Aims The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE). Methods and results Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated. Conclusion Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

Background: Electronic cigarette (EC) use has grown exponentially over the past few years. The purpose of this survey was to assess the characteristics and experiences of a large sample of EC users and examine the differences between those who partially and completely substituted smoking with EC use. Methods: A questionnaire was prepared, translated into 10 different languages and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers. Results: In total, 19,414 participants were included in the analysis, with 88 of them (0.5%) reported not being smokers at the time of EC use initiation. Complete substitution of smoking was reported by 81.0% of participants (former smokers) while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. They were using ECs for a median of 10 months. They initiated EC use with a median of 18 mg/mL nicotine-concentration liquids; 21.5% used higher than 20 mg/mL. Only 3.5% of participants were using 0-nicotine liquids at the time of the survey. Former smokers were highly dependent (Fagerström Test for Cigarette Dependence = 7) and were heavier smokers (21 cigarettes per day when smoking) compared to current smokers. The most important reasons for initiating EC use for both subgroups was to reduce the harm associated with smoking and to reduce exposure of family members to second-hand smoking. Most considered ECs as less harmful than tobacco cigarettes, while 11.0% considered them absolutely harmless. Side effects were reported by more than half of the participants (59.8%), with the most common being sore/dry mouth and throat; side effects were mild and in most cases were subsequently resolved (partially or completely). Participants experienced significant benefits in physical status and improvements in pre-existing disease conditions (including respiratory disease such as asthma and chronic obstructive lung disease). Being former smoker was independently associated with positive effects in health and improvements in disease conditions. Conclusions: The results of this worldwide survey of dedicated users indicate that ECs are mostly used to avoid the harm associated with smoking. They can be effective even in highly-dependent smokers and are used as long-term substitutes for smoking. High levels of nicotine are used at initiation; subsequently, users try to reduce nicotine consumption, with only a small minority using non-nicotine liquids. Side effects are minor and health benefits are substantial, especially for those who completely substitute smoking with EC use. Further population and interventional studies are warranted.

dilated cardiomyopathy ͉ heart failure ͉ calcium cycling ͉ mutation ͉ phosphorylation

Background: Although millions of people are using electronic cigarettes (ECs) and research on this topic has intensified in recent years, the pattern of EC use has not been systematically studied. Additionally, no comparative measure of exposure and nicotine delivery between EC and tobacco cigarette or nicotine replacement therapy (NRTs) has been established. This is important, especially in the context of the proposal for a new Tobacco Product Directive issued by the European Commission. Methods: A second generation EC device, consisting of a higher capacity battery and tank atomiser design compared to smaller cigarette-like batteries and cartomizers, and a 9 mg/mL nicotine-concentration liquid were used in this study. Eighty subjects were recruited; 45 experienced EC users and 35 smokers. EC users were video-recorded when using the device (ECIG group), while smokers were recorded when smoking (SM-S group) and when using the EC (SM-E group) in a randomized cross-over design. Puff, inhalation and exhalation duration were measured. Additionally, the amount of EC liquid consumed by experienced EC users was measured at 5 min (similar to the time needed to smoke one tobacco cigarette) and at 20 min (similar to the time needed for a nicotine inhaler to deliver 4 mg nicotine). Results: Puff duration was significantly higher in ECIG (4.2 ± 0.7 s) compared to SM-S (2.1 ± 0.4 s) and SM-E (2.3 ± 0.5 s), while inhalation time was lower (1.3 ± 0.4, 2.1 ± 0.4 and 2.1 ± 0.4 respectively). No difference was observed in exhalation duration. EC users took 13 puffs and consumed 62 ± 16 mg liquid in 5 min; they took 43 puffs and consumed 219 ± 56 mg liquid in 20 min. Nicotine delivery was estimated at 0.46 ± 0.12 mg after 5 min and 1.63 ± 0.41 mg after 20 min of use. Therefore, 20.8 mg/mL and 23.8 mg/mL nicotine-containing liquids would deliver 1 mg of nicotine in 5 min and 4 mg nicotine in 20 min, respectively. Since the ISO method significantly underestimates nicotine delivery by tobacco cigarettes, it seems that liquids with even higher than 24 mg/mL nicotine concentration would be comparable to one tobacco cigarette. Conclusions: EC use topography is significantly different compared to smoking. Four-second puffs with 20–30 s interpuff interval should be used when assessing EC effects in laboratory experiments, provided that the equipment used does not get overheated. Based on the characteristics of the device used in this study, a 20 mg/mL nicotine concentration liquid would be needed in order to deliver nicotine at amounts similar to the maximum allowable content of one tobacco cigarette (as measured by the ISO 3308 method). The results of this study do not support the statement of the European Commission Tobacco Product Directive that liquids with nicotine concentration of 4 mg/mL are comparable to NRTs in the amount of nicotine delivered to the user.

Background: A major characteristic of the electronic cigarette (EC) market is the availability of a large number of different flavours. This has been criticised by the public health authorities, some of whom believe that diverse flavours will attract young users and that ECs are a gateway to smoking. At the same time, several reports in the news media mention that the main purpose of flavour marketing is to attract youngsters. The importance of flavourings and their patterns of use by EC consumers have not been adequately evaluated, therefore, the purpose of this survey was to examine and understand the impact of flavourings in the EC experience of dedicated users. Methods: A questionnaire was prepared and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers. Results: In total, 4,618 participants were included in the analysis, with 4,515 reporting current smoking status. The vast majority (91.1%) were former smokers, while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. Both subgroups had a median smoking history of 22 years and had been using ECs for 12 months. On average they were using three different types of liquid flavours on a regular basis, with former smokers switching between flavours more frequently compared to current smokers; 69.2% of the former subgroup reported doing so on a daily basis or within the day. Fruit flavours were more popular at the time of participation, while tobacco flavours were more popular at initiation of EC use. On a scale from 1 (not at all important) to 5 (extremely important) participants answered that variability of flavours was “very important” (score = 4) in their effort to reduce or quit smoking. The majority reported that restricting variability will make ECs less enjoyable and more boring, while 48.5% mentioned that it would increase craving for cigarettes and 39.7% said that it would have been less likely for them to reduce or quit smoking. The number of flavours used was independently associated with smoking cessation. Conclusions: The results of this survey of dedicated users indicate that flavours are marketed in order to satisfy vapers’ demand. They appear to contribute to both perceived pleasure and the effort to reduce cigarette consumption or quit smoking. Due to the fact that adoption of ECs by youngsters is currently minimal, it seems that implementing regulatory restrictions to flavours could cause harm to current vapers while no public health benefits would be observed in youngsters. Therefore, flavours variability should be maintained; any potential future risk for youngsters being attracted to ECs can be sufficiently minimized by strictly prohibiting EC sales in this population group.

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca2+-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy

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Background: Electronic cigarettes (ECs) have been marketed as an alternative-to-smoking habit. Besides chemical studies of the content of EC liquids or vapour, little research has been conducted on their in vitro effects. Smoking is an important risk factor for cardiovascular disease and cigarette smoke (CS) has well-established cytotoxic effects on myocardial cells. The purpose of this study was to evaluate the cytotoxic potential of the vapour of 20 EC liquid samples and a “base” liquid sample (50% glycerol and 50% propylene glycol, with no nicotine or flavourings) on cultured myocardial cells. Included were 4 samples produced by using cured tobacco leaves in order to extract the tobacco flavour. Methods: Cytotoxicity was tested according to the ISO 10993-5 standard. By activating an EC device at 3.7 volts (6.2 watts—all samples, including the “base” liquid) and at 4.5 volts (9.2 watts—four randomly selected samples), 200 mg of liquid evaporated and was extracted in 20 mL of culture medium. Cigarette smoke (CS) extract from three tobacco cigarettes was produced according to ISO 3308 method (2 s puffs of 35 mL volume, one puff every 60 s). The extracts, undiluted (100%) and in four dilutions (50%, 25%, 12.5%, and 6.25%), were applied to myocardial cells (H9c2); percent-viability was measured after 24 h incubation. According to ISO 10993-5, viability of <70% was considered cytotoxic. Results: CS extract was cytotoxic at extract concentrations >6.25% (viability: 76.9 ± 2.0% at 6.25%, 38.2 ± 0.5% at 12.5%, 3.1 ± 0.2% at 25%, 5.2 ± 0.8% at 50%, and 3.9 ± 0.2% at 100% extract concentration). Three EC extracts (produced by tobacco leaves) were cytotoxic at 100% and 50% extract concentrations (viability range: 2.2%–39.1% and 7.4%–66.9% respectively) and one (“Cinnamon-Cookies” flavour) was cytotoxic at 100% concentration only (viability: 64.8 ± 2.5%). Inhibitory concentration 50 was >3 times lower in CS extract compared to the worst-performing EC vapour extract. For EC extracts produced by high-voltage and energy, viability was reduced but no sample was cytotoxic according to ISO 10993-5 definition. Vapour produced by the “base” liquid was not cytotoxic at any extract concentration. Cell survival was not associated with nicotine concentration of EC liquids. Conclusions: This study indicates that some EC samples have cytotoxic properties on cultured cardiomyoblasts, associated with the production process and materials used in flavourings. However, all EC vapour extracts were significantly less cytotoxic compared to CS extract.