Edinburgh, Road Pricing and the Boundary Problem: Issues of Equity and Efficiency

Discussions of road user charging in Scotland have been confined to the proposed introduction of road user charging in Edinburgh. This report summarises the findings of a research study into some of the equity and efficiency issues surrounding the proposed introduction of road user charging in Edinburgh. Each road user pricing scheme is extremely dependent upon the specific context in which it is introduced and this report seeks to unpack some of the issues concerning the currently (Spring 2004) unfolding proposals for the scheme in Edinburgh. Using a review of the existing policy and academic literature, press reports, telephone interviews, physical interviews and reviewing the precognition statements to the Public Inquiry on Congestion Charging in Edinburgh, this report provides a stakeholder analysis of the Edinburgh Road User Charging policy environment

Investigation of host red blood cell receptors essential for rosetting in severe Plasmodium falciparum malaria

Plasmodium falciparum malaria kills almost half a million people every year, many of whom are children living in Africa. Rosetting is a pathological phenomenon which is associated with all types of severe malaria and occurs when two or more uninfected erythrocytes adhere to an erythrocyte infected with the mature form of the P. falciparum parasite. It is thought that these rosettes may cause obstruction of the microvasculature leading to the serious complications seen in severe malaria. Understanding the molecular mechanisms of rosetting could therefore lead to the development of new adjuvant therapies for severe disease. The overall aims of this work were to reassess the evidence for previously described host erythrocyte rosetting receptors, explore new methods of investigating rosetting mechanisms, including generating knockdown/out erythrocytes from CD34+ haematopoietic stem cells and immortalised erythroid precursors, and to identify novel rosetting receptors. This thesis begins by reassessing the evidence that the glycosaminoglycans, heparan sulfate (HS) and chondroitin sulfate (CS) are involved in rosetting. Contrary to previously published work, results from experiments using carefully validated enzymes to cleave HS or CS did not support the hypothesis that HS or CS are important host receptors for rosetting across the six P. falciparum strains tested. In addition, I found no evidence to suggest that HS or CS are actually present on mature erythrocytes, though HS was detected on early bone marrow-derived erythrocyte precursors. Secondly, I investigated the use of induced pluripotent stem cells (iPSC) and cells cultured from adult bone marrow CD34+ stem cells (cRBC) as a tool to produce knockdown erythrocytes using RNA inference techniques. The cRBC appeared, both morphologically and by receptor profiling with flow cytometry, to be a good approximation of reticulocytes. However, unexpectedly, the cRBC derived erythrocytes were only able to form rosettes with two of the four parasite lines tested. Further study into the subtle differences in receptor expression levels between cRBC and peripheral erythrocytes suggested that Band 3 could be a potential novel rosetting receptor. This hypothesis was supported by the results of rosette disruption experiments which showed that antibodies to the Wrightb antigen, carried on Band 3, were capable of significantly disrupting rosettes of mature erythrocytes across all parasites strains tested. Finally, I used a new, immortalised erythroid precursor line, the “EJ” cells, developed by the Duraisingh laboratory at Harvard university, to further investigate the role of Band 3 and the Wrightb antigen in rosetting. Band 3, glycophorin A (GYPA) and CR1 knockout EJ cells, created using CRISPR/Cas9 technology, were tested for rosetting ability with six parasite lines. As the Wrightb antigen requires both Band 3 and GYPA to properly form, both these knockout EJ cells also lacked Wrightb. Compared to wildtype EJ cells, GYPA and Band 3 knockout EJ cells had reduced rosetting. However, the rosetting rates were similar between the two knockout lines, suggesting that neither the presence of GYPA or Band 3 alone can rescue the poor rosetting phenotype in the absence of Wrightb. In summary, I have found that while there is little evidence to support the involvement of HS or CS in rosetting, the Wrightb antigen carried on Band 3 may be an important, strain-transcending rosetting receptor and could represent a useful therapeutic target to reduce rosetting. In addition, I have developed new techniques for investigating rosetting receptors using a novel erythroid precursor line. The EJ cells also have great potential for the development of a rosetting screen to identify other candidates to help reduce the mortality and morbidity of severe malaria in the future

UK paediatric trainee research involvement: A national mixed-methods survey to highlight opportunities and challenges [Letter]

Child health research is considered essential to paediatric training. However, due to service provision demands and workforce planning, research capacity within paediatric consultant contracts is declining.1 This affects paediatric trainees who perceive lack of leadership in this domain.2 Considering these concerns, in 2021, the Royal College of Paediatrics and Child Health (RCPCH) established the Trainee Research Network (TRN) to support regional research. To broadly evaluate trainee participation in research as a marker of future UK research capacity, we conducted a national survey of trainees’ experiences to help identify the breadth of research involvement and to identify barriers and facilitators to participation

Uptake of infant and preschool immunisations in Scotland and England during the COVID-19 pandemic: An observational study of routinely collected data

Funding: This analysis was part of the EAVE II project. EAVE II is funded by the Medical Research Council (MC_PC_19075), https://mrc.ukri.org/, with the support of BREATHE: the Health Data Research Hub for Respiratory Health (MC_PC_19004), https://www.hdruk.ac.uk/helping-with-health-data/health-data-research-hubs/breathe, which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK.Background In 2020, the SARS-CoV-2 (COVID-19) pandemic and lockdown control measures threatened to disrupt routine childhood immunisation programmes with early reports suggesting uptake would fall. In response, public health bodies in Scotland and England collected national data for childhood immunisations on a weekly or monthly basis to allow for rapid analysis of trends. The aim of this study was to use these data to assess the impact of different phases of the pandemic on infant and preschool immunisation uptake rates. Methods and findings We conducted an observational study using routinely collected data for the year prior to the pandemic (2019) and immediately before (22 January to March 2020), during (23 March to 26 July), and after (27 July to 4 October) the first UK “lockdown”. Data were obtained for Scotland from the Public Health Scotland “COVID19 wider impacts on the health care system” dashboard and for England from ImmForm. Five vaccinations delivered at different ages were evaluated; 3 doses of “6-in-1” diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B vaccine (DTaP/IPV/Hib/HepB) and 2 doses of measles, mumps, and rubella (MMR) vaccine. This represented 439,754 invitations to be vaccinated in Scotland and 4.1 million for England. Uptake during the 2020 periods was compared to the previous year (2019) using binary logistic regression analysis. For Scotland, uptake within 4 weeks of a child becoming eligible by age was analysed along with geographical region and indices of deprivation. For Scotland and England, we assessed whether immunisations were up-to-date at approximately 6 months (all doses 6-in-1) and 16 to 18 months (first MMR) of age. We found that uptake within 4 weeks of eligibility in Scotland for all the 5 vaccines was higher during lockdown than in 2019. Differences ranged from 1.3% for first dose 6-in-1 vaccine (95.3 versus 94%, odds ratio [OR] compared to 2019 1.28, 95% confidence intervals [CIs] 1.18 to 1.39) to 14.3% for second MMR dose (66.1 versus 51.8%, OR compared to 2019 1.8, 95% CI 1.74 to 1.87). Significant increases in uptake were seen across all deprivation levels. In England, fewer children due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in-1 (95.8 versus 96.3%, OR compared to 2019 0.89, 95% CI 0.86– to 0.91) to 2.1% for third 6-in-1 (86.6 versus 88.7%, OR compared to 2019 0.82, 95% CI 0.81 to 0.83). The use of routinely collected data used in this study was a limiting factor as detailed information on potential confounding factors were not available and we were unable to eliminate the possibility of seasonal trends in immunisation uptake. Conclusions In this study, we observed that the national lockdown in Scotland was associated with an increase in timely childhood immunisation uptake; however, in England, uptake fell slightly. Reasons for the improved uptake in Scotland may include active measures taken to promote immunisation at local and national levels during this period and should be explored further. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination campaigns.Publisher PDFPeer reviewe

Confirmed SARS-CoV-2 infection in Scottish neonates 2020-2022:a national, population-based cohort study

Objectives: To examine neonates in Scotland aged 0–27 days with SARS-CoV-2 infection confirmed by viral testing; the risk of confirmed neonatal infection by maternal and infant characteristics; and hospital admissions associated with confirmed neonatal infections. Design: Population-based cohort study. Setting and population: All live births in Scotland, 1 March 2020–31 January 2022. Results: There were 141 neonates with confirmed SARS-CoV-2 infection over the study period, giving an overall infection rate of 153 per 100 000 live births (141/92 009, 0.15%). Among infants born to women with confirmed infection around the time of birth, the confirmed neonatal infection rate was 1812 per 100 000 live births (15/828, 1.8%). Two-thirds (92/141, 65.2%) of neonates with confirmed infection had an associated admission to neonatal or (more commonly) paediatric care. Six of these babies (6/92, 6.5%) were admitted to neonatal and/or paediatric intensive care; however, none of these six had COVID-19 recorded as their main diagnosis. There were no neonatal deaths among babies with confirmed infection. Implications and relevance: Confirmed neonatal SARS-CoV-2 infection was uncommon over the first 23 months of the pandemic in Scotland. Secular trends in the neonatal confirmed infection rate broadly followed those seen in the general population, although at a lower level. Maternal confirmed infection at birth was associated with an increased risk of neonatal confirmed infection. Two-thirds of neonates with confirmed infection had an associated admission to hospital, with resulting implications for the baby, family and services, although their outcomes were generally good. Ascertainment of confirmed infection depends on the extent of testing, and this is likely to have varied over time and between groups: the extent of unconfirmed infection is inevitably unknown

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders