Steroid prescribing in primary care increases prior to Hodgkin lymphoma diagnosis: A UK nationwide case-control study

Background: Steroid use is associated with increased risk of Hodgkin lymphoma (HL). However, allergic symptoms commonly treated with steroids are also presenting features of HL in some patients, thereby introducing protopathic bias in estimates of aetiological associations. It is therefore important to examine steroid prescribing patterns pre-diagnosis to understand timing of associations and when healthcare use increases before cancer diagnosis to inform future epidemiological study design. Methods: We analysed steroid prescribing in 1232 HL patients and 7392 matched controls using primary care electronic health records (Clinical Practice Research Datalink (CPRD), 1987–2016). Using Poisson regression, we calculated monthly steroid prescribing rates for the 24-months preceding HL diagnosis, identifying the inflection point when they start to increase from baseline in cases, comparing rates with synchronous controls, and stratifying by route-of-administration and allergic disease status. Results: 46 % of HL patients had a steroid prescription in the 24-months preceding diagnosis compared to 26 % of controls (OR 2.55, 95 %CI 2.25–2.89, p < 0.001). Odds of underlying HL were greatest in patients receiving multiple steroid prescriptions, oral steroids and in patients with a new allergic disease diagnosis. Among HL patients, steroid prescribing rates increased progressively from 7-months pre-diagnosis, doubling from 52 to 111 prescriptions/1000 patients/month. Conclusion: Steroid prescribing increases during periods leading up to HL diagnosis, suggesting steroid-treated symptoms may be early presenting features of HL. A diagnostic window of appreciable length exists for potential earlier HL diagnosis in some patients; this 7-month ‘lag-period’ pre-diagnosis should be excluded in studies examining aetiological associations between steroids and HL

The importance of phase dynamics in generation of coherent structures

In magnetically confined plasmas (MCP), the transport of heat and particles is determined by collisional and anomalous processes caused by turbulence. A collective effort has been put into modelling the turbulent transport in plasmas using various drift wave (DW) models. However, it is evident that large-scale phenomena have a significant impact on overall transport. Heat transport can be mediated by coherent structures such as streamers and blobs through the formation of avalanche-like events that are intermittent in nature, i.e., localized in time but of large amplitude. Furthermore, at the same time, there are structures such as zonal flows (ZF) and GAMs that are non-linearly generated and mitigate turbulent transport by shearing turbulent eddies. A common denominator for these large-scale structures is the synchronization of smaller scale modes or events to a coherent structure, where phases align in a localized region of space and time. Interestingly, phase synchronization is prevalent in many other fields, such as biological clocks, physiological organisms, and chemical reactors. The dynamical evolution of amplitude and phases have been investigated through simplified equations derived from the Hasegawa - Wakatani (HW) system, where effects of synchronization are studied.Theoretical studies often deal with the amplitudes of the fluctuating quantities and assume that the phases are randomly distributed according to the random phase approximation (RPA) and thus disregard the dynamics of the phases [1,2]. In this approximation, dynamical amplitudes have a slow variation compared to the rapid change of the phases, which are distributed uniformly over a $2 \pi$ interval [3]. There have been a few general approaches to the randomness in turbulence: the RPA, the diagrammatic method by Wyld and the cumulant expansions, with the aim of systematically characterizing intermittent behavior. Unless a specific case is studied, the diagrammatic method has a drawback since there is no consistent small expansion parameter and no normalization procedure available. Moreover, the intuitive picture of the RPA approach is tempting and is thus widely adopted in turbulence theory. The underlying assumption of randomness in the RPA for the phases of Fourier modes in nonlinearly interacting waves cannot be justified since the phases as well as the amplitudes evolve due to non-linear interactions that act on the same time scales for both. Thus, the phases cannot be randomized faster than the amplitudes, see further discussion in Refs. [4,5]. Understanding the generation of coherent structures and the effects of these structures on transport and turbulence is therefore of crucial importance. In regard to plasma dynamics, simplified models are of interest, assuming an expansion of the state in amplitude and phase, i.e., $\phi \sim \phi_0 \exp(i \theta)$, the basic dynamical equations yield one dynamical equation for the amplitude and one for the phase for each field in the model. In previous papers, models using the passive advected scalar [6] and the Burgers equation [1] where it was found that under certain conditions, the RPA assumption can be invalidated using a phase dependent force and the locking of phases may increase the energy transfer to other modes. The assumption of a fully stochastic phase state of the turbulence is more relevant for high values of scale separation with the energy spectrum following a $k^{−7/2}$ decay rate. The dynamic of the three-body interactions between the phases in the non-linear Burgers’ turbulence shows that the phases lock intermittently. This is due to the k dependence of the coupling strength in the non-linear term which reduces strongly for high-k range due to the dampening effect of the dissipation which does not allow locking of the phases of the small scales. For lower scale dependence the asynchronized and synchronized phases differ significantly, and one could expect the formation of coherent modulations in the latter case. Moreover, the HW have been studied [7] and the work on the predator-prey model of DW – ZF dynamics, it is observed that synchronization may be transferred between the two populations [8].In this work, we investigate the role of phase dynamics for turbulent fluctuations in a set of direct numerical simulation (DNS) of homogeneous Taylor-Green driven turbulence, simple 2D rotating turbulence flow. The model is the forced incompressible magnetohydrodynamic (MHD) equations. It should be noted that in the study of coupled oscillators describing chemical reactors, the Kuramoto model has been established, and it has been shown that synchronization occurs when a certain threshold is exceeded. In this case the system is strongly forced to generate a vortex and where the phase locking between close neighbours can be quantified

Reversal of particle flux in collisional-finite beta tokamak discharges

The mixed gradient method [Zhong et al. Phys. Rev. Lett. 111, 265001 (2013)] is adopted and effects of collisions and finite beta are included in the Weiland 9-equation fluid model. The particle flux and particle pinch, obtained using the Weiland anomalous transport fluid model, are compared with Tore Supra experimental results. Particle transport is also studied using predictive simulation data for an experimental advanced superconducting tokamak discharge in which neutral beam heating is utilized. The effects of collisions on particle transport are studied by turning collisions on and off in the Weiland model. It is found that the particle pinch region is related to the mode structure. The particle pinch region coincides with the region where the strong ballooning modes are present due to large gradients. The general properties of the fluid model are examined by finding regions where collisions can enhance the particle pinch

Hypoalbuminaemia predicts outcome in adult patients with congenital heart disease

Background In patients with acquired heart failure, hypoalbuminaemia is associated with increased risk of death. The prevalence of hypoproteinaemia and hypoalbuminaemia and their relation to outcome in adult patients with congenital heart disease (ACHD) remains, however, unknown. Methods Data on patients with ACHD who underwent blood testing in our centre within the last 14 years were collected. The relation between laboratory, clinical or demographic parameters at baseline and mortality was assessed using Cox proportional hazards regression analysis. Results A total of 2886 patients with ACHD were included. Mean age was 33.3 years (23.6–44.7) and 50.1% patients were men. Median plasma albumin concentration was 41.0 g/L (38.0–44.0), whereas hypoalbuminaemia (<35 g/L) was present in 13.9% of patients. The prevalence of hypoalbuminaemia was significantly higher in patients with great complexity ACHD (18.2%) compared with patients with moderate (11.3%) or simple ACHD lesions (12.1%, p<0.001). During a median follow-up of 5.7 years (3.3–9.6), 327 (11.3%) patients died. On univariable Cox regression analysis, hypoalbuminaemia was a strong predictor of outcome (HR 3.37, 95% CI 2.67 to 4.25, p<0.0001). On multivariable Cox regression, after adjusting for age, sodium and creatinine concentration, liver dysfunction, functional class and disease complexity, hypoalbuminaemia remained a significant predictor of death. Conclusions Hypoalbuminaemia is common in patients with ACHD and is associated with a threefold increased risk of risk of death. Hypoalbuminaemia, therefore, should be included in risk-stratification algorithms as it may assist management decisions and timing of interventions in the growing ACHD population

Pregabalin for the treatment of generalized anxiety disorder: an update

A previous review summarized what was then known about the potential role of pregabalin in the treatment of patients with generalized anxiety disorder (GAD): this review provides an update on its pharmacological properties and presumed mechanism of action, the liability for abuse, and efficacy and tolerability in patients with GAD. Pregabalin has a similar molecular structure to the inhibitory neurotransmitter gamma amino butyric acid (GABA) but its mechanism of action does not appear to be mediated through effects on GABA. Instead, its anxiolytic effects may arise through high-affinity binding to the alpha-2-delta sub-unit of the P/Q type voltage-gated calcium channel in “over-excited” presynaptic neurons, thereby reducing the release of excitatory neurotransmitters such as glutamate. The findings of randomized controlled trials and meta-analyses together indicate that pregabalin is efficacious in both acute treatment and relapse prevention in GAD, with some evidence of an early onset of effect, and broad efficacy in reducing the severity of psychological and physical symptoms of anxiety. It also has efficacy as an augmenting agent after non-response to antidepressant treatment in GAD. Continuing vigilance is needed in assessing its potential abuse liability but the tolerability profile of pregabalin may confer some advantages over other pharmacological treatments in the short term for treatment in patients with GAD

Does changing healthcare use signal opportunities for earlier detection of cancer? A review of studies using information from electronic patient records

BACKGROUND: It has been proposed that changes in healthcare use before cancer diagnosis could signal opportunities for quicker detection, but systematic appreciation of such evidence is lacking. We reviewed studies examining pre-diagnostic changes in healthcare utilisation (e.g. rates of GP or hospital consultations, prescriptions or diagnostic tests) among patients subsequently diagnosed with cancer. METHODS: We identified studies through Pubmed searches complemented by expert elicitation. We extracted information on the earliest time point when diagnosis could have been possible for at least some cancers, together with variation in the length of such 'diagnostic windows' by tumour and patient characteristics. RESULTS: Across twenty-eight studies, changes in healthcare use were observable at least six months pre-diagnosis for many common cancers, and potentially even earlier for colorectal cancer, multiple myeloma and brain tumours. Early changes were also identified for brain and colon cancer sub-sites. CONCLUSION: Changing healthcare utilisation patterns before diagnosis indicate that future improvements in diagnostic technologies or services could help to shorten diagnostic intervals for cancer. There is greatest potential for quicker diagnosis for certain cancer types and patient groups, which can inform priorities for the development of decision support tools

Wireless recording of the calls of Rousettus aegyptiacus and their reproduction using electrostatic transducers

Bats are capable of imaging their surroundings in great detail using echolocation. To apply similar methods to human engineering systems requires the capability to measure and recreate the signals used, and to understand the processing applied to returning echoes. In this work, the emitted and reflected echolocation signals of Rousettus aegyptiacus are recorded while the bat is in flight, using a wireless sensor mounted on the bat. The sensor is designed to replicate the acoustic gain control which bats are known to use, applying a gain to returning echoes that is dependent on the incurred time delay. Employing this technique allows emitted and reflected echolocation calls, which have a wide dynamic range, to be recorded. The recorded echoes demonstrate the complexity of environment reconstruction using echolocation. The sensor is also used to make accurate recordings of the emitted calls, and these calls are recreated in the laboratory using custom-built wideband electrostatic transducers, allied with a spectral equalization technique. This technique is further demonstrated by recreating multi-harmonic bioinspired FM chirps. The ability to record and accurately synthesize echolocation calls enables the exploitation of biological signals in human engineering systems for sonar, materials characterization and imaging

Timed Implementation Relations for the Distributed Test Architecture

In order to test systems that have physically distributed interfaces, called ports, we might use a distributed approach in which there is a separate tester at each port. If the testers do not synchronise during testing then we cannot always determine the relative order of events observed at different ports and this leads to new notions of correctness that have been described using corresponding implementation relations. We study the situation in which each tester has a local clock and timestamps its observations. If we know nothing about how the local clocks relate then this does not affect the implementation relation while if the local clocks agree exactly then we can reconstruct the sequence of observations made. In practice, however, we are likely to be between these extremes: the local clocks will not agree exactly but we have some information regarding how they can differ. We start by assuming that a local tester interacts synchronously with the corresponding port of the system under test and then extend this to the case where communications can be asynchronous, considering both the first-in-first-out (FIFO) case and the non-FIFO case. The new implementation relations are stronger than implementation relations for distributed testing that do not use timestamps but still reflect the distributed nature of observations. This paper explores these alternatives and derives corresponding implementation relations

Allergic disease, corticosteroid use and risk of Hodgkin's lymphoma: A UK Nationwide case-control study

BACKGROUND: Immunodeficiency syndromes (acquired/congenital/iatrogenic) are known to increase Hodgkin's lymphoma (HL) risk, but the effect of allergic immune dysregulation and corticosteroids are poorly understood. OBJECTIVE: To assess the risk of HL associated with allergic disease (asthma, eczema and allergic rhinitis) and corticosteroid use. METHODS: We conducted a case-control study using the UK Clinical Practice Research Datalink (CPRD) linked to hospital data. Multivariable logistic regression investigated associations between allergic diseases and HL after adjusting for established risk factors. Potential confounding or effect modification by steroid treatment were examined. RESULTS: 1,236 cases of HL were matched to 7,416 controls. Immunosuppression was associated with 6-fold greater odds of HL (Adjusted Odds Ratio (AOR), 6.18; 95%CI, 3.04-12.57), with minimal change after adjusting for steroids. Any prior allergic disease or eczema alone were associated with 1.4-fold increased odds of HL (AOR, 1.41; 95%CI, 1.24-1.60; AOR, 1.41; 95%CI, 1.20-1.65, respectively). These associations decreased but remained significant after adjustment for steroids (AOR, 1.25; 95%CI, 1.09-1.43; AOR, 1.27; 95%CI, 1.08-1.49, respectively). There was no effect modification by steroid use. Previous steroid treatment was associated with 1.4-fold greater HL odds (AOR, 1.38; 95%CI, 1.20-1.59). CONCLUSIONS: In addition to established risk factors (immunosuppression and infectious mononucleosis), allergic disease and eczema are risk factors for developing HL. This association is only partially explained by steroids, which are associated with increased HL risk. These findings add to the growing evidence that immune system malfunction, following allergic disease or immunosuppression, is central to HL development