Determinants of label non-adherence to non-vitamin K oral anticoagulants in patients with newly diagnosed atrial fibrillation.

Aims: To evaluate the extent and determinants of off-label non-vitamin K oral anticoagulant (NOAC) dosing in newly diagnosed Dutch AF patients. Methods and results: In the DUTCH-AF registry, patients with newly diagnosed AF (<6 months) are prospectively enrolled. Label adherence to NOAC dosing was assessed using the European Medicines Agency labelling. Factors associated with off-label dosing were explored by multivariable logistic regression analyses. From July 2018 to November 2020, 4500 patients were registered. The mean age was 69.6 ± 10.5 years, and 41.5% were female. Of the 3252 patients in which NOAC label adherence could be assessed, underdosing and overdosing were observed in 4.2% and 2.4%, respectively. In 2916 (89.7%) patients with a full-dose NOAC recommendation, 4.6% were underdosed, with a similar distribution between NOACs. Independent determinants (with 95% confidence interval) were higher age [odds ratio (OR): 1.01 per year, 1.01-1.02], lower renal function (OR: 0.96 per ml/min/1.73 m2, 0.92-0.98), lower weight (OR: 0.98 per kg, 0.97-1.00), active malignancy (OR: 2.46, 1.19-5.09), anaemia (OR: 1.73, 1.08-2.76), and concomitant use of antiplatelets (OR: 4.93, 2.57-9.46). In the 336 (10.3%) patients with a reduced dose NOAC recommendation, 22.9% were overdosed, most often with rivaroxaban. Independent determinants were lower age (OR: 0.92 per year, 0.88-0.96) and lower renal function (OR: 0.98 per ml/min/1.73 m2, 0.96-1.00). Conclusion: In newly diagnosed Dutch AF patients, off-label dosing of NOACs was seen in only 6.6% of patients, most often underdosing. In this study, determinants of off-label dosing were age, renal function, weight, anaemia, active malignancy, and concomitant use of antiplatelets.

Family screening in patients with isolated bicuspid aortic valve : Restriction to those with aortic dilatation is not justified.

AIM: To determine the prevalence of undiagnosed bicuspid aortic valve (BAV) and isolated aortic dilatation in first-degree relatives (FDRs) of patients with isolated BAV and to explore the recurrence risk of BAV in different subgroups of probands with BAV. Recent American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines recommend family screening in patients with associated aortopathy only. METHODS: During follow-up visits, patients with isolated BAV received a printed invitation for their FDRs advising cardiac screening. RESULTS: From 2012-2019, 257 FDRs of 118 adult BAV patients were screened, among whom 63 (53%) index patients had undergone aortic valve surgery (AVS), including concomitant aortic replacement in 25 (21%). Of the non-operated index patients, 31 (26%) had aortic dilatation (> 40 mm). Mean age of the FDRs was 48 years (range 4-83) and 42% were male. The FDR group comprised 20 parents, 103 siblings and 134 offspring. Among these FDRs, 12 (4.7%) had a previously undiagnosed BAV and 23 (8.9%) had an isolated aortic dilatation. FDRs of the probands with previous AVS (n = 147) had a risk ratio for BAV of 2.25 (95% confidence interval (CI) 0.62-8.10). FDRs of the probands with BAV and repaired or unrepaired aortic dilatation (n = 127) had a risk ratio for BAV of 0.51 (95% CI 0.16-1.66). CONCLUSION: Screening FDRs of patients with isolated BAV resulted in a reasonable yield of 14% new cases of BAV or isolated aortic dilatation. A trend towards an increased risk of BAV in FDRs was observed in the probands with previous AVS, whereas this risk seemed to be diminished in the probands with associated aortic dilatation. This latter finding does not support the restrictive ACC/AHA recommendation.

The revised Atlanta criteria more accurately reflect severity of post-ERCP pancreatitis compared to the consensus criteria.

Background and objective: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most prevalent complication after ERCP with an incidence of 3.5%. PEP severity is classified according to either the consensus criteria or the revised Atlanta criteria. In this international cohort study we investigated which classification is the strongest predictor of PEP-related mortality. Methods: We reviewed 13,384 consecutive ERCPs performed between 2012 and 2017 in eight hospitals. We gathered data on all pancreatitis-related adverse events and compared the predictive capabilities of both classifications. Furthermore, we investigated the correlation between the two classifications and identified reasons underlying length of stay. Results: The total sample consisted of 387 patients. The revised Atlanta criteria have a higher sensitivity (100 vs. 55%), specificity (98 vs. 72%) and positive predictive value (58 vs. 5%). There is a significant difference (p < 0.001) between the two classifications. In 124 patients (32%), the length of stay was influenced by concomitant diseases. Conclusion: The revised Atlanta classification is superior in predicting mortality and better reflects PEP severity. This has important implications for researchers, clinicians and patients. For the diagnosis of PEP pancreatitis, the consensus criteria remain the golden standard. However, the revised Atlanta criteria are preferable for defining PEP severity.

Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review.

A number of prion diseases affect humans, including Creutzfeldt-Jakob disease; most of these are due to genetic mutations in the affected individual and occur sporadically, but some result from transmission of prion proteins from external sources. Of the known animal prion diseases, only bovine spongiform encephalopathy prions have been shown to be transmissible from animals to humans under non-experimental conditions. Chronic wasting disease (CWD) is a prion disease that affects cervids (e.g., deer and elk) in North America and isolated populations in Korea and Europe. Systematic review methodology was used to identify, select, critically appraise and analyse data from relevant research. Studies were evaluated for adherence to good conduct based on their study design following the Cochrane collaboration's approach to grading the quality of evidence and the strength of recommendations (GRADE). Twenty-three studies were included after screening 800 citations from the literature search and evaluating 78 full papers. Studies examined the transmissibility of CWD prions to humans using epidemiological study design, in vitro and in vivo experiments. Five epidemiological studies, two studies on macaques and seven studies on humanized transgenic mice provided no evidence to support the possibility of transmission of CWD prions to humans. Ongoing surveillance in the United States and Canada has not documented CWD transmission to humans. However, two studies on squirrel monkeys provided evidence that transmission of CWD prions resulting in prion disease is possible in these monkeys under experimental conditions and seven in vitro experiments provided evidence that CWD prions can convert human prion protein to a misfolded state. Therefore, future discovery of CWD transmission to humans cannot be entirely ruled out on the basis of current studies, particularly in the light of possible decades-long incubation periods for CWD prions in humans. It would be prudent to continue CWD research and epidemiologic surveillance, exercise caution when handling potentially contaminated material and explore CWD management opportunities.

Diagnosis of takotsubo cardiomyopathy is increasing over time in patients presenting as ST-elevation myocardial infarction.

BACKGROUND: Takotsubo cardiomyopathy often presents with the clinical signs of ST-elevation myocardial infarction (STEMI). The increase in scientific publications addressing this relatively rare condition may result in higher awareness and diagnosis of takotsubo cardiomyopathy. AIM: To assess the observed prevalence per year of takotsubo cardiomyopathy in a large registry of patients with STEMI, during a 12-year inclusion period. METHOD: All patients presenting with STEMI at a large regional cardiology clinic were entered into a database (n = 8,413, mean age 63 ± 13 years). Takotsubo cardiomyopathy was diagnosed in 42 patients (0.5 %). Years of evaluation were defined as 'early years' (January 2002 to December 2007; n = 4350) and 'later years' (January 2008 to December 2013). Multivariable analyses were performed to adjust for differences in demographical and clinical variables. RESULTS: In later years, the age of STEMI patients was slightly higher (64 ± 13 vs. 63 ± 13 years, p < 0.001), with more patients with clinical symptoms of shock (10 vs. 7 %, p < 0.001) or a history of percutaneous coronary intervention or hypertension (10 vs. 8 %, p = 0.001 and 37 vs. 34 %, p < 0.001). Smoking and a positive family history were less often observed during later years (39 vs. 46 %, p < 0.001 and 37 vs. 42 % p < 0.001). Patients with takotsubo cardiomyopathy were more often female (81 vs. 27 %, p = 0.001). Takotsubo cardiomyopathy was more often diagnosed in the later period (0.7 vs. 0.3 %, OR 2.4, 95 % CI 1.2-4.6, p = 0.009). The higher prevalence of takotsubo cardiomyopathy in recent years remained significant after adjustment for differences in patient characteristics (OR 2.1, 95 % CI 1.1-4.3). CONCLUSION: Takotsubo cardiomyopathy is currently more often diagnosed in patients with STEMI compared with in earlier years. This is probably due to the increased scientific and clinical awareness among doctors, but the prevalence is still low.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

Image plate characterization and absolute calibration to low kilo-electron-volt electrons.

We report on the characterization of an image plate and its absolute calibration to electrons in the low keV energy range (1-30 keV). In our case, an Agfa MD4.0 without protection layer was used in combination with a Fuji FLA7000 scanner. The calibration data are compared to other published data and a consistent picture of the sensitivity of image plates to electrons is obtained, which suggests a validity of the obtained calibration up to 100 keV.

NAIS: nuclear activation-based imaging spectroscopy.

In recent years, the development of high power laser systems led to focussed intensities of more than 10(22) W/cm(2) at high pulse energies. Furthermore, both, the advanced high power lasers and the development of sophisticated laser particle acceleration mechanisms facilitate the generation of high energetic particle beams at high fluxes. The challenge of imaging detector systems is to acquire the properties of the high flux beam spatially and spectrally resolved. The limitations of most detector systems are saturation effects. These conventional detectors are based on scintillators, semiconductors, or radiation sensitive films. We present a nuclear activation-based imaging spectroscopy method, which is called NAIS, for the characterization of laser accelerated proton beams. The offline detector system is a combination of stacked metal foils and imaging plates (IP). After the irradiation of the stacked foils they become activated by nuclear reactions, emitting gamma decay radiation. In the next step, an autoradiography of the activated foils using IPs and an analysis routine lead to a spectrally and spatially resolved beam profile. In addition, we present an absolute calibration method for IPs.

Probing the complex ion structure in liquid carbon at 100 GPa.

We present the first direct experimental test of the complex ion structure in liquid carbon at pressures around 100 GPa, using spectrally resolved x-ray scattering from shock-compressed graphite samples. Our results confirm the structure predicted by ab initio quantum simulations and demonstrate the importance of chemical bonds at extreme conditions similar to those found in the interiors of giant planets. The evidence presented here thus provides a firmer ground for modeling the evolution and current structure of carbon-bearing icy giants like Neptune, Uranus, and a number of extrasolar planets.

Energy loss and charge transfer of argon in a laser-generated carbon plasma.

This Letter reports on the measurement of the energy loss and the projectile charge states of argon ions at an energy of 4 MeV/u penetrating a fully ionized carbon plasma. The plasma of n(e)≈10(20) cm(-3) and T(e)≈180 eV is created by two laser beams at λ(Las)=532 nm incident from opposite sides on a thin carbon foil. The resulting plasma is spatially homogenous and allows us to record precise experimental data. The data show an increase of a factor of 2 in the stopping power which is in very good agreement with a specifically developed Monte Carlo code, that allows the calculation of the heavy ion beam's charge state distribution and its energy loss in the plasma.

Disease transmission model for community-associated Clostridium difficile infection.

Participating researchers and public health personnel at a Canadian workshop in 2007, noted considerable gaps in current understanding of community-associated Clostridium difficile infection (CA-CDI), specifically infection sources and risk factors. A disease transmission model for CA-CDI was requested as an initial step towards a risk assessment, to analyse infection sources and risk factors, addressing priority research areas. The developed model contains eight infection states (susceptible, gastrointestinal exposure, colonized, diseased, deceased, clinically resolved colonized, relapse diseased, and cleared) and notes directional transfers between the states. Most published research used focused on hospital-associated C. difficile infection (HA-CDI) and further studies are needed to substantiate the use of HA-CDI knowledge in the transmission of CA-CDI. The aim was to provide a consistent framework for researchers, and provide a theoretical basis for future quantitative risk assessment of CA-CDI.

Ultrafast melting of carbon induced by intense proton beams.

Laser-produced proton beams have been used to achieve ultrafast volumetric heating of carbon samples at solid density. The isochoric melting of carbon was probed by a scattering of x rays from a secondary laser-produced plasma. From the scattering signal, we have deduced the fraction of the material that was melted by the inhomogeneous heating. The results are compared to different theoretical approaches for the equation of state which suggests modifications from standard models.

Adherence to patient selection criteria in patients undergoing transcatheter aortic valve implantation with the 18F CoreValve ReValving System.

BACKGROUND: Anecdotal evidence suggests that transcatheter aortic valve implantation (TAVI) is being used beyond pre-market label indications. METHODS: To assess the frequency and outcomes associated with "off-label" use of TAVI, we conducted a retrospective study, examining adherence to patient selection criteria in 63 patients undergoing implantation with the 18F CoreValve ReValving System (CRS). Label status (on-label vs off-label) was determined by following (1) inclusion/exclusion criteria indicated in the 18F CRS safety and efficacy trial and (2) a patient selection matrix indicating anatomical boundaries to guide patient selection. Off-label use was defined as the presence of at least one exclusion criterion or "non-acceptable" criteria based on the patient selection matrix. RESULTS: Off-label implantation was identified in 42 patients (67%)-40% had one, 19% had two and 8% had three or more off-label criteria. Baseline demographics were similar between the groups except for a higher logistic EuroSCORE in the on-label group (19.8 (11.2) vs 14.5 (7.3), p = 0.029). There was no significant difference in the procedural success rates between the on-label and off-label groups (91% vs 95%, respectively, p = 0.47). The frequency of angiographic moderate-severe aortic regurgitation, post-implant dilatation or implantation of a second valve was also similar between the groups. At 30 days, the cumulative death rate was 10%; there were four deaths in the "on-label" and three deaths in the "off-label" group. CONCLUSION: In this study we found that "off-label" implantation of the CRS was common. Further studies are needed to evaluate the consequences of "label status" for patients undergoing TAVI.

Evolution of elastic x-ray scattering in laser-shocked warm dense lithium.

We have studied the dynamics of warm dense Li with near-elastic x-ray scattering. Li foils were heated and compressed using shock waves driven by 4-ns-long laser pulses. Separate 1-ns-long laser pulses were used to generate a bright source of 2.96 keV Cl Ly- alpha photons for x-ray scattering, and the spectrum of scattered photons was recorded at a scattering angle of 120 degrees using a highly oriented pyrolytic graphite crystal operated in the von Hamos geometry. A variable delay between the heater and backlighter laser beams measured the scattering time evolution. Comparison with radiation-hydrodynamics simulations shows that the plasma is highly coupled during the first several nanoseconds, then relaxes to a moderate coupling state at later times. Near-elastic scattering amplitudes have been successfully simulated using the screened one-component plasma model. Our main finding is that the near-elastic scattering amplitudes are quite sensitive to the mean ionization state Z[over ] and by extension to the choice of ionization model in the radiation-hydrodynamics simulations used to predict plasma properties within the shocked Li.

Immunocytochemical detection of ornithine decarboxylase.

Ornithine decarboxylase (ODC), a regulatory enzyme of polyamine biosynthesis, is involved in cell growth and differentiation. Lack of information about the exact cellular and subcellular localization of ODC is one of the main obstacles to precise interpretation of the biological roles of the ODC/polyamine system. Here we describe the development and optimization of an immunocytochemical method to detect ODC in cells and tissues. For this purpose a monoclonal antibody (MP16-2) against a defined epitope of ODC protein was developed. Specificity of the antibody for ODC was substantiated by Western blotting and ELISA analysis using cell and tissue homogenates. In cultured cells, optimal staining results were obtained after fixation with crosslinking fixatives followed by permeabilization with methanol. In rat tissues, ODC immunoreactivity was best preserved in paraffin sections fixed with Bouin's fixative. Antigen retrieval using SDS and citrate buffer substantially increased ODC immunostaining and decreased background staining. Localization studies of ODC in different cell lines showed that strongest staining for ODC was found in the nucleoplasm of mitotic cells, whereas confluent cells showed moderate perinuclear staining. Immunocytochemical studies of various rat tissues showed high cytoplasmic immunostaining of ODC in epithelial cells of kidney, prostate, and adrenal medulla of testosterone-treated rats, in glandular epithelium of small intestine, and in pancreas of neonatal and adult rats. (J Histochem Cytochem 47:1395-1404, 1999)

Intravenous immunoglobulin treatment in hematological diseases.

In the last decade large amounts of intravenous immunoglobulin (i.v.Ig) have been used worldwide. Doubts exist as to whether this increased use is paralleled by a comparable growth of reliable data on the therapeutic effectiveness of i.v.Ig. We performed a literature search using MEDLINE from January 1981 to January 1997 and analysed articles on the use of i.v.Ig in hematological disorders and searched for published guidelines. For most hematological disorders, evidence to use i.v.Ig as first line therapy is not very strong. For many disorders no controlled trials have been performed. In published guidelines, i.v.Ig is only recommended, with a few exceptions, when other treatments have failed or are contraindicated. Therefore the increase of consumption of i.v.Ig can not be explained by an increase in established indications in hematology.

Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.

Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant multisystem disorder caused by the expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK protein kinase gene on chromosome 19q13.3 (refs 1-3). Although the DM mutation was identified more than five years ago, the pathogenic mechanisms underlying this most prevalent form of hereditary adult neuromuscular disease remain elusive. Previous work from our laboratory demonstrated that a DNase l-hypersensitive site located adjacent to the repeats on the wild-type allele is eliminated by repeat expansion, indicating that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Analysis of DMAHP expression in the cells of DM patients with loss of the hypersensitive site revealed a two- to fourfold reduction in steady-state DMAHP transcript levels relative to wild-type controls. Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wild-type allele. Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis.

Pain characteristics help to predict the analgesic efficacy of radiotherapy for the treatment of cancer pain.

It is recognised that radiotherapy provides relief for intractable pain in approximately 50% of patients with cancer pain. Unfortunately, traditional explanatory variables, such as age, gender, histology or radiation dose, do not help to predict which individuals will benefit from palliative radiotherapy. A non-randomised prospective clinical trial was conducted on 51 patients to evaluate the value of pain characteristics as new explanatory variables for predicting the efficacy of palliative radiotherapy for providing cancer pain relief. Two new explanatory variables were identified: the presence of radiating pain and the pain score before radiotherapy.

Inactivation of MyoD-mediated expression of p21 in tumor cell lines.

The basic helix-loop-helix protein MyoD induces muscle structural gene expression and cell cycle withdrawal in many nontransformed cell lines. We show that MyoD activation of transcription of the cyclin-dependent kinase inhibitor p21 does not require synthesis of an intermediary protein. In most of the rhabdomyosarcoma and other solid tumor cell lines that we analyzed, p21 levels were abnormally low and correlated with the combined inactivity of MyoD and p53, two known transcriptional activators of p21. Loss of MyoD activation of p21 transcription correlated with the failure to arrest in G1, and expression of p21 caused accumulation of cells in G1, further supporting a role for p21 in MyoD-induced cell cycle arrest. Finally, different tumor types have inactivated distinct factors necessary for p21 expression, because p21 expression was reconstituted in hybrid cell lines. We propose that p21 integrates growth-inhibitory signals from independent p53 and basic helix-loop-helix pathways, and that in the majority of tumor cell lines, both pathways are abrogated.

[Asystole due to complex partial epilepsy]. / Asystolie door complexe partiële epilepsie.

A 56-year-old man was seen in the Emergency Room because of sudden and transient loss of consciousness. An asystole was diagnosed with 10 S duration after which a pacemaker was implanted. The patient had experienced such collapses before, preceded by odd smell sensations. After the implantation of the pacemaker, the patient did not collapse again but still experienced attacks of the same smell sensations combined with a strange feeling in his stomach. An EEG, recorded during such an attack, showed epileptic activity predominantly over the right hemisphere while at the same moment a pacemaker rhythm was observed. After the epileptic activity had stopped, normal sinus rhythm reappeared. On anticonvulsant therapy the attacks disappeared completely.