The longitudinal associations between ambient air pollution exposure and dementia in the UK: results from the cognitive function and ageing study II and Wales.

BACKGROUND: Air pollution has been recognised as a potential risk factor for dementia. Yet recent epidemiological research shows mixed evidence. The aim of this study is to investigate the longitudinal associations between ambient air pollution exposure and dementia in older people across five urban and rural areas in the UK. METHODS: This study was based on two population-based cohort studies of 11329 people aged ≥ 65 in the Cognitive Function and Ageing Study II (2008-2011) and Wales (2011-2013). An algorithmic diagnosis method was used to identify dementia cases. Annual concentrations of four air pollutants (NO2, O3, PM10, PM2.5) were modelled for the year 2012 and linked via the participants' postcodes. Multistate modelling was used to examine the effects of exposure to air pollutants on incident dementia incorporating death and adjusting for sociodemographic factors and area deprivation. A random-effect meta-analysis was carried out to summarise results from the current and nine existing cohort studies. RESULTS: Higher exposure levels of NO2 (HR: 1.04; 95% CI: 0.94, 1.14), O3 (HR: 0.90; 95% CI: 0.70, 1.15), PM10 (HR: 1.17; 95% CI: 0.86, 1.58), PM2.5 (HR: 1.41; 95% CI: 0.71, 2.79) were not strongly associated with dementia in the two UK-based cohorts. Inconsistent directions and strengths of the associations were observed across the two cohorts, five areas, and nine existing studies. CONCLUSIONS: In contrast to the literature, this study did not find clear associations between air pollution and dementia. Future research needs to investigate how methodological and contextual factors can affect evidence in this field and clarity the influence of air pollution exposure on cognitive health over the lifecourse.

Severe Acute Respiratory Syndrome Coronavirus 2 Transmission in a Georgia School District-United States, December 2020-January 2021.

BACKGROUND: To inform prevention strategies, we assessed the extent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and settings in which transmission occurred in a Georgia public school district. METHODS: During 1 December 2020-22 January 2021, SARS-CoV-2-infected index cases and their close contacts in schools were identified by school and public health officials. For in-school contacts, we assessed symptoms and offered SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) testing; performed epidemiologic investigations and whole-genome sequencing to identify in-school transmission; and calculated secondary attack rate (SAR) by school setting (eg, sports, elementary school classroom), index case role (ie, staff, student), and index case symptomatic status. RESULTS: We identified 86 index cases and 1119 contacts, 688 (61.5%) of whom received testing. Fifty-nine of 679 (8.7%) contacts tested positive; 15 of 86 (17.4%) index cases resulted in ≥2 positive contacts. Among 55 persons testing positive with available symptom data, 31 (56.4%) were asymptomatic. Highest SARs were in indoor, high-contact sports settings (23.8% [95% confidence interval {CI}, 12.7%-33.3%]), staff meetings/lunches (18.2% [95% CI, 4.5%-31.8%]), and elementary school classrooms (9.5% [95% CI, 6.5%-12.5%]). The SAR was higher for staff (13.1% [95% CI, 9.0%-17.2%]) vs student index cases (5.8% [95% CI, 3.6%-8.0%]) and for symptomatic (10.9% [95% CI, 8.1%-13.9%]) vs asymptomatic index cases (3.0% [95% CI, 1.0%-5.5%]). CONCLUSIONS: Indoor sports may pose a risk to the safe operation of in-person learning. Preventing infection in staff members, through measures that include coronavirus disease 2019 vaccination, is critical to reducing in-school transmission. Because many positive contacts were asymptomatic, contact tracing should be paired with testing, regardless of symptoms.

Prevalence of risk behaviors and correlates of SARS-CoV-2 positivity among in-school contacts of confirmed cases in a Georgia school district in the pre-vaccine era, December 2020-January 2021.

BACKGROUND: There is a continuing risk for COVID-19 transmission in school settings while transmission is ongoing in the community, particularly among unvaccinated populations. To ensure that schools continue to operate safely and to inform implementation of prevention strategies, it is imperative to gain better understanding of the risk behaviors of staff and students. This secondary analysis describes the prevalence of COVID-19 risk behaviors in an exposed population of students and school staff in the pre-vaccine era and identifies associations between these behaviors and testing positive for SARS-CoV-2. METHODS: From December 2020-January 2021, school staff and students exposed to confirmed COVID-19 cases in a Georgia school district were tested for SARS-CoV-2 and surveyed regarding risk behaviors in and out of school. Prevalence of risk behaviors was described by age group and school level, and associations with SARS-CoV-2 positivity were identified using chi squared tests. RESULTS: Overall, 717 students and 79 school staff participated in the investigation; SARS-CoV-2 positivity was 9.2%. In the 2 weeks prior to COVID-19 exposure, 24% of participants reported unmasked indoor time at school, 40% attended social gatherings with non-household members, and 71% visited out-of-school indoor locations, including 19% who ate indoors in restaurants. Frequencies of risk behaviors increased by age. Among students, 17% participated in school sports, of whom 86% participated without a mask. SARS-CoV-2 positivity was significantly associated with school sports and unmasked time in sports. Among K-5 students, positivity was associated with exposure to a teacher index case. CONCLUSIONS: This analysis highlights the high prevalence of risk behaviors in an unvaccinated population exposed to COVID-19 in school and identifies an association between student sports participation and SARS-CoV-2 positivity. These findings illustrate the importance of school-level prevention measures to reduce SARS-CoV-2 transmission, including limiting close-contact indoor sports and promoting consistent mask use in unvaccinated individuals. Future research could explore the role of community vaccination programs as a strategy to reduce COVID-19 transmission and introductions into school settings.

Clusters of SARS-CoV-2 Infection Among Elementary School Educators and Students in One School District - Georgia, December 2020-January 2021.

In-person learning benefits children and communities (1). Understanding the context in which transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), occurs in schools is critical to improving the safety of in-person learning. During December 1, 2020-January 22, 2021, Cobb and Douglas Public Health (CDPH), the Georgia Department of Public Health (GDPH), and CDC investigated SARS-CoV-2 transmission in eight public elementary schools in a single school district. COVID-19 cases* among educators and students were either self-reported or identified by local public health officials. Close contacts (contacts)† of persons with a COVID-19 case received testing. Among contacts who received positive test results, public health investigators assessed epidemiologic links, probable transmission directionality, and the likelihood of in-school transmission.§ Nine clusters of three or more epidemiologically linked COVID-19 cases were identified involving 13 educators and 32 students at six of the eight elementary schools. Two clusters involved probable educator-to-educator transmission that was followed by educator-to-student transmission and resulted in approximately one half (15 of 31) of school-associated cases. Sixty-nine household members of persons with school-associated cases were tested, and 18 (26%) received positive results. All nine transmission clusters involved less than ideal physical distancing, and five involved inadequate mask use by students. Educators were central to in-school transmission networks. Multifaceted mitigation measures in schools, including promotion of COVID-19 precautions outside of school, minimizing in-person adult interactions at school, and ensuring universal and correct mask use and physical distancing among educators and students when in-person interaction is unavoidable, are important in preventing in-school transmission of SARS-CoV-2. Although not required for reopening schools, COVID-19 vaccination should be considered as an additional mitigation measure to be added when available.

Is Symptom Screening Useful for Identifying COVID-19 Infection in School Settings? Georgia, USA.

This study's goal was to characterize the utility of symptom screening in staff and students for COVID-19 identification and control of transmission in a school setting. We conducted a secondary analysis of cross-sectional data for staff, students and associated household members in a Georgia school district exposed to COVID-19 cases who received RT-PCR testing and symptom monitoring. Among positive contacts, 30/49 (61%) of students and 1/6 (17%) of staff reported no symptoms consistent with COVID-19. Symptom sensitivity was 30% in elementary students and 42% in middle/high students. Fifty-three percent (10/19) of symptomatic positive contacts had at least one household member test positive for SARS-CoV-2 compared with 50% (10/20) of asymptomatic positive contacts. The absence of symptoms in children is not indicative of a lack of SARS-CoV-2 infection or reduced risk of infection for associated household members. Testing all close contacts of people with COVID-19 in schools is needed to interrupt transmission networks.

An analysis of the association between older recipient age and outcomes after whole-organ pancreas transplantation - a single-centre, retrospective study.

Older people are increasingly being referred for consideration for pancreas transplantation (PT). We investigated the outcomes after PT in our older recipient cohort. A prospectively maintained database was interrogated. The cohort was analysed for associations between outcome and older recipient age. A total of 444 transplants were performed in patients aged 23-54 years and 83 transplants in patients aged 55-67 years. There was no difference in death-censored pancreas or kidney graft survival between the groups. Patient death was associated with older recipient age (HR 1.63 per 10-year increase). In multivariate Cox regression, risk of mortality was also associated with post-transplant myocardial infarction (HR 7.25, P = 0.006), pancreas failure (HR 1.91, P = 0.003) and kidney failure (HR 3.55, P < 0.001). About 40% of recipients who died in the first year post-transplant suffered early graft loss. Those alive at a year post-transplant had inferior survival if they had lost their kidney graft (P < 0.001). Mortality is higher in older patients and is strongly associated with pancreas and kidney graft failure. This suggests that pancreas transplantation is feasible in older recipients, and careful selection of donor organs is important to optimize survival.

Clinical Question: Nasal saline or intranasal corticosteroids to treat allergic rhinitis in children.

CLINICAL QUESTION: In pediatric populations, is nasal saline irrigation as effective as intranasal corticosteroids at relieving allergic rhinitis symptoms? ANSWER: No. Intranasal steroids are more effective than nasal saline alone to reduce symptoms of allergic rhinitis (AR) in children. Combination therapy further improves symptom reduction. LEVEL OF EVIDENCE FOR THE ANSWER: B SEARCH TERMS: Allergic Rhinitis, Nasal Saline, Nasal corticosteroids, children younger than age 18. DATE SEARCH WAS CONDUCTED: August and September 2014, October 2015. INCLUSION CRITERIA: Meta-analyses, randomized controlled trials, systematic reviews, cohort studies, nasal spray, hypertonic saline solution, nasal lavage, rhinitis, intranasal administration, nasal saline, human, English language. EXCLUSION CRITERIA: Antihistamines, Adults, Articles older than 2008.

Early postoperative continuous glucose monitoring in pancreas transplant recipients.

Continuous glucose monitoring (CGM) is used in people with type 1 diabetes to help with insulin treatment regimens. Its value in whole-organ pancreas transplantation (PT) is largely unknown. This study aimed to use CGM to assess the metabolic profile of pancreas transplant recipients in the early post-transplant period. We studied CGM data in 30 PT recipients and related findings to an early oral glucose tolerance test (OGTT). Complete data were available for 26 recipients. Seven days after a PT, normoglycaemia was present 77.9% of the time. Hypoglycaemic events (glucose <3.9 mmol/l) occurred in 10 of 26 (38.5%) of the cohort, but were infrequent (present 1.4% of the time). Hyperglycaemia (glucose >7.8 mmol/l) was present for 20.7% of the study period and correlated with a diagnosis of abnormal glucose tolerance. Whilst normoglycaemia is successfully achieved for the majority of the time after PT, hypoglycaemia can occur. Hyperglycaemia is more common and correlates well with the early postoperative OGTT, which is associated with graft failure. CGM is easier to perform and provides 24-h data that could inform clinical decision-making in patients in the postoperative period.

Postoperative impaired glucose tolerance is an early predictor of pancreas graft failure.

AIMS/HYPOTHESIS: The management of pancreatic transplantation is limited by a lack of clinically relevant early markers of graft dysfunction to enable intervention prior to irreversible damage. The aim of this study was to assess the OGTT as an early predictor of pancreatic graft failure. METHODS: Patients with graft failure (return to insulin dependence) were identified from a prospectively maintained clinical database. Data from OGTTs performed within 2 weeks of the transplant were retrospectively collected for 210 subjects, 42 with graft failure (21 after simultaneous pancreas-kidney transplant and 21 after isolated pancreas transplant) matched to 168 with functioning grafts. The groups were compared to assess the relationship between early OGTT result and pancreas graft failure. RESULTS: Mean 2 h glucose from the OGTT was significantly higher in the overall graft failure group compared with the control group (8.36 vs 6.81 mmol/l, p = 0.014). When interpreted in combination with fasting glucose, abnormal glucose tolerance was more common in the failed graft group (50% vs 22%, p = 0.001). In an adjusted model, abnormal glucose tolerance emerged as the most predictive independent factor for graft failure, HR 1.66 (95% CI 1.22, 2.24), p = 0.001. These findings were consistent between the different transplant procedures performed. CONCLUSIONS/INTERPRETATION: We conclude that early post-transplant abnormal glucose tolerance is associated with later whole organ pancreas graft failure. An OGTT performed within the first month postoperatively provides an easily measurable assessment of an independent early risk factor of pancreatic graft dysfunction.

Livability for all? Conceptual limits and practical implications.

Livability has risen, alongside sustainability, as a guiding principle for planning and policy. Promoted as the more tangible of the two concepts, livability shapes public perception and infrastructure investments in cities, as well as competition among cities for the attention of the public, investment communities, and potentially fickle and mobile human capital. This paper takes stock of the current discourse on livability, identifies two central elements that have yet to shape the assessments of livability and policies to promote it, and explores strategies for research and practice to transform the livability concept, and with it the places in which the lives and livelihoods of people unfold.

A blueprint for strategic urban research: the urban piazza.

Urban research in many countries has failed to keep up with the pace of rapidly and constantly evolving urban change. The growth of cities, the increasing complexity of their functions and the complex intra- and inter-urban linkages in this 'urban century' demand new approaches to urban analysis, which, from a systemic perspective, supersede the existing fragmentation in urban studies. In this paper we propose the concept of the urban piazza as a framework in order to address some of the inefficiencies associated with current urban analysis. By combining wealth-creating potential with smart urban mobility, ecological resilience and social buzz in this integrated and systemic framework, the aim is to set the basis for a 'New Urban World' research blueprint, which lays the foundation for a broader and more integrated research programme for strategic urban issues.

Autonomous Synthesis of Functional, Permanently Phosphorylated Proteins for Defining the Interactome of Monomeric 14-3-3ζ.

14-3-3 proteins are dimeric hubs that bind hundreds of phosphorylated "clients" to regulate their function. Installing stable, functional mimics of phosphorylated amino acids into proteins offers a powerful strategy to study 14-3-3 function in cellular-like environments, but a previous genetic code expansion (GCE) system to translationally install nonhydrolyzable phosphoserine (nhpSer), with the γ-oxygen replaced with CH2, site-specifically into proteins has seen limited usage. Here, we achieve a 40-fold improvement in this system by engineering into Escherichia coli a six-step biosynthetic pathway that produces nhpSer from phosphoenolpyruvate. Using this autonomous "PermaPhos" expression system, we produce three biologically relevant proteins with nhpSer and confirm that nhpSer mimics the effects of phosphoserine for activating GSK3ß phosphorylation of the SARS-CoV-2 nucleocapsid protein, promoting 14-3-3/client complexation, and monomerizing 14-3-3 dimers. Then, to understand the biological function of these phosphorylated 14-3-3ζ monomers (containing nhpSer at Ser58), we isolate its interactome from HEK293T lysates and compare it with that of wild-type 14-3-3ζ. These data identify two new subsets of 14-3-3 client proteins: (i) those that selectively bind dimeric 14-3-3ζ and (ii) those that selectively bind monomeric 14-3-3ζ. We discover that monomeric-but not dimeric-14-3-3ζ interacts with cereblon, an E3 ubiquitin-ligase adaptor protein of pharmacological interest.

Making Space in Geographical Analysis.

In this commentary we reflect on the potential and power of geographical analysis, as a set of methods, theoretical approaches, and perspectives, to increase our understanding of how space and place matter for all. We emphasize key aspects of the field, including accessibility, urban change, and spatial interaction and behavior, providing a high-level research agenda that indicates a variety of gaps and routes for future research that will not only lead to more equitable and aware solutions to local and global challenges, but also innovative and novel research methods, concepts, and data. We close with a set of representation and inclusion challenges to our discipline, researchers, and publication outlets.

Growing Up and Cleaning Up: The Environmental Kuznets Curve Redux.

Borrowing from the Kuznets curve literature, researchers have coined the term "environmental Kuznets curve" or EKC to characterize the relationship between pollution levels and income: pollution levels will increase with income but some threshold of income will eventually be reached, beyond which pollution levels will decrease. The link between the original Kuznets curve, which posited a similar relationship between income and inequality, and its pollution-concerned offspring lies primarily with the shape of both curves (an upside-down U) and the central role played by income change. Although the EKC literature has burgeoned over the past several years, few concrete conclusions have been drawn, the main themes of the literature have remained constant, and no consensus has been reached regarding the existence of an environmental Kuznets curve. EKC research has used a variety of types of data and a range of geographical units to examine the effects of income levels on pollution. Changes in pollution levels might also be at least partly explained by countries' position in the demographic transition and their general population structure, however little research has included this important aspect in the analysis. In addition, few analyses confine themselves to an evaluation for one country of the long-term relationship between income and pollution. Using United States CO2 emissions as well as demographic, employment, trade and energy price data, this paper seeks to highlight the potential impact of population and economic structure in explaining the relationship between income and pollution levels.

Determining Copper and Zinc Content in Superoxide Dismutase Using Electron Capture Dissociation Under Native Spray Conditions.

Localizing metal binding to specific sites in proteins remains a challenging analytical problem in vitro and in vivo. Although metal binding can be maintained by "native" electrospray ionization with intact proteins for quantitation by mass spectrometry, subsequent fragmentation of proteins with slow-heating methods like collision-induced dissociation (CID) can scramble and detach metals. In contrast, electron capture dissociation (ECD) fragmentation produces highly localized bond cleavage that is well known to preserve posttranslational modifications. We show how a newly available ECD tool that can be retrofitted on standard QTOF mass spectrometers allows the sites of copper and zinc binding to be localized in the antioxidant enzyme Cu, Zn superoxide dismutase (SOD1). The loss of zinc from Cu, Zn SOD1 has been shown to induce motor neuron death and could have a causal role in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The methods described enable copper loss to be distinguished from zinc using distinct ECD fragments of SOD1 and are broadly applicable to other metalloproteins.

The longitudinal associations between proximity to local grocery shops and functional ability in the very old living with and without multimorbidity: Results from the Newcastle 85+ study.

BACKGROUNDS: The very old, people aged ≥85, is a fast-growing age group with high risk of disability and dependence. To identify environmental factors that support maintenance of functional ability, the aim of this study is to investigate the longitudinal associations between proximity to local grocery shops and the ability to shop for groceries in the very old and to examine the potential variation between those living with and without multimorbidity. METHODS: This study was based on the Newcastle 85+ study, a population-based cohort of people aged 85 in North-East England. The numbers of grocery shops were identified within a 500 m road distance to participants' residence. Multilevel Poisson regression modelling was used to investigate whether proximity to local grocery shops was associated with the ability to do grocery shopping over five years in those with and without multimorbidity adjusting for sociodemographic factors and area deprivation. RESULTS: The very old who lived in more deprived areas were more likely to have a grocery shop within 500 m than those in less deprived areas. Proximity to local grocery shops was not associated with the ability to do grocery shopping in the participants who had none or one chronic condition (IRR: 1.00; 95% CI: 0.89, 1.12) but moderated loss of the ability in those living with multimorbidity (IRR: 0.82; 95% CI: 0.70, 0.96). CONCLUSIONS: For the very old living with multimorbidity, proximity to local grocery shops may support their functional ability. Future research should investigate how to support older people with poor health to access local grocery shops.

Nanobody assemblies with fully flexible topology enabled by genetically encoded tetrazine amino acids.

Assembling nanobodies (Nbs) into polyvalent multimers is a powerful strategy for improving the effectiveness of Nb-based therapeutics and biotechnological tools. However, generally effective approaches to Nb assembly are currently restricted to the amino or carboxyl termini, greatly limiting the diversity of Nb multimer topologies that can be produced. Here, we show that reactive tetrazine groups-site-specifically inserted by genetic code expansion at Nb surface sites-are compatible with Nb folding and function, enabling Nb assembly at any desired point. Using two anti-SARS-CoV-2 Nbs with viral neutralization ability, we created Nb homo- and heterodimers with improved properties compared with conventionally linked Nb homodimers, which, in the case of our tetrazine-conjugated trimer, translated into enhanced viral neutralization. Thus, this tetrazine-based approach is a generally applicable strategy that greatly increases the accessible range of Nb assembly topologies, and thereby adds the optimization of topology as an effective avenue to generate Nb assemblies with improved efficacy.

Genetic Incorporation of Two Mutually Orthogonal Bioorthogonal Amino Acids That Enable Efficient Protein Dual-Labeling in Cells.

The ability to site-specifically modify proteins at multiple sites in vivo will enable the study of protein function in its native environment with unprecedented levels of detail. Here, we present a versatile two-step strategy to meet this goal involving site-specific encoding of two distinct noncanonical amino acids bearing bioorthogonal handles into proteins in vivo followed by mutually orthogonal labeling. This general approach, that we call dual encoding and labeling (DEAL), allowed us to efficiently encode tetrazine- and azide-bearing amino acids into a protein and demonstrate for the first time that the bioorthogonal labeling reactions with strained alkene and alkyne labels can function simultaneously and intracellularly with high yields when site-specifically encoded in a single protein. Using our DEAL system, we were able to perform topologically defined protein-protein cross-linking, intramolecular stapling, and site-specific installation of fluorophores all inside living Escherichia coli cells, as well as study the DNA-binding properties of yeast Replication Protein A in vitro. By enabling the efficient dual modification of proteins in vivo, this DEAL approach provides a tool for the characterization and engineering of proteins in vivo.

PermaPhos Ser : autonomous synthesis of functional, permanently phosphorylated proteins.

Installing stable, functional mimics of phosphorylated amino acids into proteins offers a powerful strategy to study protein regulation. Previously, a genetic code expansion (GCE) system was developed to translationally install non-hydrolyzable phosphoserine (nhpSer), with the γ-oxygen replaced with carbon, but it has seen limited usage. Here, we achieve a 40-fold improvement in this system by engineering into Escherichia coli a biosynthetic pathway that produces nhpSer from the central metabolite phosphoenolpyruvate. Using this "PermaPhos Ser " system - an autonomous 21-amino acid E. coli expression system for incorporating nhpSer into target proteins - we show that nhpSer faithfully mimics the effects of phosphoserine in three stringent test cases: promoting 14-3-3/client complexation, disrupting 14-3-3 dimers, and activating GSK3ß phosphorylation of the SARS-CoV-2 nucleocapsid protein. This facile access to nhpSer containing proteins should allow nhpSer to replace Asp and Glu as the go-to pSer phosphomimetic for proteins produced in E. coli .

I come to bury (population) growth, not to praise it.

In this paper, I reflect on regional perspectives on a postgrowth world, taking the case of population loss as my example. Building on existing knowledge and illustrating with descriptive examples, I highlight three aspects of population loss that bear further study-its ubiquity, dynamism, and geography. I close by emphasizing the importance of researching, thinking about, and engaging with population loss, to contribute to our understanding of a world of less, not more.