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Severe tuberculosis in London: Investigation of factors contributing to tuberculosis severity and deaths in London between 2010 and 2021
No full textTuberculosis continues to cause significant morbidity and mortality, even in countries considered to have low-tuberculosis incidence globally. The true case:fatality ratio for tuberculosis is not known for a number of reasons including unidentified infections, late sequelae, and misattribution of deaths on national registers and vital registration. As a result studies of risk factors for all-cause mortality on tuberculosis treatment may incorrectly emphasise the contribution of comorbidities and age as the study population include non-TB deaths. The situation has been further complicated by the COVID-19 pandemic which has introduced many barriers to accessing healthcare for an already vulnerable patient group.
To address the issue of misattribution all TB deaths from Public Health England records and the London TB register for two high-incidence areas of London were reviewed to establish cause of death, and where tuberculosis contributed, were included in an age-matched case-control study to identify risk factors for death. In addition, morbidity and mortality risk factors for two further groups were explored: people admitted to intensive care with tuberculosis, and TB-COVID-19 coinfected patients in 2020. Impact of COVID-19 on local tuberculosis services was also reviewed.
Of 313 deaths, 242 were either directly or indirectly caused by tuberculosis, and 29 of these had tuberculosis diagnosed post-mortem. Significant adjusted risk factors for TB-caused deaths included thrombocytopenia, hypoalbuminaemia and pulmonary tuberculosis. Hypoalbuminaemia and either severe pulmonary TB, or secondary respiratory infection or failure were consistent risk factors across other groups including TB-contributed deaths, pulmonary TB deaths and deaths in-hospital following intensive care. While TB-COVID-19 coinfection was not associated with increased mortality, there was a sharp increase in diagnosis of disseminated TB following early pandemic lockdown measures with consequent morbidity.
Correct attribution and detailed understanding of the factors contributing to TB-deaths will help services support the most vulnerable patients and strengthen response to future crises.Open Acces
Multilevel regularized Newton methods with fast convergence rates
No full textWe introduce new multilevel methods for solving large-scale unconstrained optimization problems. Specifically, the philosophy of multilevel methods is applied to Newton-type methods that regularize the Newton subproblem using second-order information from a coarse (low dimensional) subproblem. The new regularized multilevel methods provably converge from any initialization point and enjoy faster convergence rates than gradient descent. In particular, for arbitrary functions with Lipschitz continuous Hessians, we show that their convergence rate interpolates between the rate of gradient descent and that of the cubic Newton method. If, additionally, the objective function is assumed to be convex, then the proposed method converges with the fast O(−2) rate. Hence, since the updates are generated using a coarse model in low dimensions, the theoretical results of this paper significantly speed up the convergence of Newton-type or preconditioned gradient methods in practical applications. Preliminary numerical results suggest that the proposed multilevel algorithms are significantly faster than current state-of-the-art methods
Left atrial reservoir strain predicts atrial fibrillation in hypertrophic cardiomyopathy
No full textDevelopment of an acoustic dose-profile measurement technique for short pulse proton and ion beams
No full textCancer is the second leading cause of death globally, with radiotherapy treating about 50\% of patients. Conventional radiotherapy uses photons, however, it often irradiates healthy cells surrounding the cancerous region. New treatment facilities are turning to protons and light ions, which deposit a maximum dose within a small volume at the end of their range.
This thesis introduces LhARA, the Laser-hybrid Accelerator for Radiobiological Applications, which aims to advance radiobiology by exploring how different particle beam characteristics affect therapeutic outcomes. Using pulsed proton and light-ion beams, LhARA offers flexibility in ion species, beam widths, and pulse duration.
To minimize uncertainties, real-time dose delivery monitoring is essential. This work presents the SmartPhantom, a novel detector for monitoring three-dimensional dose accumulation delivered using nanosecond-scale ion beam pulses. Unlike existing devices that provide only relative dose values, the SmartPhantom delivers calibrated feedback.
The detector uses ultrasound waves induced by the transient pressure increase as the beam propagates through matter. Due to the high speed of ultrasound, feedback is nearly instantaneous. To calibrate the acoustic response, a liquid scintillator is used as the propagating medium inside the detector. The scintillation light emitted during beam propagation, combined with known photon yields, enables absolute dose reconstruction.
The SmartPhantom was evaluated at the MC40 cyclotron in Birmingham and the LION accelerator at CALA in Munich. To optimize the design, a simulation pipeline was developed using Python for source parametrization, BDSIM for particle tracking, Geant4 for energy deposition calculations, and Matlab for acoustic modeling.
The results revealed strong correlation between optical and acoustic measurements, validating the detector's potential. This lays the foundation for a clinically viable, real-time dose monitoring system.Open Acces
Broadening the lens: a commentary on Sheard and Cauana-Finkel's account of women's progress in UK academic health economics
No full textStructure prediction and engineering of de novo proteins
No full textDe novo proteins represent a challenging frontier at the intersection of evolutionary biology and synthetic biology. Broadly, the term encompasses two distinct categories: naturally evolved de novo proteins, which arise from previously non-coding DNA, and synthetically designed de novo proteins, which are created from scratch through computational and experimental methods. This review provides an overview of the definitions, history, functional significance, and investigation methods for both categories. By examining potential challenges in current de novo protein research, this review highlights the growing convergence between natural evolutionary processes and rational protein engineering, reflecting their importance in biological discovery and human innovations
Continuous infusion of Beta-Lactams in the critically ill: considerations for global implementation
No full textβ-lactam antibiotics are the most commonly used antibiotics for the empiric and targeted treatment of infection in the critically ill. Timely administration of an effective dose of β-lactams is critical to reduce infection-associated morbidity and mortality.
Continuous infusion (CI) of β-lactam antibiotics is now an evidence-based strategy to optimise treatment in critically ill patients with infection. However, the widespread implementation of CI of β-lactams requires consideration of various practical and pharmaceutical related factors.
The following addresses barriers to the implementation of CI of β-lactam antibiotics, including specific considerations for low resource settings, and aims to provide practical solutions for the translation of evidence into practice
Significance of the amino acid at position 2561 in the C4 domain of Von Willebrand factor
No full textBackground
The von Willebrand factor (VWF) Phe2561Tyr variant has been previously shown to exhibit gain-of-function–like activity and increase the risk of repeated myocardial infarction in patients aged <55 years. It was hypothesized that altered stem dynamics enhanced the responsiveness of the molecule to shear stress.
Objectives
In this study, we investigated the evolutionary significance of the amino acid at position 2561 and functional impacts of variants at this site.
Methods
Variants at 2561 identified by protein sequence alignments were generated by mutagenesis and expressed in HEK293T cells and function investigated using static and flow-based assays and biophysical methods.
Results
Phe2561 was heavily conserved in mammals; however, nonmammals occupied the site with tyrosine, threonine, or serine. Recombinant expression of Phe2561Tyr/Thr/Ser showed no effects on expression, multimers, collagen or glycoprotein IIbIIIa binding, but Ser2561 and Thr2561 demonstrated enhanced binding to gain-of-function glycoprotein Ibα. While none of the variants, including Tyr2561, enhanced VWF-mediated platelet capture to collagen at 1500/s or 5000/s, the Tyr2561, Ser2561, and Thr2561 variants exhibited enhanced formation of rolling VWF-platelet aggregates, with Ser2561 demonstrating the greatest gain-of-function activity. Optical tweezer pulling experiments using VWF-D'CK dimers revealed altered unfolding properties of the Tyr, Thr, and Ser2561 protein and atomic force microscopy imaging of VWF dimeric stems demonstrated that Tyr, Thr, and Ser2561 favored a more open stem state, suggesting this is responsible for the enhanced response to shear stress.
Conclusion
This study indicates that the amino acid at 2561 is crucial for modulating VWF function by helping to mediate stem dynamics
Recognising the neurological burden of onchocerciasis: the need to include onchocerciasis-associated epilepsy in onchocerciasis global health metrics
No full textBackground
Historically, onchocerciasis has been recognised for its dermatological and ophthalmological manifestations, such as blindness. However, growing epidemiological evidence indicates that onchocerciasis is also associated with neurological complications, particularly onchocerciasis-associated epilepsy (OAE). These complications are not currently reflected in disease burden estimates and associated disability-adjusted life years (DALYs) for onchocerciasis.
Main text
The most recent global burden of disease estimates for onchocerciasis in 2019 reported 1.23 million DALYs without accounting for OAE. Yet, a preliminary study suggested that 128,000 years of life lost to disability (YLD, a key component of DALYs) may be attributable to epilepsy in onchocerciasis-endemic areas of East and Central Africa. This figure, which would represent over 13% of the total onchocerciasis morbidity burden and 10% of the global epilepsy morbidity burden, is likely still an underestimation. Current disability weights for epilepsy YLD estimation may not fully capture the spectrum of OAE, which often involves nodding syndrome, developmental delays, motor disabilities, cognitive impairments and stigma. In regions where access to antiseizure medication treatment is sparse, poorly controlled seizures can exacerbate disability and lead to premature mortality. Targeted integrated strategies—combining onchocerciasis control measures with improved epilepsy care—could help address these critical gaps.
Conclusions
Recognising OAE as part of the disease burden associated with onchocerciasis may encourage global health stakeholders to allocate resources for targeted interventions, thereby refining disease burden estimates, reducing disability, averting premature deaths and improving overall health outcomes