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).

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.

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.

Guidelines for heart transplantation.

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).THE INDICATION FOR HEART TRANSPLANTATION IS DEFINED AS: 'End-stage heart disease not remediable by more conservative measures'.CONTRAINDICATIONS ARE: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation.Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.).

Is topical local anaesthesia necessary when performing paediatric flexible nasendoscopy? A double-blind randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of lignocain 2% and oxymetazoline 0.025% compared to oxymetazoline 0.025% alone when administered prior to fibreoptic nasendoscopy in paediatric patients. STUDY DESIGN: Prospective, randomized controlled, double-blind study. A group of 56 children, undergoing nasendoscopy to determine adenoidal size, were randomized into two groups and received either lignocain 2% and oxymetazoline 0.025% or oxymetazoline 0.025% alone prior to fibreoptic nasendoscopy. SETTING: A tertiary care Paediatric Hospital. METHOD: The endoscopist recorded the ease of performance of the procedure, cooperation of patient and quality of the view achieved using a visual analogue scale (VAS). The pain and anxiety levels of the child were recorded before, during and immediately after the procedure, using a VAS. The duration of performing the procedure was recorded from insertion of the endoscope into the nostril until removal. RESULTS: All 56 children were able to undergo the endoscopy and the full anxiety and pain assessment was done. Three children were excluded because they have undergone nasendoscopies before. Of the 53 patients included, 27 children received solution A (oxymetazoline 0.025%) and 26 children received solution B (oxymetazoline 0.025% and lignocain 2%). There was no statistical difference between the two groups regarding the duration of the endoscopy, quality of view, ease of performance and cooperation of the patients. The median pain and anxiety scores were not significantly different between the two groups. CONCLUSIONS: This study concludes that the use of a decongestant (oxymetazoline) for paediatric nasendoscopy is just as effective as the use of oxymetazoline with lignocain. Pain and anxiety is not increased in the absence of lignocain.

Glutathione S-transferase as predictor of functional outcome in transplantation of machine-preserved non-heart-beating donor kidneys.

Non-heart-beating (NHB) donors are a valuable source of kidneys for transplantation. The organs, however, sustain substantial warm ischemic damage that may jeopardize the transplantability and result in nonfunction of the grafts. Quantification of warm ischemic time (WIT) and prediction of transplant outcome are essential for the use of NHB donor organs. During machine preservation (MP) the viability of NHB donor kidneys was evaluated through calculating intrarenal vascular resistance and determining lactate dehydrogenase and alpha-glutathione S-transferase (alphaGST) in the perfusate. Thirty-seven functioning (F) and nine nonfunctioning kidneys (NF) were compared. WIT was longer in NF; serum creatinine, donor age, and preservation time were not different. WIT correlated well with alphaGST after 4 and 8 hr of MP (r=0.353, P=0.009, and r=0.346, P=0.011, respectively). When compared with F, intrarenal vascular resistance was increased in NF after 4 and 8 hr of perfusion (P<0.05); at all time points, alphaGST levels were elevated in NF (P<0.05). Lactate dehydrogenase activity was not different between the groups, but could identify immediate functioning grafts within the F group. In conclusion, alphaGST levels correlated strongly with WIT and were also able to distinguish NF from F grafts. alphaGST can adequately predict the functional outcome of NHB donor grafts before transplantation; levels of alphaGST can be used to define reliable safety margins for viability. Therefore, MP is useful in evaluating the viability of NHB donor kidneys, and the parameters discussed will help to select nonviable grafts from this valuable pool of kidneys for transplantation.