The role of DSC MR perfusion in predicting IDH mutation and 1p19q codeletion status in gliomas: meta-analysis and technical considerations

Purpose: Isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion status are important for managing glioma patients. However, current practice dictates invasive tissue sampling for histomolecular classification. We investigated the current value of dynamic susceptibility contrast (DSC) MR perfusion imaging as a tool for the non-invasive identification of these biomarkers. Methods: A systematic search of PubMed, Medline, and Embase up to 2023 was performed, and meta-analyses were conducted. We removed studies employing machine learning models or using multiparametric imaging. We used random-effects standardized mean difference (SMD) and bivariate sensitivity-specificity meta-analyses, calculated the area under the hierarchical summary receiver operating characteristic curve (AUC) and performed meta-regressions using technical acquisition parameters (e.g., time to echo [TE], repetition time [TR]) as moderators to explore sources of heterogeneity. For all estimates, 95% confidence intervals (CIs) are provided. Results: Sixteen eligible manuscripts comprising 1819 patients were included in the quantitative analyses. IDH mutant (IDHm) gliomas had lower rCBV values compared to their wild-type (IDHwt) counterparts. The highest SMD was observed for rCBVmean, rCBVmax, and rCBV 75th percentile (SMD≈ − 0.8, 95% CI ≈ [− 1.2, − 0.5]). In meta-regression, shorter TEs, shorter TRs, and smaller slice thicknesses were linked to higher absolute SMDs. When discriminating IDHm from IDHwt, the highest pooled specificity was observed for rCBVmean (82% [72, 89]), and the highest pooled sensitivity (i.e., 92% [86, 93]) and AUC (i.e., 0.91) for rCBV 10th percentile. In the bivariate meta-regression, shorter TEs and smaller slice gaps were linked to higher pooled sensitivities. In IDHm, 1p19q codeletion was associated with higher rCBVmean (SMD = 0.9 [0.2, 1.5]) and rCBV 90th percentile (SMD = 0.9 [0.1, 1.7]) values. Conclusions: Identification of vascular signatures predictive of IDH and 1p19q status is a novel promising application of DSC perfusion. Standardization of acquisition protocols and post-processing of DSC perfusion maps are warranted before widespread use in clinical practice

Testing, tracing and isolation in compartmental models

Existing compartmental mathematical modelling methods for epidemics, such as SEIR models, cannot accurately represent effects of contact tracing. This makes them inappropriate for evaluating testing and contact tracing strategies to contain an outbreak. An alternative used in practice is the application of agent- or individual-based models (ABM). However ABMs are complex, less well-understood and much more computationally expensive. This paper presents a new method for accurately including the effects of Testing, contact-Tracing and Isolation (TTI) strategies in standard compartmental models. We derive our method using a careful probabilistic argument to show how contact tracing at the individual level is reflected in aggregate on the population level. We show that the resultant SEIR-TTI model accurately approximates the behaviour of a mechanistic agent-based model at far less computational cost. The computational efficiency is such that it can be easily and cheaply used for exploratory modelling to quantify the required levels of testing and tracing, alone and with other interventions, to assist adaptive planning for managing disease outbreaks

Evaluating the next generation of RSV intervention strategies:a mathematical modelling study and cost-effectiveness analysis

BACKGROUND: With a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued. METHODS: To compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to 7 years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes. FINDINGS: Our transmission model suggests that maternal protection of infants is seasonal, with 38-62% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around £4350 but dropping to £200 for vaccinated heightened risk infants or £90 for all infants. A seasonal maternal vaccine would have to be priced less than £85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than £80. CONCLUSIONS: In a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal

A novel approach to evaluating the UK childhood immunisation schedule: estimating the effective coverage vector across the entire vaccine programme

BACKGROUND: The availability of new vaccines can prompt policy makers to consider changes to the routine childhood immunisation programme in the UK. Alterations to one aspect of the schedule may have implications for other areas of the programme (e.g. adding more injections could reduce uptake of vaccines featuring later in the schedule). Colleagues at the Department of Health (DH) in the UK therefore wanted to know whether assessing the impact across the entire programme of a proposed change to the UK schedule could lead to different decisions than those made on the current case-by-case basis. This work is a first step towards addressing this question. METHODS: A novel framework for estimating the effective coverage against all of the diseases within a vaccination programme was developed. The framework was applied to the current (August 2015) UK childhood immunisation programme, plausible extensions to it in the foreseeable future (introducing vaccination against Meningitis B and/or Hepatitis B) and a "what-if" scenario regarding a Hepatitis B vaccine scare that was developed in close collaboration with DH. RESULTS: Our applications of the framework demonstrate that a programme-view of hypothetical changes to the schedule is important. For example, we show how introducing Hepatitis B vaccination could negatively impact aspects of the current programme by reducing uptake of vaccines featuring later in the schedule, and illustrate that the potential benefits of introducing any new vaccine are susceptible to behaviour changes affecting uptake (e.g. a vaccine scare). We show how it may be useful to consider the potential benefits and scheduling needs of all vaccinations on the horizon of interest rather than those of an individual vaccine in isolation, e.g. how introducing Meningitis B vaccination could saturate the early (2-month) visit, thereby potentially restricting scheduling options for Hepatitis B immunisation should it be introduced to the programme in the future. CONCLUSIONS: Our results demonstrate the potential benefit of considering the programme-wide impact of changes to an immunisation schedule, and our framework is an important step in the development of a means for systematically doing so

Are we prepared for the next influenza pandemic? Lessons from modelling different preparedness policies against four pandemic scenarios.

In the event of a novel influenza strain that is markedly different to the current strains circulating in humans, the population have little/no immunity and infection spreads quickly causing a global pandemic. Over the past century, there have been four major influenza pandemics: the 1918 pandemic ("Spanish Flu"), the 1957-58 pandemic (the "Asian Flu"), the 1967-68 pandemic (the "Hong Kong Flu") and the 2009 pandemic (the "Swine flu"). To inform planning against future pandemics, this paper investigates how different is the net-present value of employing pre-purchase and responsive- purchased vaccine programmes in presence and absence of anti-viral drugs to scenarios that resemble these historic influenza pandemics. Using the existing literature and in discussions with policy decision makers in the UK, we first characterised the four past influenza pandemics by their transmissibility and infection-severity. For these combinations of parameters, we then projected the net-present value of employing pre-purchase vaccine (PPV) and responsive-purchase vaccine (RPV) programmes in presence and absence of anti-viral drugs. To differentiate between PPV and RPV policies, we changed the vaccine effectiveness value and the time to when the vaccine is first available. Our results are "heat-map" graphs displaying the benefits of different strategies in pandemic scenarios that resemble historic influenza pandemics. Our results suggest that immunisation with either PPV or RPV in presence of a stockpile of effective antiviral drugs, does not have positive net-present value for all of the pandemic scenarios considered. In contrast, in the absence of effective antivirals, both PPV and RPV policies have positive net-present value across all the pandemic scenarios. Moreover, in all considered circumstances, vaccination was most beneficial if started sufficiently early and covered sufficiently large number of people. When comparing the two vaccine programmes, the RPV policy allowed a longer timeframe and lower coverage to attain the same benefit as the PPV policy. Our findings suggest that responsive-purchase vaccination policy has a bigger window of positive net-present value when employed against each of the historic influenza pandemic strains but needs to be rapidly available to maximise benefit. This is important for future planning as it suggests that future preparedness policies may wish to consider utilising timely (i.e. responsive-purchased) vaccines against emerging influenza pandemics

Proučavanje stvaranja agregata rekombinantnog humanog granulocitnog faktora stimulacije kolonija (rHuG-CSF), lenograstima, pomoću kromatografije isključenjem prema veličini i SDS-PAGE

The stability of proteins is a subject of intense current interest. Aggregation, as a dominant degradation pathway for therapeutic proteins, may cause multiple adverse effects, including loss of efficacy and immunogenicity. In the present study, the formation of aggregates in lenograstim under physiological conditions was monitored. For this purpose, a simple and selective size-exclusion high-performance liquid chromatography method for detection and separation of aggregates from intact protein was developed. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis was performed under reducing and non-reducing conditions to determine the nature of aggregate bond formation. Using both techniques, the presence of a low aggregate content attached via disulfide bonds was detected.Stabilnost proteina vrlo je aktualna problematika. Agregacija, kao dominantni put razgradnje terapijskih proteina, može uzrokovati različite nuspojave, koje uključuju i gubitak učinkovitosti imunološkog sustava. U ovom radu praćeno je stvaranje agregata u lenograstimu pod fiziološkim uvjetima. Razvijena je jednostavna i selektivna tekućinska kromatografija visoke djelotvornost s isključenjem prema veličini za detekciju i razdvajanje agregata od intaktnog proteina. Pomoću natrij-dodecil sulfat poliakrilamidne gel elektroforeze u reducirajućim i nereducirajućim uvjetima utvrđen je način stvaranja agregata. Pomoću obje tehnike moguće je detektirati prisutnost malih količina agregata koji su spojeni disulfidnim vezama

Impact of national‑scale targeted point‑of‑care symptomatic lateral flow testing on trends in COVID‑19 infections, hospitalisations and deaths during the second epidemic wave in Austria (REAP3)

Background In October 2020, amidst the second COVID-19 epidemic wave and before the second-national lockdown, Austria introduced a policy of population-wide point-of-care lateral flow antigen testing (POC-LFT). This study explores the impact of this policy by quantifying the association between trends in POC-LFT-activity with trends in PCR-positivity (as a proxy for symptomatic infection), hospitalisations and deaths related to COVID-19 between October 22 and December 06, 2020. Methods We stratified 94 Austrian districts according to POC-LFT-activity (number of POC-LFTs performed per 100,000 inhabitants over the study period), into three population cohorts: (i) high(N = 24), (ii) medium(N = 45) and (iii) low(N = 25). Across the cohorts we a) compared trends in POC-LFT-activity with PCR-positivity, hospital admissions and deaths related to COVD-19; b) compared the epidemic growth rate before and after the epidemic peak; and c) calculated the Pearson correlation coefficients between PCR-positivity with COVID-19 hospitalisations and with COVID -19 related deaths. Results The trend in POC-LFT activity was similar to PCR-positivity and hospitalisations trends across high, medium and low POC-LFT activity cohorts, with association with deaths only present in cohorts with high POC-LFT activity. Compared to the low POC-LFT-activity cohort, the high-activity cohort had steeper pre-peak daily increase in PCR-positivity (2.24 more cases per day, per district and per 100,000 inhabitants; 95% CI: 2.0–2.7; p < 0.001) and hospitalisations (0.10; 95% CI: 0.02, 0.18; p = 0.014), and 6 days earlier peak of PCR-positivity. The high-activity cohort also had steeper daily reduction in the post-peak trend in PCR-positivity (-3.6; 95% CI: -4.8, -2.3; p < 0.001) and hospitalisations (-0.2; 95% CI: -0.32, -0.08; p = 0.001). PCR-positivity was positively correlated to both hospitalisations and deaths, but with lags of 6 and 14 days respectively. Conclusions High POC-LFT-use was associated with increased and earlier case finding during the second Austrian COVID-19 epidemic wave, and early and significant reduction in cases and hospitalisations during the second national lockdown. A national policy promoting symptomatic POC-LFT in primary care, can capture trends in PCR-positivity and hospitalisations. Symptomatic POC-LFT delivered at scale and combined with immediate self-quarantining and contact tracing can thus be a proxy for epidemic status, and hence a useful tool that can replace large-scale PCR testing

A method for evaluating the cost-benefit of different preparedness planning policies against pandemic influenza.

�Our work presents a unifying method to calculate the net-benefit of different preparedness policies against different pandemic influeunza strains. Unlike previous methods, which have focused on evaluating specific strategies against specific pandemics, our method allows assessment of mass immunisation strategies in presence and absence of antiviral drugs for a large range of pandemic influenza strain characteristics and programme features. Overall, the model described here combines two parts to evaluate different preparedness planning policies against pandemic influenza.�The first part is adaptation of an existing transmission model for seasonal influenza to include generalisation across large number of pandemic influenza scenarios.�The second part is development of a tailor-made health economic model devised in collaboration with colleagues at the UK Department of Health and Social Care