Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Identification of emerging safety and sustainability issues of advanced materials: Proposal for a systematic approach.

The EU Chemicals Strategy for Sustainability is a first step to achieve the Green Deal ambition for a toxic-free environment, and ensure that chemicals are produced and used in a way that maximises their contribution to society while avoiding harm to our planet and to future generations. Advanced materials are predicted to play a pivotal role in achieving this ambition and the underlying sustainability goals, and considerable efforts are invested in designing new classes of materials. Examples of such materials are metamaterials, artificially architectured materials designed to have material properties beyond those of the individual ingredient materials, or active materials at the boundary between materials and devices (e.g., new biomedical soft materials). Such innovative advanced materials raise concern about possible future safety and sustainability issues and would benefit from appropriate risk governance that promotes innovation, while pushing for safety and sustainability. To balance these aspects, a methodology is proposed for the early-stage identification of emerging safety and sustainability issues of advanced materials. As exemplified by two case studies, the methodology aims to be of use for innovators, risk assessors, and regulators. Extension of the methodology is highlighted, as well as implementation in broader initiatives like the EU's industrial policy approach.

Insights into possibilities for grouping and read-across for nanomaterials in EU chemicals legislation.

This paper presents a comprehensive review of European Union (EU) legislation addressing the safety of chemical substances, and possibilities within each piece of legislation for applying grouping and read-across approaches for the assessment of nanomaterials (NMs). Hence, this review considers both the overarching regulation of chemical substances under REACH (Regulation (EC) No 1907/2006 on registration, evaluation, authorization, and restriction of chemicals) and CLP (Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures) and the sector-specific pieces of legislation for cosmetic, plant protection and biocidal products, and legislation addressing food, novel food, and food contact materials. The relevant supporting documents (e.g. guidance documents) regarding each piece of legislation were identified and reviewed, considering the relevant technical and scientific literature. Prospective regulatory needs for implementing grouping in the assessment of NMs were identified, and the question whether each particular piece of legislation permits the use of grouping and read-across to address information gaps was answered.

Detection of titanium particles in human liver and spleen and possible health implications.

BACKGROUND: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal studies. A health risk from nanosized TiO2 particle consumption could not be excluded then. RESULTS: Here we show the first quantification of both total titanium (Ti) and TiO2 particles in 15 post-mortem human livers and spleens. These low-level analyses were enabled by the use of fully validated (single particle) inductively coupled plasma high resolution mass spectrometry ((sp)ICP-HRMS) detection methods for total Ti and TiO2 particles. The presence of TiO2 in the particles in tissues was confirmed by Scanning Electron Microscopy with energy dispersive X-ray spectrometry. CONCLUSIONS: These results prove that TiO2 particles are present in human liver and spleen, with ≥24% of nanosize (< 100 nm). The levels are below the doses regarded as safe in animals, but half are above the dose that is deemed safe for liver damage in humans when taking into account several commonly applied uncertainty factors. With these new and unique human data, we remain with the conclusion that health risks due to oral exposure to TiO2 cannot be excluded.

Catheter ablation of symptomatic idiopathic ventricular arrhythmias : A five-year single-centre experience.

AIMS: This study was designed to gain insight into the patient characteristics, results and possible complications of ablation procedures for symptomatic idiopathic premature ventricular complexes (PVC) and idiopathic ventricular tachycardia (VT). METHODS: Data were collected from all patients who underwent radiofrequency catheter ablation for symptomatic PVCs and idiopathic VT in the Catharina Hospital between 1 January 2011 and 31 December 2015. The procedural endpoint was elimination or non-inducibility of the clinical arrhythmia. Successful sustained ablation was defined as the persistent elimination of at least 80% of the PVCs or the absence of VTs at follow-up. In case of suspected PVC-induced cardiomyopathy, the systolic left ventricular function was reassessed 3 months post procedure. RESULTS: Our cohort consisted of 131 patients who underwent one or more ablation procedures; 99 because of symptomatic premature ventricular complexes, 32 because of idiopathic VT. In total 147 procedures were performed. The procedural ablation success rate was 89%. Successful sustained ablation rate was 82%. Eighteen (13.2%) patients had suspected PVC-induced cardiomyopathy. In 15 of them (83%), successful sustained ablation was achieved and the left ventricular ejection fraction improved from a mean of 39% (±8.8) to 55.4% (±8.1). Most arrhythmias originated from the right ventricular outflow tract (60%) or aortic cusps (13%). Complications included three tamponades. CONCLUSION: Catheter ablation therapy for idiopathic ventricular arrhythmias is very effective with a sustained success rate of 82%. In patients with PVC-induced cardiomyopathy, it leads to improvement of systolic left ventricular function. However, risk for complications is not negligible, even in experienced hands.

Feasibility and barriers of treating clubfeet in four countries.

PURPOSE: The purpose of this study was to elucidate why neglected clubfeet still exists despite the availability of a highly (cost)-effective treatment-the Ponseti treatment. METHODS: A qualitative and partly quantitative study with semi-structured interviews was conducted in four countries: the Netherlands, South Africa, Argentina and Indonesia with both caregivers, mostly parents, of children with clubfoot and practitioners treating clubfoot. The topics discussed with the caregivers (n = 51) were the conceptions of the cause of clubfeet, received information, accessibility, financial aspects, and social stigma. With the practitioners (n = 11) the focus of the interviews was the treatment protocol and finance. RESULTS: Several barriers towards the start of the treatment were highlighted. At all places treatment was financed by the government, insurance or charity. Nevertheless, the cost of transport and missed working days formed a barrier, although there is a large difference between and within countries. Poverty, long travel duration, and beliefs of supernatural causes for the clubfoot result in delay in the start of treatment. CONCLUSION: These are problems we need to address when making effective treatment available for every child to diminish the burden of neglected clubfoot; especially accessible clinics in rural areas can be a good alternative to highly specialized hospitals in large cities. We as a community should try to find and overcome the barriers to treat these patients, because we have a relatively easy and highly cost-effective treatment option which can be given by trained non-physicians supervised by an interested medical doctor.

Variation in training regimens in professional showjumping yards.

REASONS FOR PERFORMING STUDY: Training regimens of showjumping horses under field conditions are largely undocumented. OBJECTIVES: The aims of this study were to quantify and compare training regimens used in professional-level showjumping yards, with respect to time exercised and type of activity. STUDY DESIGN: Prospective cohort study. METHODS: A prospective 6-month cohort study of showjumping horses in 4 European countries (The Netherlands, Sweden, Switzerland, Great Britain) was designed to analyse training and health data, in yards with several horses in training and riders competing at professional level. Riders documented the daily frequency and duration of all physical activities of the horses. Variation in training routines were compared between riders, location and time. Mixed-models analysis was used to examine factors associated with total time exercised and time spent in flatwork. RESULTS: In 4 countries, the 31 participating riders trained 263 European Warmbloods. The total days at risk (e.g. days in which the horses were considered fit for exercise) was 39,262. Mean time spent in daily exercise, including ridden work, lungeing and treadmill exercise, varied between riders from 19-52 min/day at risk. There was considerable variation in activities and level of heavy work and light exercise, i.e. turnout. Total time exercised and time spent in flatwork differed with month, country and proportion of days lost to training. Low variation of activities was associated with decreased total time trained and increased time spent in flatwork. CONCLUSIONS: Riders at this elite professional level of showjumping used training regimens that vary substantially in time spent training and other physical activities and showjumping horses are challenged differently during training despite competing at the same level. Whether all training regimens prepare the horses equally for the demands of competition remains to be determined.

Days-lost to training and competition in relation to workload in 263 elite show-jumping horses in four European countries.

Orthopaedic, or other, injuries in sports medicine can be quantified using the 'days-lost to training' concept. Both the training regimen and the surface used in training and racing can affect the health of racehorses. Our aim was to associate 'days-lost to training' in elite-level show-jumpers to horse characteristics, training and management strategies, and the time spent working on various training and competition surfaces. We designed a longitudinal study of professional riders in four European countries. Data were recorded using training diaries. Reasons for days-lost were classified into non-acute and acute orthopaedic, medical, hoof-related, and undefined. We produced descriptive statistics of training durations, relative to type of training, surfaces used, and days-lost. We created zero-inflated negative-binomial random-effects models using the overall days-lost as outcome. In the whole dataset, duration variables related to training surfaces were analysed as independent. The Swedish data only were also used to test whether duration variables were related to competition surfaces. Thirty-one riders with 263 horses provided data on 39,028 days at risk. Of these, 2357 (6.0%) were days-lost (55% and 22% of these were due to non-acute and acute orthopaedic injuries, respectively) in 126 horses. In the all-country model, controlling for season, a significant variable was country. Switzerland and the UK had lower incidence-rate ratios (IR) compared to Sweden (IRs 0.2 and 0.03, respectively). Horses with previous orthopaedic problems had almost a doubled IR (1.8) of days-lost due to orthopaedic injury, compared to baseline. If the horse had jumping training more than 1 min per day at risk the IRs were 6.9-7 (compared to less than this amount of time); this was, however, likely an effect of a small baseline. Variation in training was a protective factor with a dose-response relationship; the category with the highest variation had an IR of 0.1. In the Swedish model, controlling for season, there was an association of year (IR 2.8 year 2010). Further, if the horse rested >17-25% of the days at risk, or >33% of the DAR2, had IRs 3.5 and 3.0, compared to less time. Horses ≥ 6 years had IRs of 1.8-2.0, compared to younger horses. Limited training use of sand surface was a risk-factor (IR 2.2; >4 ≤ 12 min/day at risk), compared to not training on sand. Training/competing on sand-wood was a protective factor (IRs 0.4-0.5) compared to not using this surface.

WITHDRAWN: Distraction osteogenesis using monolateral external fixator for post-traumatic skeletal defects of the femur.

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