Time-dependent markers of comorbidity and prognosis in heart failure patients: transitions across the life course

Heart failure (HF) disease carries a poor prognosis despite optimisation of cardiovascular (CVD) treatments. Non-CVD comorbid diseases are common and known to influence the HF clinical course. These comorbidities change in severity over time from new onset yet, only static measures of comorbidity have been included in prognosis. A major gap in the management and prognosis of HF is how non-CVD comorbidity severity and longitudinal change influences individual risk.A systematic review (SR) and two phase observational study were conducted in the general HF population to test the hypothesis that increasing severity and change of non-CVD comorbidity would be associated with worse outcomes. The SR showed that the three most common non-CVD comorbidities included in prognosis were diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Hospital admission outcome studies were limited and there were no studies on quality of life. With the exception of hospital based renal studies, comorbidity severity and change evidence was scarce.The observational studies used a case-control study nested within the UK Clinical Practice Research Datalink database (2002- 2014), of 50,114 incident HF patients. Using risk set sampling, multiple controls were matched to cases on follow-up time. A framework for measuring recent comorbidity severity and change was devised using drug or physiological indicators for DM, COPD and CKD measured in two time-windows prior to the match date. Conditional logistic regression was used to estimate adjusted odds ratios for all-cause hospital admission and mortality.The observational study findings were that all three comorbidities were common and associated with both outcomes. Severe and worsening comorbid disease was also common and independently and significantly associated with increased risk of hospital admission and mortality. These dynamic measures of non-CVD comorbidity significantly improved HF prognostic models which has important implications for HF management and prognosis

Time-dependent markers of comorbidity and prognosis in heart failure patients: transitions across the life course

Heart failure (HF) disease carries a poor prognosis despite optimisation of cardiovascular (CVD) treatments. Non-CVD comorbid diseases are common and known to influence the HF clinical course. These comorbidities change in severity over time from new onset yet, only static measures of comorbidity have been included in prognosis. A major gap in the management and prognosis of HF is how non-CVD comorbidity severity and longitudinal change influences individual risk. A systematic review (SR) and two phase observational study were conducted in the general HF population to test the hypothesis that increasing severity and change of non-CVD comorbidity would be associated with worse outcomes. The SR showed that the three most common non-CVD comorbidities included in prognosis were diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Hospital admission outcome studies were limited and there were no studies on quality of life. With the exception of hospital based renal studies, comorbidity severity and change evidence was scarce. The observational studies used a case-control study nested within the UK Clinical Practice Research Datalink database (2002- 2014), of 50,114 incident HF patients. Using risk set sampling, multiple controls were matched to cases on follow-up time. A framework for measuring recent comorbidity severity and change was devised using drug or physiological indicators for DM, COPD and CKD measured in two time-windows prior to the match date. Conditional logistic regression was used to estimate adjusted odds ratios for all-cause hospital admission and mortality. The observational study findings were that all three comorbidities were common and associated with both outcomes. Severe and worsening comorbid disease was also common and independently and significantly associated with increased risk of hospital admission and mortality. These dynamic measures of non-CVD comorbidity significantly improved HF prognostic models which has important implications for HF management and prognosis

Early career teacher mentoring in England: a case study of compliance and mediation

This paper reports the findings from a small-scale study of ten mentors’ experiences of supporting Early Career Teachers (ECTs) in secondary schools in England following the introduction of the Early Career Framework (ECF) in 2021. Data were collected via semi-structured interviews with individual mentors based in London, Manchester and York, UK. The findings suggest that mentors experience some challenges supporting ECTs through the use of mandated training materials. The data report the contradictions of being required to support trainees through a programme governed by the statutory requirements of the Department for Education (DfE) in England, whilst also being part of a complex, nuanced school community. The authors examine mentors’ experiences as they balance the compliance requirements of the ECF alongside seeking to support ECTs with the realities of classroom life in their own settings. The paper discusses the emergence of a mediated mentor professionalism as mentors seek to navigate competing demands. We argue that this case study illustrates the potential for the international sector to challenge postulated solutions of homogenised mentoring curricula and practices to the recruitment and retention of ECTs

Reflecting on ’classroom readiness’ in initial teacher education in a time of global pandemic from the perspectives of eight university providers from across England, UK

In the context of a decade of change and reform in Initial Teacher Education (ITE) policy making, we assess the impact of the substantial changes caused by Covid-19 affecting ITE from the perspectives of eight university providers in England. Whilst previous research has documented the impact of the first period of lockdown in the UK, initiated in March 2020, we draw on the conceptual framework of classroom readiness to consider the continued and variable disruption caused by Covid-19 on ITE programmes in England during the period September 2020 – June 2021. Through a participatory workshop, which included identifying key questions, group discussion and written reflections with teacher educators working across eight institutions, we assess the changes to pre-service teacher education provision over this period, with a focus on postgraduate programmes. We identify that the nature and implementation of school visits and the role of technology and digital pedagogies are key areas of change during the pandemic period, whilst continuity in the value and strength of school and university partnerships remain. We consider the ways in which ideas of developing ‘classroom readiness’ have been informed and shaped through changes to teacher education brought about during the pandemic period. We argue that conceptualisations of classroom readiness need to be grounded in reflective professional learning in the context of collaborative professional communities so to enable pre-service teachers to become adaptable pastorally engaged subject specialists. We reflect on how learning from this period might be incorporated into future international ITE programmes and policy

Cryptic Eimeria genotypes are common across the southern but not northern hemisphere

The phylum Apicomplexa includes parasites of medical, zoonotic and veterinary significance. Understanding the global distribution and genetic diversity of these protozoa is of fundamental importance for efficient, robust and long-lasting methods of control. Eimeria spp. cause intestinal coccidiosis in all major livestock animals and are the most important parasites of domestic chickens in terms of both economic impact and animal welfare. Despite having significant negative impacts on the efficiency of food production, many fundamental questions relating to the global distribution and genetic variation of Eimeria spp. remain largely unanswered. Here, we provide the broadest map yet of Eimeria occurrence for domestic chickens, confirming that all the known species (Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria mitis, Eimeria necatrix, Eimeria praecox, Eimeria tenella) are present in all six continents where chickens are found (including 21 countries). Analysis of 248 internal transcribed spacer sequences derived from 17 countries provided evidence of possible allopatric diversity for species such as E. tenella (FST values ⩽0.34) but not E. acervulina and E. mitis, and highlighted a trend towards widespread genetic variance. We found that three genetic variants described previously only in Australia and southern Africa (operational taxonomic units x, y and z) have a wide distribution across the southern, but not the northern hemisphere. While the drivers for such a polarised distribution of these operational taxonomic unit genotypes remains unclear, the occurrence of genetically variant Eimeria may pose a risk to food security and animal welfare in Europe and North America should these parasites spread to the northern hemisphere

Preeclampsia and Future Cardiovascular Health

Background—Preeclampsia is a pregnancy-specific disorder resulting in hypertension and multiorgan dysfunction. There is growing evidence that these effects persist after pregnancy. We aimed to systematically evaluate and quantify the evidence on the relationship between preeclampsia and the future risk of cardiovascular diseases.Methods and Results—We studied the future risk of heart failure, coronary heart disease, composite cardiovascular disease, death because of coronary heart or cardiovascular disease, stroke, and stroke death after preeclampsia. A systematic search of MEDLINE and EMBASE was performed to identify relevant studies. We used random-effects meta-analysis to determine the risk. Twenty-two studies were identified with >6.4 million women including >258?000 women with preeclampsia. Meta-analysis of studies that adjusted for potential confounders demonstrated that preeclampsia was independently associated with an increased risk of future heart failure (risk ratio [RR], 4.19; 95% confidence interval [CI], 2.09–8.38), coronary heart disease (RR, 2.50; 95% CI, 1.43–4.37), cardiovascular disease death (RR, 2.21; 95% CI, 1.83–2.66), and stroke (RR, 1.81; 95% CI, 1.29–2.55). Sensitivity analyses showed that preeclampsia continued to be associated with an increased risk of future coronary heart disease, heart failure, and stroke after adjusting for age (RR, 3.89; 95% CI, 1.83–8.26), body mass index (RR, 3.16; 95% CI, 1.41–7.07), and diabetes mellitus (RR, 4.19; 95% CI, 2.09–8.38).Conclusions—Preeclampsia is associated with a 4-fold increase in future incident heart failure and a 2-fold increased risk in coronary heart disease, stroke, and death because of coronary heart or cardiovascular disease. Our study highlights the importance of lifelong monitoring of cardiovascular risk factors in women with a history of preeclampsia

Willingness to pay for contagious bovine pleuropneumonia vaccination in Narok South District of Kenya

Contagious bovine pleuropneumonia (CBPP) is an economically important trans-boundary cattle disease which affects food security and livelihoods. A conjoint analysis–contingent valuation was carried out on 190 households in Narok South District of Kenya to measure willingness to pay (WTP) and demand for CBPP vaccine and vaccination as well as factors affecting WTP. The mean WTP was calculated at Kenya Shillings (KSh) 212.48 (USD 3.03) for vaccination using a vaccine with the characteristics that were preferred by the farmers (preferred vaccine and vaccination) and KSh −71.45 (USD −1.02) for the currently used vaccine and vaccination. The proportion of farmers willing to pay an amount greater than zero was 66.7% and 34.4% for the preferred and current vaccine and vaccination respectively. About one third (33.3%) of farmers would need to be compensated an average amount of KSh 1162.62 (USD 13.68) per animal to allow their cattle to be vaccinated against CBPP using the preferred vaccine and vaccination. About two-thirds (65.6%) of farmers would need to be compensated an average amount of KSh 853.72 (USD 12.20) per animal to allow their cattle to be vaccinated against CBPP using the current vaccine and vaccination. The total amount of compensation would be KSh 61.39 million (USD 0.88 million) for the preferred vaccine and vaccination and KSh 90.15 million (USD 1.29 million) for the current vaccine and vaccination. Demand curves drawn from individual WTP demonstrated that only 59% and 27% of cattle owners with a WTP greater than zero were willing to pay a benchmark cost of KSh 34.60 for the preferred and current vaccine respectively. WTP was negatively influenced by the attitude about household economic situation (p = 0.0078), presence of cross breeds in the herd (p < 0.0001) and years since CBPP had been experienced in the herd (p = 0.0375). It was positively influenced by education (p = 0.0251) and the practice of treating against CBPP (p = 0.0432). The benefit cost ratio (BCR) for CBPP vaccination was 2.9–6.1 depending on the vaccination programme. In conclusion, although a proportion of farmers was willing to pay, participation levels may be lower than those required to interrupt transmission of CBPP. Households with characteristics that influence WTP negatively need persuasion to participate in CBPP vaccination. It is economically worthwhile to vaccinate against CBPP. A benefit cost analysis (BCA) using aggregated WTP as benefits can be used as an alternative method to the traditional BCA which uses avoided production losses (new revenue) and costs saved as benefits

Synthetic Heparan Sulfate Oligosaccharides Inhibit Endothelial Cell Functions Essential for Angiogenesis

Heparan sulfate (HS) is an important regulator of the assembly and activity of various angiogenic signalling complexes. However, the significance of precisely defined HS structures in regulating cytokine-dependent angiogenic cellular functions and signalling through receptors regulating angiogenic responses remains unclear. Understanding such structure-activity relationships is important for the rational design of HS fragments that inhibit HS-dependent angiogenic signalling complexes.We synthesized a series of HS oligosaccharides ranging from 7 to 12 saccharide residues that contained a repeating disaccharide unit consisting of iduronate 2-O-sulfate linked to glucosamine with or without N-sulfate. The ability of oligosaccharides to compete with HS for FGF2 and VEGF165 binding significantly increased with oligosaccharide length and sulfation. Correspondingly, the inhibitory potential of oligosaccharides against FGF2- and VEGF165-induced endothelial cell responses was greater in longer oligosaccharide species that were comprised of disaccharides bearing both 2-O- and N-sulfation (2SNS). FGF2- and VEGF165-induced endothelial cell migration were inhibited by longer 2SNS oligosaccharide species with 2SNS dodecasaccharide activity being comparable to that of receptor tyrosine kinase inhibitors targeting FGFR or VEGFR-2. Moreover, the 2SNS dodecasaccharide ablated FGF2- or VEGF165-induced phosphorylation of FAK and assembly of F-actin in peripheral lamellipodia-like structures. In contrast, FGF2-induced endothelial cell proliferation was only moderately inhibited by longer 2SNS oligosaccharides. Inhibition of FGF2- and VEGF165-dependent endothelial tube formation strongly correlated with oligosaccharide length and sulfation with 10-mer and 12-mer 2SNS oligosaccharides being the most potent species. FGF2- and VEGF165-induced activation of MAPK pathway was inhibited by biologically active oligosaccharides correlating with the specific phosphorylation events in FRS2 and VEGFR-2, respectively.These results demonstrate structure-function relationships for synthetic HS saccharides that suppress endothelial cell migration, tube formation and signalling induced by key angiogenic cytokines

Monthly variation in the probability of presence of adult Culicoides populations in nine European countries and the implications for targeted surveillance

Background: Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are small hematophagous insects responsible for the transmission of bluetongue virus, Schmallenberg virus and African horse sickness virus to wild and domestic ruminants and equids. Outbreaks of these viruses have caused economic damage within the European Union. The spatio-temporal distribution of biting midges is a key factor in identifying areas with the potential for disease spread. The aim of this study was to identify and map areas of neglectable adult activity for each month in an average year. Average monthly risk maps can be used as a tool when allocating resources for surveillance and control programs within Europe. Methods : We modelled the occurrence of C. imicola and the Obsoletus and Pulicaris ensembles using existing entomological surveillance data from Spain, France, Germany, Switzerland, Austria, Denmark, Sweden, Norway and Poland. The monthly probability of each vector species and ensembles being present in Europe based on climatic and environmental input variables was estimated with the machine learning technique Random Forest. Subsequently, the monthly probability was classified into three classes: Absence, Presence and Uncertain status. These three classes are useful for mapping areas of no risk, areas of high-risk targeted for animal movement restrictions, and areas with an uncertain status that need active entomological surveillance to determine whether or not vectors are present. Results: The distribution of Culicoides species ensembles were in agreement with their previously reported distribution in Europe. The Random Forest models were very accurate in predicting the probability of presence for C. imicola (mean AUC = 0.95), less accurate for the Obsoletus ensemble (mean AUC = 0.84), while the lowest accuracy was found for the Pulicaris ensemble (mean AUC = 0.71). The most important environmental variables in the models were related to temperature and precipitation for all three groups. Conclusions: The duration periods with low or null adult activity can be derived from the associated monthly distribution maps, and it was also possible to identify and map areas with uncertain predictions. In the absence of ongoing vector surveillance, these maps can be used by veterinary authorities to classify areas as likely vector-free or as likely risk areas from southern Spain to northern Sweden with acceptable precision. The maps can also focus costly entomological surveillance to seasons and areas where the predictions and vector-free status remain uncertain

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society