6-thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity. Copyright (c) 2006 S. Karger AG, Basel

Paediatric Residents and Fellows Ethics (PERFEct) survey: Perceptions of European trainees regarding ethical dilemmas

With an increasingly complex healthcare environment, ethics is becoming a more critical part of medical education. We aimed to explore European paediatric trainees’ experiences of facing ethical dilemmas and their medical ethics education whilst assessing their perceptions of ethical dilemmas in current and future practice. The Young Sections of the European Academy of Paediatrics and European Society of Paediatric and Neonatal Intensive Care developed an explorative online survey covering demographics, ethical dilemmas faced and ethics training. The survey was made available in nine languages from November 2019 to January 2020 via newsletters and social media. Participants (n = 253) from 22 countries, predominantly female (82%) and residents (70%), with a median age of 29-years, completed the survey. The majority (58%) faced ethical dilemmas monthly or more frequently. Most ethics training was received by ethics lectures in medical school (81%) and on the job (60%). A disagreement between the healthcare team and patient/family was the most frequently faced moral dilemma (45%); the second was withholding/withdrawing life-prolonging measures (33%). The latter was considered the most challenging dilemma to resolve (50%). Respondents reported that ethical issues are not sufficiently addressed during their training and wished for more case-based teaching. Many have been personally affected by moral dilemmas, especially regarding withholding/withdrawing life-prolonging measures, and often felt inadequately supported. Conclusion: Paediatric trainees face many moral issues in daily practice and consider that training about managing current and future ethical dilemmas should be improved, such as by the provision of a core European paediatric ethics curriculum. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00431-021-04231-8

Orientifolds and the Refined Topological String

We study refined topological string theory in the presence of orientifolds by counting second-quantized BPS states in M-theory. This leads us to propose a new integrality condition for both refined and unrefined topological strings when orientifolds are present. We define the SO(2N) refined Chern-Simons theory which computes refined open string amplitudes for branes wrapping Seifert three-manifolds. We use the SO(2N) refined Chern-Simons theory to compute new invariants of torus knots that generalize the Kauffman polynomials. At large N, the SO(2N) refined Chern-Simons theory on the three-sphere is dual to refined topological strings on an orientifold of the resolved conifold, generalizing the Gopakumar-Sinha-Vafa duality. Finally, we use the (2,0) theory to define and solve refined Chern-Simons theory for all ADE gauge groups

Hamilton-Jacobi Renormalization for Lifshitz Spacetime

Just like AdS spacetimes, Lifshitz spacetimes require counterterms in order to make the on-shell value of the bulk action finite. We study these counterterms using the Hamilton-Jacobi method. Rather than imposing boundary conditions from the start, we will derive suitable boundary conditions by requiring that divergences can be canceled using only local counterterms. We will demonstrate in examples that this procedure indeed leads to a finite bulk action while at the same time it determines the asymptotic behavior of the fields. This puts more substance to the belief that Lifshitz spacetimes are dual to well-behaved field theories. As a byproduct, we will find the analogue of the conformal anomaly for Lifshitz spacetimes.Comment: 27 pages; minor improvements, references added, published versio

Classical integrability and quantum aspects of the AdS(3) x S(3) x S(3) x S(1) superstring

In this paper we continue the investigation of aspects of integrability of the type IIA AdS(3) x S(3) x S(3) x S(1) and AdS(3) x S(3) x T(4) superstrings. By constructing a one parameter family of flat connections we prove that the Green-Schwarz string is classically integrable, at least to quadratic order in fermions, without fixing the kappa-symmetry. We then compare the quantum dispersion relation, fixed by integrability up to an unknown interpolating function h(lambda), to explicit one-loop calculations on the string worldsheet. For AdS(3) x S(3) x S(3) x S(1) the spectrum contains heavy, as well as light and massless modes, and we find that the one-loop contribution differs depending on how we treat these modes showing that similar regularization ambiguities as appeared in AdS(4)/CFT(3) occur also here.Comment: 29 pages; v2: updated references and acknowledgmen

A risk profile for identifying community-dwelling elderly with a highrisk of recurrent falling: results of a 3-year prospective study

Introduction: The aim of the prospective study reported here was to develop a risk profile that can be used to identify community-dwelling elderly at a high risk of recurrent falling. Materials and methods: The study was designed as a 3-year prospective cohort study. A total of 1365 community-dwelling persons, aged 65 years and older, of the population-based Longitudinal Aging Study Amsterdam participated in the study. During an interview in 1995/1996, physical, cognitive, emotional and social aspects of functioning were assessed. A follow-up on the number of falls and fractures was conducted during a 3-year period using fall calendars that participants filled out weekly. Recurrent fallers were identified as those who fell at least twice within a 6-month period during the 3-year follow-up. Results: The incidence of recurrent falls at the 3-year follow-up point was 24.9% in women and 24.4% in men. Of the respondents, 5.5% reported a total of 87 fractures that resulted from a fall, including 20 hip fractures, 21 wrist fractures and seven humerus fractures. Recurrent fallers were more prone to have a fall-related fracture than those who were not defined as recurrent fallers (11.9% vs. 3.4%; OR: 3.8; 95% CI: 2.3-6.1). Backward logistic regression analysis identified the following predictors in the risk profile for recurrent falling: two or more previous falls, dizziness, functional limitations, weak grip strength, low body weight, fear of falling, the presence of dogs/cats in the household, a high educational level, drinking 18 or more alcoholic consumptions per week and two interaction terms (high educationx18 or more alcohol consumptions per week and two or more previous falls x fear of falling) (AUC=0.71). Discussion: At a cut-off point of 5 on the total risk score (range 0-30), the model predicted recurrent falling with a sensitivity of 59% and a specificity of 71%. At a cut-off point of 10, the sensitivity and specificity were 31% and 92%, respectively. A risk profile including nine predictors that can easily be assessed seems to be a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling. © International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Synthetic Oligodeoxynucleotide CpG Motifs Activate Human Complement through Their Backbone Structure and Induce Complement-Dependent Cytokine Release

Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone–dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p = 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2–deficient serum. CpG-B increased levels of IL-1β, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1–dependent cytokine release

ONCOR: design of the Dutch cardio-oncology registry

Background: The relative new subspecialty ‘cardio-oncology’ was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy–related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established. / Aim: The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice. / Methods: Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment. / Discussion: Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy–related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate

The low-energy limit of AdS(3)/CFT2 and its TBA

We investigate low-energy string excitations in AdS3 × S3 × T4. When the worldsheet is decompactified, the theory has gapless modes whose spectrum at low energies is determined by massless relativistic integrable S matrices of the type introduced by Al. B. Zamolodchikov. The S matrices are non-trivial only for excitations with identical worldsheet chirality, indicating that the low-energy theory is a CFT2. We construct a Thermodynamic Bethe Ansatz (TBA) for these excitations and show how the massless modes’ wrapping effects may be incorporated into the AdS3 spectral problem. Using the TBA and its associated Y-system, we determine the central charge of the low-energy CFT2 to be c = 6 from calculating the vacuum energy for antiperiodic fermions — with the vacuum energy being zero for periodic fermions in agreement with a supersymmetric theory — and find the energies of some excited states