Analysis of primary care electronic health record data of people living with hepatitis B virus: infection and hepatocellular carcinoma risk associated with socio-economic deprivation.

OBJECTIVES: We set out to characterise chronic hepatitis B (CHB) in the primary care population in England and investigate risk factors for progression to hepatocellular carcinoma (HCC). STUDY DESIGN: Retrospective cohort study. METHODS: We identified 8039 individuals with CHB in individuals aged ≥18 years between 1999 and 2019 in the English primary care database QResearch. HCC risk factors were investigated using Cox proportional hazards modelling. RESULTS: Most of those with a record of CHB were males (60%) of non-White ethnicity (>70%), and a high proportion were in the most deprived Townsend deprivation quintile (44%). Among 7029 individuals with longitudinal data, 161 HCC cases occurred. Increased HCC hazards were significantly associated with male sex (adjusted hazards ratio [aHR] 3.17, 95% confidence interval [95% CI] 1.92-5.23), in the fifth deprivation quintile as compared to the third quintile (aHR 1.69, 95% CI 1.01-2.84), with older age (for age groups 56-65 and ≥66 years, compared to 26-35 years, aHRs 2.82 [95% CI 1.45-5.46] and 3.76 [95% CI 1.79-7.9], respectively), Caribbean ethnicity (aHR 3.32, 95% CI 1.43-7.71, compared to White ethnicity), ascites (aHR 3.15, 95% CI 1.30-7.67), cirrhosis (aHR 6.55, 95% CI 4.57-9.38) and peptic ulcer disease (aHR 2.26, 95% CI 1.45-3.51). CONCLUSIONS: Targeting interventions and HCC surveillance at vulnerable groups is essential to improve CHB outcomes and to support progress towards international goals for the elimination of hepatitis infection as a public health threat.

Characteristics, management and outcome of a large necrotising otitis externa case series: need for standardised case definition.

BACKGROUND: Necrotising otitis externa is a severe ear infection for which there are no established diagnostic or treatment guidelines. METHOD: This study described clinical characteristics, management and outcomes for patients managed as necrotising otitis externa cases at a UK tertiary referral centre. RESULTS: A total of 58 (63 per cent) patients were classified as definite necrotising otitis externa cases, 31 (34 per cent) as probable cases and 3 (3 per cent) as possible cases. Median duration of intravenous and oral antimicrobial therapy was 6.0 weeks (0.49-44.9 weeks). Six per cent of patients relapsed a median of 16.4 weeks (interquartile range, 23-121) after stopping antimicrobials. Twenty-eight per cent of cases had complex disease. These patients were older (p = 0.042), had a longer duration of symptoms prior to imaging (p < 0.0001) and higher C-reactive protein at diagnosis (p = 0.005). Despite longer courses of intravenous antimicrobials (23 vs 14 days; p = 0.032), complex cases were more likely to relapse (p = 0.016). CONCLUSION: A standardised case-definition of necrotising otitis externa is needed to optimise diagnosis, management and research.

Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints.

UNLABELLED: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE: HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

Variational approximations to homoclinic snaking.

We investigate the snaking of localized patterns, seen in numerous physical applications, using a variational approximation. This method naturally introduces the exponentially small terms responsible for the snaking structure, which are not accessible via standard multiple-scales asymptotic techniques. We obtain the symmetric snaking solutions and the asymmetric "ladder" states, and also predict the stability of the localized states. The resulting approximate formulas for the width of the snaking region show good agreement with numerical results.

Variational approximations to homoclinic snaking in continuous and discrete systems.

Localized structures appear in a wide variety of systems, arising from a pinning mechanism due to the presence of a small-scale pattern or an imposed grid. When there is a separation of length scales, the width of the pinning region is exponentially small and beyond the reach of standard asymptotic methods. We show how this behavior can be obtained using a variational method, for two systems. In the case of the quadratic-cubic Swift-Hohenberg equation, this gives results that are in agreement with recent work using exponential asymptotics. In addition, the method is applied to a discrete system with cubic-quintic nonlinearity, giving results that agree well with numerical simulations.

Banting Memorial Lecture 2010

We are currently facing a global pandemic of obesity and Type 2 diabetes. In some settings, the population prevalence of Type 2 diabetes is 50%, and half of those affected will die from diabetes-related complications. Eight centuries ago, an epidemic of bubonic plague swept across Europe, killing at least half of its victims. We here draw comparisons between these two pandemics, proposing close analogies between the 'Black Death' of the 14th century and the modern-day equivalent of Type 2 diabetes. Both diseases can be considered in terms of an aetiological agent, a reservoir, a vector and a predisposing toxic environment; populations can be considered as highly susceptible to the transmissable agents of Type 2 diabetes in the setting of calorie excess, inadequate food labelling, poorly regulated advertising and sedentary lifestyles. As for tackling a pandemic of a contagious microbial pathogen, we believe that breaking the cycle of transmission in the diabetes epidemic must be underpinned by political will and prompt, decisive legislation backed by the medical community. Far from fearing that such measures edge us towards a 'nanny state', we believe individuals should expect a responsible government to safeguard them from the toxic milieu that puts them at risk of obesity and its complications, and that communities and populations have the right to have their health protected.

Staphylococcus lugdunensis endocarditis following cardiac catheterisation.

We report the case of a 77 year old with Staphylococcus lugdunensis endocarditis following cardiac catheterisation via a femoral approach. We underline the association between this pathogen and inguinal skin breaks, and discuss the potential diagnostic pitfalls in clinical and laboratory diagnosis.

Pattern formation in the damped Nikolaevskiy equation.

The Nikolaevskiy equation has been proposed as a model for seismic waves, electroconvection, and weak turbulence; we show that it can also be used to model transverse instabilities of fronts. This equation possesses a large-scale "Goldstone" mode that significantly influences the stability of spatially periodic steady solutions; indeed, all such solutions are unstable at onset, and the equation exhibits spatiotemporal chaos. In many applications, a weak damping of this neutral mode will be present, and we study the influence of this damping on solutions to the Nikolaevskiy equation. We examine the transition to the usual Eckhaus instability as the damping of the large-scale mode is increased, through numerical calculation and weakly nonlinear analysis. The latter is accomplished using asymptotically consistent systems of coupled amplitude equations. We find that there is a critical value of the damping below which (for a given value of the supercriticality parameter) all periodic steady states are unstable. The last solutions to lose stability lie in a cusp close to the left-hand side of the marginal stability curve.

Interactions between pattern formation and domain growth.

In this paper we develop a theoretical framework for investigating pattern formation in biological systems for which the tissue on which the spatial pattern resides is growing at a rate which is itself regulated by the diffusible chemicals that establish the spatial pattern. We present numerical simulations for two cases of interest, namely exponential domain growth and chemically controlled growth. Our analysis reveals that for domains undergoing rapid exponential growth dilution effects associated with domain growth influence both the spatial patterns that emerge and the concentration of chemicals present in the domain. In the latter case, there is complex interplay between the effects of the chemicals on the domain size and the influence of the domain size on the formation of patterns. The nature of these interactions is revealed by a weakly nonlinear analysis of the full system. This yields a pair of nonlinear equations for the amplitude of the spatial pattern and the domain size. The domain is found to grow (or shrink) at a rate that depends quadratically on the pattern amplitude, the particular functional forms used to model the local tissue growth rate and the kinetics of the two diffusible species dictating the resulting behaviour.

Airway emergency in tuberculosis.

We report a case of acute fatal stridor in a patient newly diagnosed with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection. No evidence of direct airway encroachment was identified at autopsy. We review mechanisms by which tuberculosis may cause stridor and discuss the implications of co-existent HIV infection with reference to the recent literature. The report highlights the need for recognition of acute or evolving airway compromise as an uncommon manifestation of tuberculosis.

Swift-Hohenberg model for magnetoconvection.

A model system of partial differential equations in two dimensions is derived from the three-dimensional equations for thermal convection in a horizontal fluid layer in a vertical magnetic field. The model consists of an equation of Swift-Hohenberg type for the amplitude of convection, coupled to an equation for a large-scale mode representing the local strength of the magnetic field. The model facilitates both analytical and numerical studies of magnetoconvection in large domains. In particular, we investigate the phenomenon of flux separation, where the domain divides into regions of strong convection with a weak magnetic field and regions of weak convection with a strong field. Analytical predictions of flux separation based on weakly nonlinear analysis are extended into the fully nonlinear regime through numerical simulations. The results of the model are compared with simulations of the full three-dimensional magnetoconvection problem.

Pattern formation on a sphere.

Pattern formation on the surface of a sphere is described by equations involving interactions of spherical harmonics of degree l. When l is even, the leading-order equations are determined uniquely by the symmetry, regardless of the physical context. Existence and stability results are found for even l up to l=12. Using either a variational or eigenvalue criterion, the preferred solution has icosahedral symmetry for l=6, l=10, and l=12. Numerical simulations of a model pattern-forming equation are in agreement with these theoretical predictions near onset and show more complex patterns further from onset.

Instability of convection in a fluid layer rotating about an oblique axis.

We analyze thermal convection in a fluid layer confined between isothermal horizontal boundaries at which the tangential component of the fluid stress vanishes. The layer rotates about an oblique, nearly vertical axis. Using a model set of equations for w, the horizontal planform of the vertical velocity component, and psi, a stream function related to a large-scale vertical vorticity field, we describe the instabilities of convection rolls. We show how the usual Küppers-Lortz instability, which leads to a continual precession of the roll pattern, can be suppressed by the oblique rotation vector. Of particular interest is the small-angle instability of rolls, to perturbations in the form of rolls that are almost aligned with the primary rolls; at finite Prandtl number, this instability is not prevented by the horizontal component of the rotation vector, unless this component is sufficiently strong, in which case stability is confined to small-amplitude rolls near the marginal stability boundary. A one-dimensional instability leading to amplitude-modulated rolls is unaffected by the oblique rotation. Numerical simulations of the model equations are presented, which illustrate the instabilities analyzed.

Sweet's syndrome associated with systemic inflammatory response syndrome.

Septic shock is characterised by infection causing a systemic inflammatory response, end-organ failure and acute circulatory collapse. Treatment consists of antimicrobial therapy and the supportive management of multi-organ failure. We report a case of what we believed to be septic shock due to pyelonephritis in a patient whose condition continued to deteriorate despite conventional treatment until the diagnosis of Sweet's syndrome was made. Once she was started on high dose steroids, her condition improved and she made a full recovery. We believe this to be the first case of a severe systemic inflammatory response syndrome associated with Sweet's syndrome.

Attempted murder of a newborn: a case history.

In this report we have examined the evaluation of a teenage mother who has attempted murder of her newborn. We have also assessed her for competency to mother the infant she attempted to murder and reassessed the outcome a year later. We argued in this case that with sufficient supervision and psycho-social counselling she could be given the possibility of parenting her infant. Upon follow-up a year later we found the child and mother to be supported within an extended family group and the mother managing the needs of her infant.