatigue protocol induced only minimal changes in the EMG activity of the examined muscles during obstacle crossing. Therefore, it is suggested that the neuromuscular system of healthy young individuals is able to respond to the decreased force capacity after fatigue during obstacle crossing of heights up to the 20% of the limb length. Key PointsExhaustion after running on a treadmill induces significant reduction in plantar flexion strength and changes in the positioning of the feet relative to the obstacle during obstacle crossing.EMG activity of the calf muscles of the trailing limb does not change significantly after fatigue during the stance phaseDuring swing phase, medial gastrocnemius EMG activity of the trailing limb increases after fatigue when obstacle height increases.These minor changes in EMG after fatigue, reveals that untrained, healthy, young subjects may compensate the deficit in muscular force due to fatigue when performing obstacle crossing.

Can vigilance predict the status of safe functional gait and risk of falls in patients with peripheral vestibular disorders? A cross-sectional study.

OBJECTIVES: Peripheral vestibular disorders except from reflexes dysfunction correspond also to cognitive decline. The objectives of this cross-sectional study were to a) identify correlations among variables of functional gait, cognitive function, and perceived dizziness and b) explore variables that could be used as prognostic factors of functional gait in people with peripheral vestibular deficits. METHODS: We recruited 154 people with peripheral vestibular deficits. The participants presented with moderate disability in terms of the Dizziness Handicap Inventory questionnaire (mean: 48.00, 95% confidence interval: 45.24-50.75), deficits in the Functional Gait Assessment test (mean: 22.75, 95% confidence interval: 22.13-23.40) and indication of mild cognitive impairment based on Montreal Cognitive Assessment tool (mean: 25.18, 95% confidence interval: 24.75-25.60). RESULTS: Statistically significant correlations found among functional gait and gender, age, educational level, perceived level of disability and the total score of the Montreal Cognitive Assessment tool. Several components of the cognitive screening test (executive function, vigilance, language skills, verbal fluency) also correlated statistically significant with functional gait. Linear regression models revealed that age, perceived level of disability and vigilance significantly predicted functional gait variability (R2 = 0.350; p < 0.001) as well as high risk of falling, as indicated by a score on Functional Gait Assessment test <22/30 (R2 = 0.380). CONCLUSIONS: Cognitive impairments affect functional gait in people with peripheral vestibular disorders. Thus, the integration of cognitive functional assessment must be considered as a prerequisite for functional assessment and designing rehabilitation programs that will include dual task training.

Head mounted display effect on vestibular rehabilitation exercises performance.

Objectives: Vestibular rehabilitation clinical guidelines document the additional benefit offered by the Mixed Reality environments in the reduction of symptoms and the improvement of balance in peripheral vestibular hypofunction. The HOLOBalance platform offers vestibular rehabilitation exercises, in an Augmented Reality (AR) environment, projecting them using a low- cost Head Mounted Display. The effect of the AR equipment on the performance in three of the commonest vestibular rehabilitation exercises is investigated in this pilot study. Methods: Twenty-five healthy adults (12/25 women) participated, executing the predetermined exercises with or without the use of the AR equipment. Results: Statistically significant difference was obtained only in the frequency of head movements in the yaw plane during the execution of a vestibular adaptation exercise by healthy adults (0.97 Hz; 95% CI=(0.56, 1.39), p<0.001). In terms of difficulty in exercise execution, the use of the equipment led to statistically significant differences at the vestibular-oculomotor adaptation exercise in the pitch plane (OR=3.64, 95% CI (-0.22, 7.50), p=0.049), and in the standing exercise (OR=28.28. 95% CI (23.6, 32.96), p=0.0001). Conclusion: Τhe use of AR equipment in vestibular rehabilitation protocols should be adapted to the clinicians' needs.

Effect of Crosshead Speed and Volume Ratio on Compressive Mechanical Properties of Mono- and Double-Gyroid Structures Made of Inconel 718.

The current development of additive technologies brings not only new possibilities but also new challenges. One of them is the use of regular cellular materials in various components and constructions so that they fully utilize the potential of porous structures and their advantages related to weight reduction and material-saving while maintaining the required safety and operational reliability of devices containing such components. It is therefore very important to know the properties of such materials and their behavior under different types of loads. The article deals with the investigation of the mechanical properties of porous structures made by the Direct Metal Laser Sintering (DMLS) of Inconel 718. Two types of basic cell topology, mono-structure Gyroid (G) and double-structure Gyroid + Gyroid (GG), with material volume ratios of 10, 15 and 20 %, were studied within our research to compare their properties under quasi-static compressive loading. The testing procedure was performed at ambient temperature with a servo-hydraulic testing machine at three different crosshead testing speeds. The recorded data were processed, while the stress-strain curves were plotted, and Young's modulus, the yield strength Re0.2, and the stress at the first peak of the local maximum σLocMax were identified. The results showed the best behavior under compression load among the studied structures displayed by mono-structure Gyroid at 10 %. At the same time, it can be concluded that the wall thickness of the structure plays an important role in the compressive properties but on the other hand, crosshead speed doesn´t influence results significantly.

Hamstring exercises for track and field athletes: injury and exercise biomechanics, and possible implications for exercise selection and primary prevention.

Hamstring strain injuries are the most prevalent muscle injuries in track and field (TF). These injuries often cause prolonged symptoms and a high risk of re-injury. Strengthening of the hamstring muscles has been recommended for injury prevention. The authors review the possible role of eccentric training in TF hamstring injury prevention and introduce exercise classification criteria to guide clinicians in designing strengthening programmes adapted to TF. The principles exposed may serve as a foundation for future development and application of new eccentric programmes to decrease the high incidence of this type of injury in other sports.

Exploring the Acceptability and Feasibility of Providing a Balance Tele-Rehabilitation Programme to Older Adults at Risk for Falls: An Initial Assessment.

Falls are a major health concern. The HOLOBALANCE tele-rehabilitation system was developed to deliver an evidence based, multi-sensory balance rehabilitation programme, to the elderly at risk of falls. The system delivers a series of balance physiotherapy exercises and cognitive and auditory training tasks prescribed by an expert balance physiotherapist following an initial balance assessment. The HOLOBALANCE system uses augmented reality (AR) to deliver exercises and games, and records task performance via a combination of body worn sensors and a depth camera. The HOLOBALANCE tele-rehabilitation system provides feedback to the supervising clinical team regarding task performance, participant usage and user feedback. Herewith we present the findings from the first 25 study participants regarding the feasibility and acceptability of the proposed system. The results of the clinical study indicate that the system is acceptable by the end users and also feasible for using in hospital and home environments.

Chelator-Free/Chelator-Mediated Radiolabeling of Colloidally Stabilized Iron Oxide Nanoparticles for Biomedical Imaging.

The aim of this study was to develop a bioimaging probe based on magnetic iron oxide nanoparticles (MIONs) surface functionalized with the copolymer (p(MAA-g-EGMA)), which were radiolabeled with the positron emitter Gallium-68. The synthesis of the hybrid MIONs was realized by hydrolytic condensation of a single ferrous precursor in the presence of the copolymer. The synthesized MagP MIONs displayed an average Dh of 87 nm, suitable for passive targeting of cancerous tissues through the enhanced permeation and retention (EPR) effect after intravenous administration, while their particularly high magnetic content ascribes strong magnetic properties to the colloids. Two different approaches were explored to develop MIONs radiolabeled with 68Ga: the chelator-mediated approach, where the chelating agent NODAGA-NHS was conjugated onto the MIONs (MagP-NODAGA) to form a chelate complex with 68Ga, and the chelator-free approach, where 68Ga was directly incorporated onto the MIONs (MagP). Both groups of NPs showed highly efficient radiolabeling with 68Ga, forming constructs which were stable with time, and in the presence of PBS and human serum. Ex vivo biodistribution studies of [68Ga]Ga- MIONs showed high accumulation in the mononuclear phagocyte system (MPS) organs and satisfactory blood retention with time. In vivo PET imaging with [68Ga]Ga-MagP MIONs was in accordance with the ex vivo biodistribution results. Finally, the MIONs showed low toxicity against 4T1 breast cancer cells. These detailed studies established that [68Ga]Ga- MIONs exhibit potential for application as tracers for early cancer detection.

Adenovirus genome in the placenta: association with histological chorioamnionitis and preterm birth.

Adenovirus is isolated frequently from the amniotic fluid and has been implicated in severe neonatal infections. A case control study was carried out to examine the association of detection of adenovirus in placentas with preterm birth and histological chorioamnionitis. Placentas from preterm and full term deliveries were collected prospectively. Preterm cases were divided into three subgroups according to the gestational age. PCR was carried out on placental tissues for the detection of adenovirus genome. Placentas were evaluated histologically for the presence of chorioamnionitis. Chi-square and odds ratios (OR) were used to determine if detection of adenovirus is associated with preterm birth and histological evidence of inflammation. Seventy-one preterm and 122 full term placentas were studied. Adenovirus genome was detected in 29 (40.8%) of preterm cases and in 25 (20.5%) of the full term controls (OR = 2.6; 95% CI, 1.4-5.1; P = 0.002). Detection of adenovirus in preterm placentas was significantly higher compared to full term particularly in the lower gestational age. Detection of adenovirus in placenta followed the seasonal variation of adenovirus infections. Thirty-seven preterm and 21 full term placentas were also selected for paraffin inclusion and histological examination. Chorioamnionitis was present more frequently in preterm adenovirus-positive placentas compared to preterm adenovirus-negative placentas (75% vs. 36%; P = 0.026) as well as compared to term adenovirus-positive placentas (75% vs. 19%; P = 0.003). This study demonstrates that adenovirus infection of the placenta is associated strongly with histological chorioamnionitis and preterm birth.

Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease.

BACKGROUND: Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. METHODS AND RESULTS: A total of 1102 adult patients with congenital heart disease (age 36.0+/-14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (> or =90 mL . min(-1) . 1.73 m(-2)), mildly impaired GFR (60 to 89 mL . min(-1) . 1.73 m(-2)), and moderately/severely impaired GFR (<60 mL . min(-1) . 1.73 m(-2)). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL . min(-1) . 1.73 m(-2), P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). CONCLUSIONS: Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Afro-Caribbean Heart Failure in the United Kingdom: Cause, Outcomes, and ATTR V122I Cardiac Amyloidosis.

BACKGROUND: It has been reported that subjects of African descent present with heart failure at a younger age and because of different causes than whites. We present contemporary data from UK Afro-Caribbean patients in London. METHODS AND RESULTS: All patients with heart failure presenting to St George's Hospital Heart Failure clinic between 2005 and 2012 were included (n=1392). Patients were predominantly white (71%) and male (67%), and median age at presentation was 73 years (range, 18-100 years). In 211 Afro-Caribbean patients, the most common cause of heart failure was nonischemic dilated cardiomyopathy in 27.5% (whites, 19.9%; P<0.001). Lower rates of ischemic cardiomyopathy were observed (13% versus 41%; P<0.001). The fourth most common cause of heart failure in Afro-Caribbeans was cardiac amyloidosis (11.4%). The prevalence may have been even higher as not all patients were tested for amyloidosis. Patients with ATTR V122I had the worst prognosis compared with other causes of Afro-Caribbean heart failure and white patients. To better understand this condition, we analyzed data from the largest international cohort of ATTR V122I patients, followed up at the UK National Amyloidosis Center (n=72). Patients presented with cardiac failure (median age, 75 [range, 59-90] years). Median survival was 2.6 years from diagnosis. CONCLUSIONS: In London, the cause of heart failure varies depending on ethnicity and affects age of presentation and outcomes. In Afro-Caribbean patients, ATTR V122I is an underappreciated cause of heart failure, and cardiomyopathy is often misattributed to hypertension. As promising TTR therapies are in development, increased awareness and proactive detection are needed.

Cross-cultural Adaptation and Validation of the Exercise-Induced Leg Pain Questionnaire for English- and Greek-Speaking Individuals.

STUDY DESIGN: Clinical measurement. OBJECTIVES: To translate the German version of the Exercise-Induced Leg Pain Questionnaire (EILP-G) to Greek and English and evaluate the psychometric properties of the Greek version. BACKGROUND: The EILP-G was developed to evaluate the severity of symptoms and sports ability in individuals with exercise-induced leg pain (EILP). Translation of the questionnaire to other languages will provide a standard outcome measure across populations. METHODS: The EILP-G questionnaire was cross-culturally adapted to Greek and English, according to established guidelines. The validity and reliability of the Greek version were assessed in 40 patients with EILP, 40 patients with other lower extremity injuries, 40 track-and-field athletes with no history of EILP, and 40 young adults without pathology. Participants completed the questionnaire at baseline and again after 7 to 10 days. RESULTS: The expert committee and the participants considered the questionnaire to have good face and content validity. Concurrent validity as assessed using the Schepsis score was almost perfect (rho = 0.947, P<.001). Dimensionality analysis revealed a 1-factor solution, explaining 83.8% of the total variance. Known group validity was demonstrated by significant differences between patients compared with the asymptomatic groups (P<.001). The Greek version exhibited excellent test-retest reliability (intraclass correlation coefficient = 0.995 for the EILP group) and internal consistency (Cronbach α = .942 for the EILP group). Finally, no ceiling or floor effects were found, as none of the individuals with EILP scored the maximum or minimum possible values on the questionnaire. CONCLUSION: The Greek version, adapted from the original EILP-G, is a valid and reliable questionnaire, and its psychometric properties are comparable with the original version.

Cathepsin B and cathepsin D expression in the progression of colorectal adenoma to carcinoma.

Lysosomal proteinases, cathepsin B (CB) and cathepsin D (CD) have been implicated in the progression of several human tumors. In the present study, the antigen levels of CB and CD, and their immunohistochemical staining were compared in paired colorectal tumors (n =64) and background colon tissue of the same patients with clinicopathological staging. The antigen levels, were found to be significantly higher in cancer tissue (mean 35.79 ng/mg protein for CB and 3.97 ng/mg protein for CD) than in corresponding normal mucosa (24.62 ng/mg protein for CB and 2.69 ng/mg protein for CD). CB antigen levels were positively correlated with differentiation grade and Duke's stage (P < 0.001 and P = 0.041, respectively), but not correlated with nodal status. CD antigen levels were not correlated with the previous parameters. Staining intensity for both antigens increased from adenoma to adenocarcinoma. The degree of staining for CB and CD was associated with differentiation grade (P = 0.004 and 0.001, respectively), Dukes' stage (P = 0.002 and 0.001, respectively) and lymph node involvement (P = 0.002 and P < 0.001, respectively).

Ischaemic heart disease in the ageing woman.

Cardiovascular disease is one of the leading causes of death worldwide. Since 1984, the total number of deaths from cardiovascular disease has been greater for women compared with men. This might be, in part, related to gender-specific differences in the presentation of people with chest pain but, importantly, the risk of heart disease in women is often underestimated owing to the misperception that women are 'protected' against cardiovascular disease. Studies have shown that medical services are underused, delays occur in health-care seeking behaviour, resource use patterns are less intensive, and it takes longer to diagnose women compared with men. This often leads to less aggressive treatment strategies which, in turn, may translate into poorer outcomes compared with those in men. In this chapter, we review the gender-specific differences in epidemiology, diagnosis, and management of people with ischaemic heart disease, and focus particularly on the effect of ageing and menopause in ischaemic heart disease.

Near miss sudden cardiac death on a young patient with repaired atrioventricular septal defect.

Patients with congenital heart disease often face the prospect of long-term haemodynamic or arrhythmic complications for which lifelong follow-up in specialist adult congenital heart disease (ACHD) centres is required. We describe the case of a 25-year-old man with repaired atrioventricular septal defect who was referred to our centre after a ventricular fibrillation arrest. Serial echocardiograms in previous years had shown progressive severe left ventricular outflow obstruction, but the patient had not been operated on as he was deemed asymptomatic and reluctant to consider surgery. Management and criteria for further intervention in ACHD patients often differ from those of patients with acquired heart disease and reliance on symptoms alone is not good practice and may prove catastrophic.