PACS-1 Defines a Novel Gene Family of Cytosolic Sorting Proteins Required for trans-Golgi Network Localization

AbstractWe report the role of one member of a novel gene family, PACS-1, in the localization of trans-Golgi network (TGN) membrane proteins. PACS-1 directs the TGN localization of furin by binding to the protease’s phosphorylated cytosolic domain. Antisense studies show TGN localization of furin and mannose-6-phosphate receptor, but not TGN46, is strictly dependent on PACS-1. Analyses in vitro and in vivo show PACS-1 has properties of a coat protein and connects furin to components of the clathrin-sorting machinery. Cell-free assays indicate TGN localization of furin is directed by a PACS-1-mediated retrieval step. Together, these findings explain a mechanism by which membrane proteins in mammalian cells are localized to the TGN

A randomised controlled trial comparing opt-in and opt-out home visits for tracing lost participants in a prospective birth cohort study

© 2015 Bray et al. Background: Attrition is an important problem in cohort studies. Tracing cohort members who have moved or otherwise lost contact with the study is vital. There is some debate about the acceptability and relative effectiveness of opt-in versus opt-out methods of contacting cohort members to re-engage them in this context. We conducted a randomised controlled trial to compare the two approaches in terms of effectiveness (tracing to confirm address and consenting to continue in the study), cost-effectiveness and acceptability. Methods: Participants in this trial were individuals (young people and mothers) recruited to the Avon Longitudinal Study of Parents and Children (ALSPAC), who had not engaged with the study in the previous 5 years and for whom mail had been returned from their last known address. The sampling frame was restricted to those for whom database searching led to a potential new address being found in the Bristol area. 300 participants were randomly selected and assigned using stratified randomisation to the opt-in or opt-out arm. A tailored letter was sent to the potential new address, either asking participants to opt in to a home visit, or giving them the option to opt out of a home visit. Fieldworkers from Ipsos MORI conducted home visits to confirm address details. Results: The proportion who were traced was higher in the opt-out arm (77/150∈=∈51 %) than the opt-in arm (6/150∈=∈4 %), as was the proportion who consented to continue in ALSPAC (46/150∈=∈31 % v 4/150∈=∈3 %). The mean cost per participant was £8.14 in the opt-in arm and £71.93 in the opt-out arm. There was no evidence of a difference in acceptability between the opt-in and opt-out approaches. Conclusion: Since the opt-in approach yielded very low response rates, and there were no differences in terms of acceptability, we conclude that the opt-out approach is the most effective method of tracing disengaged study members. The gains made in contacting participants must be weighed against the increase in cost using this methodology

The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research:Antibody testing results, April – June 2021

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort which recruited pregnant women in 1990-1992 and has followed these women, their partners (Generation 0; G0) and their offspring (Generation 1; G1) ever since. The study reacted rapidly and repeatedly to the coronavirus disease 2019 (COVID-19) pandemic, deploying multiple online questionnaires and a previous home-based antibody test in October 2020. A second antibody test, in collaboration with ten other longitudinal population studies, was completed by 4,622 ALSPAC participants between April and June 2021. Of 4,241 participants with a valid spike protein antibody test result (8.2% were void), indicating antibody response to either COVID-19 vaccination or natural infection, 3,172 were positive (74.8%). Generational differences were substantial, with 2,463/2,555 G0 participants classified positive (96.4%) compared to 709/1,686 G1 participants (42.1%). Of 4,199 participants with a valid nucleocapsid antibody test result (9.2% were void), suggesting potential and recent natural infection, 493 were positive (11.7%); 248/2,526 G0 participants (9.8%) and 245/1,673 G1 participants (14.6%) tested positive, respectively. We also compare results for this round of testing to that undertaken in October 2020. Future work will combine these test results with additional sources of data to identify participants’ COVID-19 infection and vaccination status. These ALSPAC COVID-19 serology data are being complemented with linkage to health records and Public Health England pillar testing results as they become available, in addition to four previous questionnaire waves and a prior antibody test. Data have been released as an update to the previous COVID-19 datasets. These comprise: 1) a standard dataset containing all participant responses to all four previous questionnaires with key sociodemographic factors; and 2) individual participant-specific release files enabling bespoke research across all areas supported by the study. This data note describes the second ALSPAC antibody test and the data obtained from it

Mode of delivery affected questionnaire response rates in a birth cohort study

© 2016 The Author(s) Objectives Cohort studies must collect data from their participants as economically as possible, while maintaining response rates. This randomized controlled trial investigated whether offering a choice of online or paper questionnaires resulted in improved response rates compared with offering online first. Study Design and Setting Eligible participants were young people in the Avon Longitudinal Study of Parents and Children (ALSPAC) study (born April 1, 1991, to December 31, 1992, in the Avon area). After exclusions, 8,795 participants were randomized. The “online first” group were invited to complete the questionnaire online. The “choice” group were also sent a paper questionnaire and offered a choice of completion method. The trial was embedded within routine data collection. The main outcome measure was the number of questionnaires returned. Data on costs were also collected. Results Those in the “online first” arm of the trial were less likely to return a questionnaire [adjusted odds ratio: 0.90; 95% confidence interval (CI): 0.82, 0.99]. The “choice” arm was more expensive (mean difference per participant £0.71; 95% CI: £0.65, £0.76). It cost an extra £47 to have one extra person to complete the questionnaire in the “choice” arm. Conclusion Offering a choice of completion methods (paper or online) for questionnaires in ALSPAC increased response rates but was more expensive than offering online first

Comparison of frailty screening instruments in the emergency department

Early identification of frailty through targeted screening can facilitate the delivery of comprehensive geriatric assessment (CGA) and may improve outcomes for older inpatients. As several instruments are available, we aimed to investigate which is the most accurate and reliable in the Emergency Department (ED). We compared the ability of three validated, short, frailty screening instruments to identify frailty in a large University Hospital ED. Consecutive patients aged ≥70 attending ED were screened using the Clinical Frailty Scale (CFS), Identification of Seniors at Risk Tool (ISAR), and the Programme on Research for Integrating Services for the Maintenance of Autonomy 7 item questionnaire (PRISMA-7). An independent CGA using a battery of assessments determined each patient’s frailty status. Of the 280 patients screened, complete data were available for 265, with a median age of 79 (interquartile ±9); 54% were female. The median CFS score was 4/9 (±2), ISAR 3/6 (±2), and PRISMA-7 was 3/7 (±3). Based upon the CGA, 58% were frail and the most accurate instrument for separating frail from non-frail was the PRISMA-7 (AUC 0.88; 95% CI:0.83–0.93) followed by the CFS (AUC 0.83; 95% CI:0.77–0.88), and the ISAR (AUC 0.78; 95% CI:0.71–0.84). The PRISMA-7 was statistically significantly more accurate than the ISAR (p = 0.008) but not the CFS (p = 0.15). Screening for frailty in the ED with a selection of short screening instruments, but particularly the PRISMA-7, is reliable and accurate

Harmonising data on the correlates of physical activity and sedentary behaviour in young people: Methods and lessons learnt from the international Children's Accelerometry database (ICAD).

BACKGROUND: Large, heterogeneous datasets are required to enhance understanding of the multi-level influences on children's physical activity and sedentary behaviour. One route to achieving this is through the pooling and co-analysis of data from multiple studies. Where this approach is used, transparency of the methodology for data collation and harmonisation is essential to enable appropriate analysis and interpretation of the derived data. In this paper, we describe the acquisition, management and harmonisation of non-accelerometer data in a project to expand the International Children's Accelerometry Database (ICAD). METHOD: Following a consultation process, ICAD partners were requested to share accelerometer data and information on selected behavioural, social, environmental and health-related constructs. All data were collated into a single repository for cataloguing and harmonisation. Harmonised variables were derived iteratively, with input from the ICAD investigators and a panel of invited experts. Extensive documentation, describing the source data and harmonisation procedure, was prepared and made available through the ICAD website. RESULTS: Work to expand ICAD has increased the number of studies with longitudinal accelerometer data, and expanded the breadth of behavioural, social and environmental characteristics that can be used as exposure variables. A set of core harmonised variables, including parent education, ethnicity, school travel mode/duration and car ownership, were derived for use by the research community. Guidance documents and facilities to enable the creation of new harmonised variables were also devised and made available to ICAD users. An expanded ICAD database was made available in May 2017. CONCLUSION: The project to expand ICAD further demonstrates the feasibility of pooling data on physical activity, sedentary behaviour and potential determinants from multiple studies. Key to this process is the rigorous conduct and reporting of retrospective data harmonisation, which is essential to the appropriate analysis and interpretation of derived data. These documents, made available through the ICAD website, may also serve as a guide to others undertaking similar projects

Harmonising data on the correlates of physical activity and sedentary behaviour in young people: Methods and lessons learnt from the International Children's Accelerometry database (ICAD)

Background: Large, heterogeneous datasets are required to enhance understanding of the multi-level influences on children's physical activity and sedentary behaviour. One route to achieving this is through the pooling and co-analysis of data from multiple studies. Where this approach is used, transparency of the methodology for data collation and harmonisation is essential to enable appropriate analysis and interpretation of the derived data. In this paper, we describe the acquisition, management and harmonisation of non-accelerometer data in a project to expand the International Children's Accelerometry Database (ICAD). Method: Following a consultation process, ICAD partners were requested to share accelerometer data and information on selected behavioural, social, environmental and health-related constructs. All data were collated into a single repository for cataloguing and harmonisation. Harmonised variables were derived iteratively, with input from the ICAD investigators and a panel of invited experts. Extensive documentation, describing the source data and harmonisation procedure, was prepared and made available through the ICAD website. Results: Work to expand ICAD has increased the number of studies with longitudinal accelerometer data, and expanded the breadth of behavioural, social and environmental characteristics that can be used as exposure variables. A set of core harmonised variables, including parent education, ethnicity, school travel mode/duration and car ownership, were derived for use by the research community. Guidance documents and facilities to enable the creation of new harmonised variables were also devised and made available to ICAD users. An expanded ICAD database was made available in May 2017. Conclusion: The project to expand ICAD further demonstrates the feasibility of pooling data on physical activity, sedentary behaviour and potential determinants from multiple studies. Key to this process is the rigorous conduct and reporting of retrospective data harmonisation, which is essential to the appropriate analysis and interpretation of derived data. These documents, made available through the ICAD website, may also serve as a guide to others undertaking similar projects

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors

SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. From cross-sectional antibody testing of 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies (jointly in April-May 2021, and TwinsUK only in November 2021-January 2022), we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables. Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months, compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK "Shielded Patient List" had consistently greater odds (2 to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer\u27s disease: Associations with Aβ-PET, neurodegeneration, and cognition

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer\u27s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer\u27s disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not