Showing papers by "University College London published in 2022"

Immediate and Longer-Term Changes in the Mental Health and Well-being of Older Adults in England During the COVID-19 Pandemic

Abstract: Despite the emphasis placed on the psychological impact of the COVID-19 pandemic, evidence from representative studies of older adults including pre-COVID-19 data and repeated assessments during the pandemic is scarce.To examine changes in mental health and well-being before and during the initial and later phases of the COVID-19 pandemic and test whether patterns varied with sociodemographic characteristics in a representative sample of older adults living in England.This longitudinal cohort study analyzed data from 5146 older adults participating in the English Longitudinal Study of Ageing who provided data before the COVID-19 pandemic (2018 and 2019) and at 2 occasions in 2020 (June or July as well as November or December).The COVID-19 pandemic and sociodemographic characteristics, including sex, age, partnership status, and socioeconomic position.Changes in depression (8-item Centre for Epidemiological Studies Depression scale), anxiety (7-item Generalized Anxiety Disorder scale), quality of life (12-item Control, Autonomy, Self-realization, and Pleasure scale), and loneliness (3-item Revised University of California, Los Angeles, loneliness scale) were tested before and during the COVID-19 pandemic using fixed-effects regression models.Of 5146 included participants, 2723 (52.9%) were women, 4773 (92.8%) were White, and the mean (SD) age was 67.7 (10.6) years. The prevalence of clinically significant depressive symptoms increased from 12.5% (95% CI, 11.5-13.4) before the COVID-19 pandemic to 22.6% (95% CI, 21.6-23.6) in June and July 2020, with a further rise to 28.5% (95% CI, 27.6-29.5) in November and December 2020. This was accompanied by increased loneliness and deterioration in quality of life. The prevalence of anxiety rose from 9.4% (95% CI, 8.8-9.9) to 10.9% (95% CI, 10.3-11.5) from June and July 2020 to November and December 2020. Women and nonpartnered people experienced worse changes in mental health. Participants with less wealth had the lowest levels of mental health before and during the COVID-19 pandemic. Higher socioeconomic groups had better mental health overall but responded to the COVID-19 pandemic with more negative changes.In this longitudinal cohort study of older adults living in England, mental health and well-being continued to worsen as the COVID-19 pandemic progressed, and socioeconomic inequalities persisted. Women and nonpartnered people experienced greater deterioration in mental health.

Therapeutic targeting of “undruggable” MYC

Abstract: c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC.

Brain-inspired computing needs a master plan

Abstract: New computing technologies inspired by the brain promise fundamentally different ways to process information with extreme energy efficiency and the ability to handle the avalanche of unstructured and noisy data that we are generating at an ever-increasing rate. To realize this promise requires a brave and coordinated plan to bring together disparate research communities and to provide them with the funding, focus and support needed. We have done this in the past with digital technologies; we are in the process of doing it with quantum technologies; can we now do it for brain-inspired computing?

Using sound to synthesize covalent organic frameworks in water

Abstract: Covalent organic frameworks (COFs) are typically synthesized using solvothermal conditions (>120 °C, >72 hours) in harmful organic solvents. Here we report a strategy to rapidly (<60 minutes) synthesize imine-linked COFs in aqueous acetic acid using sonochemistry and thus avoid most of the disadvantages of solvothermal methods. Using the sonochemical method, we synthesized to our knowledge previously unreported COFs. The crystallinity and porosity of these COFs is comparable to or better than those of the same materials made by established solvothermal routes. The sonochemical method even works in sustainable solvents, such as food-grade vinegar. The generality of the method is shown in the preparation of a 2D COF with pendant functionalization and of a COF with 3D connectivity. Finally, a COF synthesized sonochemically acts as an excellent photocatalyst for the sacrificial hydrogen evolution from water, showing a more sustained catalytic performance compared with that of its solvothermal analogue. The speed, ease and generality of this sonochemical method together with improved material quality makes the use of sound an enabling methodology for the rapid discovery of functional COFs. A sonochemical route rapidly synthesizes covalent organic frameworks (COFs) in aqueous solutions of acetic acid. This method has operational advantages compared with conventional solvothermal routes and yields COFs of higher crystallinity and porosity, and hence improved materials properties.

COVID-19 vaccination and Guillain-Barré syndrome: analyses using the National Immunoglobulin Database

Abstract: Abstract Vaccination against viruses has rarely been associated with Guillain-Barré syndrome (GBS), and an association with the COVID-19 vaccine is unknown. We performed a population-based study of National Health Service data in England and a multicentre surveillance study from UK hospitals to investigate the relationship between COVID-19 vaccination and GBS. Firstly, case dates of GBS identified retrospectively in the National Immunoglobulin Database from 8 December 2021 to 8 July 2021 were linked to receipt dates of COVID-19 vaccines using data from the National Immunisation Management System in England. For the linked dataset, GBS cases temporally associated with vaccination within a 6-week risk window of any COVID-19 vaccine were identified. Secondly, we prospectively collected incident UK-wide (four nations) GBS cases from 1 January 2021 to 7 November 2021 in a separate UK multicentre surveillance database. For this multicentre UK-wide surveillance dataset, we explored phenotypes of reported GBS cases to identify features of COVID-19 vaccine-associated GBS. Nine hundred and ninety-six GBS cases were recorded in the National Immunoglobulin Database from January to October 2021. A spike of GBS cases above the 2016–2020 average occurred in March–April 2021. One hundred and ninety-eight GBS cases occurred within 6 weeks of the first-dose COVID-19 vaccination in England [0.618 cases per 100,000 vaccinations; 176 ChAdOx1 nCoV-19 (AstraZeneca), 21 tozinameran (Pfizer) and one mRNA-1273 (Moderna)]. The 6-week excess of GBS (compared to the baseline rate of GBS cases 6–12 weeks after vaccination) occurred with a peak at 24 days post-vaccination; first-doses of ChAdOx1 nCoV-19 accounted for the excess. No excess was seen for second-dose vaccination. The absolute number of excess GBS cases from January–July 2021 was between 98–140 cases for first-dose ChAdOx1 nCoV-19 vaccination. First-dose tozinameran and second-dose of any vaccination showed no excess GBS risk. Detailed clinical data from 121 GBS patients were reported in the separate multicentre surveillance dataset during this timeframe. No phenotypic or demographic differences identified between vaccine-associated and non-vaccinated GBS cases occurring in the same timeframe. Analysis of the linked NID/NIMS dataset suggested that first-dose ChAdOx1 nCoV-19 vaccination is associated with an excess GBS risk of 0.576 (95% confidence interval 0.481–0.691) cases per 100 000 doses. However, examination of a multicentre surveillance dataset suggested that no specific clinical features, including facial weakness, are associated with vaccination-related GBS compared to non-vaccinated cases. The pathogenic cause of the ChAdOx1 nCoV-19 specific first dose link warrants further study.

Anxiety, enjoyment, and boredom in language learning amongst junior secondary students in rural China: How do they contribute to L2 achievement?

Abstract: Abstract Building on the control-value theory, the present study examined the independent and joint predictive effects of three emotions—enjoyment, anxiety, and boredom—on L2 achievement over time. The participants of the study were a group of junior secondary English learners in rural China, a population that has hitherto never featured in L2 learning research. Questionnaire data and achievement data were collected at four different time points (Time 1–Time 4: T1–T4) from a large sample of 954 learners. Structural equation modeling results show that: (a) the three emotions at T1 predicted English achievement at T2 (one week after T1) and T3 (five weeks after T1) independently, while only enjoyment predicted achievement at T4 (nine weeks after T1); (b) when combined, enjoyment was the strongest and most enduring predictor across T2–T4, followed by anxiety predicting achievement at T2–T3 negatively, while boredom completely lost its predictive power across T2–T4.

Indirect effects of the covid-19 pandemic on childhood infection in England: population based observational study

Abstract: To assess the impact of the covid-19 pandemic on hospital admission rates and mortality outcomes for childhood respiratory infections, severe invasive infections, and vaccine preventable disease in England.Population based observational study of 19 common childhood respiratory, severe invasive, and vaccine preventable infections, comparing hospital admission rates and mortality outcomes before and after the onset of the pandemic in England.Hospital admission data from every NHS hospital in England from 1 March 2017 to 30 June 2021 with record linkage to national mortality data.Children aged 0-14 years admitted to an NHS hospital with a selected childhood infection from 1 March 2017 to 30 June 2021.For each infection, numbers of hospital admissions every month from 1 March 2017 to 30 June 2021, percentage changes in the number of hospital admissions before and after 1 March 2020, and adjusted odds ratios to compare 60 day case fatality outcomes before and after 1 March 2020.After 1 March 2020, substantial and sustained reductions in hospital admissions were found for all but one of the 19 infective conditions studied. Among the respiratory infections, the greatest percentage reductions were for influenza (mean annual number admitted between 1 March 2017 and 29 February 2020 was 5379 and number of children admitted from 1 March 2020 to 28 February 2021 was 304, 94% reduction, 95% confidence interval 89% to 97%), and bronchiolitis (from 51 655 to 9423, 82% reduction, 95% confidence interval 79% to 84%). Among the severe invasive infections, the greatest reduction was for meningitis (50% reduction, 47% to 52%). For the vaccine preventable infections, reductions ranged from 53% (32% to 68%) for mumps to 90% (80% to 95%) for measles. Reductions were seen across all demographic subgroups and in children with underlying comorbidities. Corresponding decreases were also found for the absolute numbers of 60 day case fatalities, although the proportion of children admitted for pneumonia who died within 60 days increased (age-sex adjusted odds ratio 1.71, 95% confidence interval 1.43 to 2.05). More recent data indicate that some respiratory infections increased to higher levels than usual after May 2021.During the covid-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions) and societal strategies (school closures, lockdowns, and restricted travel) were used to reduce transmission of SARS-CoV-2, which also reduced admissions for common and severe childhood infections. Continued monitoring of these infections is required as social restrictions evolve.

Social isolation: An underappreciated determinant of physical health.

Abstract: While a sizable body of research demonstrates the associations between social connection and health, much of the recent focus in the broader public and to some extent among academics has been on loneliness, with more objective/structural aspects often assumed to be proxies for more influential relationship factors such as relationship functions and quality. However, evidence suggests the actual presence of others (proximity and regular contact) is essential, and many studies document these structural indicators have just as powerful and, in some cases, more potent effects on indicators of health and well-being. This paper summarizes the evidence on social isolation and health and provides a framework for why social isolation may be a powerful predictor of health and mortality.

IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment

Abstract: Abstract The overall response rate for anti–PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNα and anti–PD-1–based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immunocompetent orthotopic and spontaneous HCC models, IFNα therapy synergized with anti–PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+CD8+ T cells. Mechanistically, IFNα suppressed HIF1α signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR–FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFNα reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade–induced immune response. Our findings suggest that IFNα and anti–PD-1 cotreatment is an effective novel combination strategy for patients with HCC. Significance: Our study supports a role of tumor glucose metabolism in IFNα-mediated antitumor immunity in HCC, and tumor-infiltrating CD27+CD8+ T cells may be a promising biomarker for stratifying patients for anti–PD-1 therapy. See related commentary by Kao et al., p. 1615. This article is highlighted in the In This Issue feature, p. 1599

A transcriptomic axis predicts state modulation of cortical interneurons

Abstract: Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes1-6, but it is not known whether these subtypes have correspondingly diverse patterns of activity in the living brain. Here we show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, which are organized by a single factor: position along the main axis of transcriptomic variation. We combined in vivo two-photon calcium imaging of mouse V1 with a transcriptomic method to identify mRNA for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 subclasses, 11 types and 35 subtypes using previously defined transcriptomic clusters3. Responses to visual stimuli differed significantly only between subclasses, with cells in the Sncg subclass uniformly suppressed, and cells in the other subclasses predominantly excited. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory subtypes that fired more in resting, oscillatory brain states had a smaller fraction of their axonal projections in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro7, and expressed more inhibitory cholinergic receptors. Subtypes that fired more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 subtypes shape state-dependent cortical processing.

<scp>CosmoPower</scp>: emulating cosmological power spectra for accelerated Bayesian inference from next-generation surveys

Abstract: ABSTRACT We present CosmoPower, a suite of neural cosmological power spectrum emulators providing orders-of-magnitude acceleration for parameter estimation from two-point statistics analyses of Large-Scale Structure (LSS) and Cosmic Microwave Background (CMB) surveys. The emulators replace the computation of matter and CMB power spectra from Boltzmann codes; thus, they do not need to be re-trained for different choices of astrophysical nuisance parameters or redshift distributions. The matter power spectrum emulation error is less than $0.4{{\ \rm per\ cent}}$ in the wavenumber range $k \in [10^{-5}, 10] \, \mathrm{Mpc}^{-1}$ for redshift z ∈ [0, 5]. CosmoPower emulates CMB temperature, polarization, and lensing potential power spectra in the 5-σ region of parameter space around the Planck best-fitting values with an error ${\lesssim}10{{\ \rm per\ cent}}$ of the expected shot noise for the forthcoming Simons Observatory. CosmoPower is showcased on a joint cosmic shear and galaxy clustering analysis from the Kilo-Degree Survey, as well as on a Stage IV Euclid-like simulated cosmic shear analysis. For the CMB case, CosmoPower is tested on a Planck 2018 CMB temperature and polarization analysis. The emulators always recover the fiducial cosmological constraints with differences in the posteriors smaller than sampling noise, while providing a speed-up factor up to O(104) to the complete inference pipeline. This acceleration allows posterior distributions to be recovered in just a few seconds, as we demonstrate in the Planck likelihood case. CosmoPower is written entirely in python, can be interfaced with all commonly used cosmological samplers, and is publicly available at: https://github.com/alessiospuriomancini/cosmopower.

Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

Abstract: Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.