A study on the epidemiology of Stevens-Johnson syndrome and toxic epidermal necrolysis

Pharmacoepidemiology is the science of the use and the effects of drugs in large human populations. Although originally confined to post-marketing drug surveillance of rare or long-latency adverse drug events, the science is gaining increased importance and is regularly applied to assess drug utilization patterns and cost-effectiveness, to characterize target populations of drugs in development, to evaluate undiscovered beneficial or detrimental drug effects, or to provide evidence of effectiveness when randomized controlled trials face ethical or practical barriers. Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but life-threatening mucocutaneous diseases that predominantly occur as adverse reactions to newly administered drugs. The current knowledge of SJS/TEN is sparse, mainly due to the rare nature of SJS/TEN and the long-time unclear classification of the disease. As a consequence many aspects of SJS/TEN remain unclear despite the severe impact of SJS/TEN on affected patients. The aim of this comprehensive SJS/TEN project presented within this thesis was to contribute to the general understanding of SJS/TEN, thereby focusing on the epidemiology and potential culprit drugs. The project comprises five individual observational studies using data from the Clinical Practice Research Datalink (CPRD). This United Kingdom (UK)-based database contains longitudinal primary-care records of millions of patients, representative of the UK population. Information is recorded by general practitioners and includes demographics, lifestyle factors, medical diagnoses, referrals to secondary care, laboratory and diagnostic results, and a complete history of drug prescriptions. In Study 3.1 we comprehensively validated incident SJS/TEN diagnoses recorded in the CPRD between 1995 and 2013. The aim of this study was to assess whether SJS/TEN can be studied using CPRD data, and to establish a large and valid SJS/TEN case population. Using diagnoses from secondary care as a gold standard, we managed to compose a case population consisting of 551 SJS/TEN patients with a positive predictive value of 90% in cooperation with two specialised clinicians. In Study 3.2 we calculated an overall incidence rate in the UK of 5.76 SJS/TEN cases/1’000’000 person-years, whereby incidence rates were highest in patients aged <10 or ≥80 years. In a case-control analysis, we further found that patients of black, Asian, or mixed ethnicity were at increased risk of SJS/TEN when compared to Caucasians, and observed associations between SJS/TEN and pre-existing depression, lupus erythematosus, chronic kidney disease, recent pneumonia, and active cancer. In the Studies 3.3, 3.4, and 3.5, we conducted case-control analyses to assess associations between SJS/TEN and drugs which have previously been associated with SJS/TEN. We furthermore calculated cumulative incidences of SJS/TEN for each of these drugs to assess the absolute risk of SJS/TEN among drug users. Study 3.3 confirms associations between SJS/TEN and the aromatic antiepileptics carbamazepine, phenytoin, and lamotrigine, with absolute risks of 20-46 SJS/TEN cases/100’000 new users. Conversely to previous reports we did not find any exposed cases for valproate, gabapentin and pregabalin despite high number of new users (>40’000). While previous case-control studies reported a strong association between SJS/TEN and cotrimoxazole (sulfamethoxazole+trimethoprim), Study 3.4 was the first to show an association between SJS/TEN and trimethoprim as a single agent with an absolute risk of 1 SJS/TEN case/100’000 users. Only few patients were exposed to sulfonamide antibiotics in the CPRD which is why we were not able to study associations for sulfamethoxazole and other anti-infective sulfonamides. This study further corroborates previously reported associations between SJS/TEN and use of penicillins, quinolones, cephalosporins, and macrolides (0.3-1.0 SJS/TEN cases/100’000 users). Study 3.5 confirms the previously reported association between SJS/TEN and allopurinol with an absolute risk of 6 SJS/TEN cases/100’000 new users. Further drugs identified as possible triggers of SJS/TEN were coxibs (1.9 cases/100’000 new users), sulfasalazine (4.3 cases/100’000 new users), mesalamine (3.8 cases/100’000 new users), mirtazapine (1.6 cases/100’000 new users), and fluoxetine (0.2 cases/100’000 new users). We further observed an association between SJS/TEN and proton pump inhibitors (0.5-1.3 cases/100’000 new users). However, proton pumps are often used in combination with other drugs (e.g nonsteroidal anti-inflammatory drugs) which could potentially confound such an association. Only little evidence previously suggested associations between SJS/TEN and these drugs. For various other drugs which have been suggested as culprit drugs of SJS/TEN in case reports (oxicam analgesics, benzodiazepines, citalopram, sertraline, paroxetine, venlafaxine, and phosphodiesterase-5 inhibitors), we did not find any exposed SJS/TEN cases despite a high number of new users (>100’000) in the CPRD. Our results suggest that these drugs appear to be at least relatively safe in terms of SJS/TEN. In summary, the population-based observational studies presented in this thesis contribute to the understanding of the epidemiology of SJS/TEN yielding the first calculated incidence rates of SJS/TEN in the UK and information on patients at higher risk of SJS/TEN. They further include comprehensive analyses of culprit drugs of SJS/TEN, which provide important evidence for the successful treatment of SJS/TEN patients, as early discontinuation of the culprit drug is crucial and often decisive for the outcome of SJS/TEN

JAK2 Unmutated Polycythaemia-Real-World Data of 10 Years from a Tertiary Reference Hospital.

(1) Background: Polycythaemia is defined by an increase in haemoglobin (Hb) concentration, haematocrit (Hct) or red blood cell (RBC) count above the reference range adjusted to age, sex and living altitude. JAK2 unmutated polycythaemia is frequent but under-investigated in original publications. In this retrospective cohort study, we investigated the clinical and laboratory data, underlying causes, management and outcomes of JAK2 unmutated polycythaemia patients. (2) Methods: The hospital database was searched to identify JAK2 unmutated patients fulfilling WHO 2016 Hb/Hct criteria for PV (Hb &gt;16.5 g/dL in men and &gt;16 g/dL in women, or Hct &gt; 49% in men and &gt;48% in women, or RBC mass &gt; 25% above mean normal predicted value) between 2008 and 2019. Clinical and laboratory data were collected and analysed. (3) Results: From 727,731 screened patients, 294 (0.04%) were included, the median follow-up time was 47 months. Epo and P50 showed no clear pattern in differentiating causes of polycythaemia. In 30%, the cause remained idiopathic, despite extensive work-up. Sleep apnoea was the primary cause, also in patients under 30. Around 20% had received treatment at any time, half of whom had ongoing treatment at the end of follow-up. During follow-up, 17.2% developed a thromboembolic event, of which 8.5% were venous and 8.8% arterial. The mortality was around 3%. (4) Conclusions: Testing for Epo and P50 did not significantly facilitate identification of underlying causes. The frequency of sleep apnoea stresses the need to investigate this condition. Idiopathic forms are common. A diagnostic flowchart based on our data is proposed here. NGS testing should be considered in young patients with persisting polycythaemia, irrespective of Epo and P50 levels

Structured frameworks to increase the transparency of the assessment of benefits and risks of medicines: current status and possible future directions

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Searching for gravitational waves from known pulsars

We present upper limits on the amplitude of gravitational waves from 28 isolated pulsars using data from the second science run of LIGO. The results are also expressed as a constraint on the pulsars' equatorial ellipticities. We discuss a new way of presenting such ellipticity upper limits that takes account of the uncertainties of the pulsar moment of inertia. We also extend our previous method to search for known pulsars in binary systems, of which there are about 80 in the sensitive frequency range of LIGO and GEO 600.Comment: Accepted by CQG for the proceeding of GWDAW9, 7 pages, 2 figure

Cyclic game dynamics driven by iterated reasoning

Recent theories from complexity science argue that complex dynamics are ubiquitous in social and economic systems. These claims emerge from the analysis of individually simple agents whose collective behavior is surprisingly complicated. However, economists have argued that iterated reasoning--what you think I think you think--will suppress complex dynamics by stabilizing or accelerating convergence to Nash equilibrium. We report stable and efficient periodic behavior in human groups playing the Mod Game, a multi-player game similar to Rock-Paper-Scissors. The game rewards subjects for thinking exactly one step ahead of others in their group. Groups that play this game exhibit cycles that are inconsistent with any fixed-point solution concept. These cycles are driven by a "hopping" behavior that is consistent with other accounts of iterated reasoning: agents are constrained to about two steps of iterated reasoning and learn an additional one-half step with each session. If higher-order reasoning can be complicit in complex emergent dynamics, then cyclic and chaotic patterns may be endogenous features of real-world social and economic systems.Comment: 8 pages, 4 figures, and supplementary informatio

The glaciers climate change initiative: Methods for creating glacier area, elevation change and velocity products

Glaciers and their changes through time are increasingly obtained from a wide range of satellite sensors. Due to the often remote location of glaciers in inaccessible and high-mountain terrain, satellite observations frequently provide the only available measurements. Furthermore, satellite data provide observations of glacier character- istics that are difficult to monitor using ground-based measurements, thus complementing the latter. In the Glaciers_cci project of the European Space Agency (ESA), three of these characteristics are investigated in detail: glacier area, elevation change and surface velocity. We use (a) data from optical sensors to derive glacier outlines, (b) digital elevation models from at least two points in time, (c) repeat altimetry for determining elevation changes, and (d) data from repeat optical and microwave sensors for calculating surface velocity. For the latter, the two sensor types provide complementary information in terms of spatio-temporal coverage. While (c) and (d) can be generated mostly automatically, (a) and (b) require the intervention of an analyst. Largely based on the results of various round robin experiments (multi-analyst benchmark studies) for each of the products, we suggest and describe the most suitable algorithms for product creation and provide recommendations concerning their practical implementation and the required post-processing. For some of the products (area, velocity) post-processing can influence product quality more than the main-processing algorithm

Amorphous and Polycrystalline Photoconductors for Direct Conversion Flat Panel X-Ray Image Sensors

In the last ten to fifteen years there has been much research in using amorphous and polycrystalline semiconductors as x-ray photoconductors in various x-ray image sensor applications, most notably in flat panel x-ray imagers (FPXIs). We first outline the essential requirements for an ideal large area photoconductor for use in a FPXI, and discuss how some of the current amorphous and polycrystalline semiconductors fulfill these requirements. At present, only stabilized amorphous selenium (doped and alloyed a-Se) has been commercialized, and FPXIs based on a-Se are particularly suitable for mammography, operating at the ideal limit of high detective quantum efficiency (DQE). Further, these FPXIs can also be used in real-time, and have already been used in such applications as tomosynthesis. We discuss some of the important attributes of amorphous and polycrystalline x-ray photoconductors such as their large area deposition ability, charge collection efficiency, x-ray sensitivity, DQE, modulation transfer function (MTF) and the importance of the dark current. We show the importance of charge trapping in limiting not only the sensitivity but also the resolution of these detectors. Limitations on the maximum acceptable dark current and the corresponding charge collection efficiency jointly impose a practical constraint that many photoconductors fail to satisfy. We discuss the case of a-Se in which the dark current was brought down by three orders of magnitude by the use of special blocking layers to satisfy the dark current constraint. There are also a number of polycrystalline photoconductors, HgI2 and PbO being good examples, that show potential for commercialization in the same way that multilayer stabilized a-Se x-ray photoconductors were developed for commercial applications. We highlight the unique nature of avalanche multiplication in a-Se and how it has led to the development of the commercial HARP video-tube. An all solid state version of the HARP has been recently demonstrated with excellent avalanche gains; the latter is expected to lead to a number of novel imaging device applications that would be quantum noise limited. While passive pixel sensors use one TFT (thin film transistor) as a switch at the pixel, active pixel sensors (APSs) have two or more transistors and provide gain at the pixel level. The advantages of APS based x-ray imagers are also discussed with examples

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo