Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function.

Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.

Ethnic differences in COVID-19 mortality in the second and third waves of the pandemic in England during the vaccine rollout: a retrospective, population-based cohort study.

BACKGROUND: Ethnic minority groups in England have been disproportionately affected by the COVID-19 pandemic and have lower vaccination rates than the White British population. We examined whether ethnic differences in COVID-19 mortality in England have continued since the vaccine rollout and to what extent differences in vaccination rates contributed to excess COVID-19 mortality after accounting for other risk factors. METHODS: We conducted a retrospective, population-based cohort study of 28.8 million adults aged 30-100 years in England. Self-reported ethnicity was obtained from the 2011 Census. The outcome was death involving COVID-19 during the second (8 December 2020 to 12 June 2021) and third wave (13 June 2021 to 1 December 2021). We calculated hazard ratios (HRs) for death involving COVID-19, sequentially adjusting for age, residence type, geographical factors, sociodemographic characteristics, pre-pandemic health, and vaccination status. RESULTS: Age-adjusted HRs of death involving COVID-19 were elevated for most ethnic minority groups during both waves, particularly for groups with lowest vaccination rates (Bangladeshi, Pakistani, Black African, and Black Caribbean). HRs were attenuated after adjusting for geographical factors, sociodemographic characteristics, and pre-pandemic health. Further adjusting for vaccination status substantially reduced residual HRs for Black African, Black Caribbean, and Pakistani groups in the third wave. Fully adjusted HRs only remained elevated for the Bangladeshi group (men: 2.19 [95% CI 1.72-2.78]; women: 2.12 [1.58-2.86]) and Pakistani men (1.24 [1.06-1.46]). CONCLUSIONS: Lower COVID-19 vaccination uptake in several ethnic minority groups may drive some of the differences in COVID-19 mortality compared to White British. Public health strategies to increase vaccination uptake in ethnic minority groups would help reduce inequalities in COVID-19 mortality, which have remained substantial since the start of the vaccination campaign.

Sex-dependent effects of Setd1a haploinsufficiency on development and adult behaviour.

Loss of function (LoF) mutations affecting the histone methyl transferase SETD1A are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of Setd1a haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male Setd1a+/- mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male Setd1a+/- mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in Setd1a+/ samples. In adulthood, we found enhanced acoustic startle responding in male Setd1a+/- mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female Setd1a+/- mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, Setd1a haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.

Inequalities in SARS-CoV-2 case rates by ethnicity, religion, measures of socioeconomic position, English proficiency, and self-reported disability: cohort study of 39 million people in England during the alpha and delta waves.

Objective: To examine sociodemographic inequalities in people with SARS-CoV-2 during the second (alpha) and third (delta) waves of the covid-19 pandemic. Design: Retrospective, population based cohort study. Setting: Resident population of England. Participants: 39 006 194 people aged 10 years and older who were enumerated in the 2011 census, registered with the NHS, and alive on 1 September 2020. Main outcome measures: Age standardised SARS-CoV-2 case rates (ie, the number of people who received a positive test result per 100 000 person weeks at risk) during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. Age standardised rates were calculated by sociodemographic characteristics and adjusted rate ratios were estimated using generalised linear regression models with a Poisson distribution (models were adjusted for covariates including sex, age, geographical variables, and sociodemographic characteristics). Results: During the study period, 5 767 584 people (14.8% of the study population) tested positive for SARS-CoV-2. In the second wave, the fully adjusted relative risks of having a positive test were highest for the Bangladeshi and Pakistani ethnic groups compared with the white British group, with rate ratios of 1.75 (95% confidence interval 1.73 to 1.77) and 1.69 (1.68 to 1.70), respectively. Muslim and Sikh religious groups had fully adjusted rate ratios of 1.51 (1.50 to 1.51) and 1.64 (1.63 to 1.66), respectively, compared with the Christian group. Greater area deprivation, disadvantaged socioeconomic position, living in a care home, and low English language proficiency were also associated with higher relative risk of having a positive test. However, the inequalities among groups varied over time. Being Christian, white British, without a disability, and from a more advantaged socioeconomic position were associated with increased relative risk of testing positive during the third wave. Conclusion: Research is urgently needed to understand the large sociodemographic inequalities in SARS-CoV-2 case rates in order to inform policy interventions in future waves or pandemics.

Risk of New-Onset Long COVID Following Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2: A Community-Based Cohort Study.

Background: Little is known about the risk of long COVID following reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We estimated the likelihood of new-onset, self-reported long COVID after a second SARS-CoV-2 infection, compared to a first infection. Methods: We included UK COVID-19 Infection Survey participants who tested positive for SARS-CoV-2 between 1 November 2021 and 8 October 2022. The primary outcome was self-reported long COVID 12-20 weeks after each infection. Separate analyses were performed for those <16 years and ≥16 years. We estimated adjusted odds ratios (aORs) for new-onset long COVID using logistic regression, comparing second to first infections, controlling for sociodemographic characteristics and calendar date of infection, plus vaccination status in participants ≥16 years of age. Results: Overall, long COVID was reported by those ≥16 years after 4.0% and 2.4% of first and second infections, respectively; the corresponding estimates among those aged <16 years were 1.0% and 0.6%. The aOR for long COVID after second compared to first infections was 0.72 (95% confidence interval [CI], .63-.81) for those ≥16 years and 0.93 (95% CI, .57-1.53) for those <16 years. Conclusions: The risk of new-onset long COVID after a second SARS-CoV-2 infection is lower than that after a first infection for persons aged ≥16 years, though there is no evidence of a difference in risk for those <16 years. However, there remains some risk of new-onset long COVID after a second infection, with around 1 in 40 of those aged ≥16 years and 1 in 165 of those <16 years reporting long COVID after a second infection.

Vaccine effectiveness for prevention of covid-19 related hospital admission during pregnancy in England during the alpha and delta variant dominant periods of the SARS-CoV-2 pandemic: population based cohort study.

Objective: To estimate vaccine effectiveness for preventing covid-19 related hospital admission in individuals first infected with the SARS-CoV-2 virus during pregnancy compared with those of reproductive age who were not pregnant when first infected with the virus. Design: Population based cohort study. Setting: Office for National Statistics Public Health Data Asset linked dataset, providing national linked census and administrative data in England, 8 December 2020 to 31 August 2021. Participants: 815 477 females aged 18-45 years (mean age 30.4 years) who had documented evidence of a first SARS-CoV-2 infection in the NHS Test and Trace or Hospital Episode Statistics data. Main outcome measures: Hospital admission where covid-19 was recorded as the primary diagnosis. Cox proportional hazards models, adjusted for calendar time of infection, sociodemographic factors, and pre-existing health conditions related to uptake of the covid-19 vaccine and risk of severe covid-19 outcomes, were used to estimate vaccine effectiveness as the complement of the hazard ratio for hospital admission for covid-19. Results: Compared with pregnant individuals who were not vaccinated, the adjusted rate of hospital admission for covid-19 was 77% (95% confidence interval 70% to 82%) lower for pregnant individuals who had received one dose and 83% (76% to 89%) lower for those who had received two doses of vaccine. These estimates were similar to those found in the non-pregnant group: 79% (77% to 81%) for one dose and 83% (82% to 85%) for two doses of vaccine. Among those who were vaccinated >90 days before infection, having two doses of vaccine was associated with a greater reduction in risk than one dose. Conclusions: Covid-19 vaccination was associated with reduced rates of hospital admission in pregnant individuals infected with the SARS-CoV-2 virus, and the reduction in risk was similar to that in non-pregnant individuals. Waning of vaccine effectiveness occurred more quickly after one than after two doses of vaccine.

Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study.

We investigated long COVID incidence by vaccination status in a random sample of UK adults from April 2020 to November 2021. Persistent symptoms were reported by 9.5% of 3090 breakthrough severe acute respiratory syndrome coronavirus 2 infections and 14.6% of unvaccinated controls (adjusted odds ratio, 0.59 [95% confidence interval, .50-.69]), emphasizing the need for public health initiatives to increase population-level vaccine uptake.

Deaths involving COVID-19 by self-reported disability status during the first two waves of the COVID-19 pandemic in England: a retrospective, population-based cohort study.

BACKGROUND: People with learning disabilities are at substantially increased risk of COVID-19 mortality, but evidence on risks of COVID-19 mortality for disabled people more generally is limited. We aimed to use population-level data to estimate the association between self-reported disability and death involving COVID-19 during the first two waves of the COVID-19 pandemic in England. METHODS: We conducted a retrospective, population-based cohort study of adults aged 30-100 years living in private households or communal establishments in England, using data from the Office for National Statistics Public Health Data Asset. Participants were present at the 2011 Census and alive on Jan 24, 2020. Participants reported being limited a lot in their daily activities, limited a little, or not limited at all, in response to a question from the 2011 Census. The outcome was death involving COVID-19, occurring between Jan 24, 2020, and Feb 28, 2021. We used Cox proportional hazards regression to calculate hazard ratios (HRs) for the association between disability and death involving COVID-19, sequentially adjusting for age, residence type (private household, care home, or other communal establishment), geographical characteristics (local authority district and population density), sociodemographic characteristics (ethnicity, highest qualification, Index of Multiple Deprivation decile, household characteristics [National Statistics Socio-economic Classification of the household reference person, tenure of household, household size, family status, household composition, and key worker in household], key worker type, individual and household exposure to disease, and individual and household proximity to others), and health status (pre-existing health conditions, body-mass index, and number of admissions to hospital and days spent in hospital over the previous 3 years). FINDINGS: 29 293 845 adults were included in the study (13 806 623 [47%] men, 15 487 222 [53%] women), of whom 3 038 772 (10%) reported being limited a little and 2 011 576 (7%) reported being limited a lot. During follow-up, 105 213 people died from causes involving COVID-19 in England, 61 416 (58%) of whom were disabled. Age-adjusted analyses showed higher mortality involving COVID-19 among disabled people who were limited a lot (HR 3·05 [95% CI 2·98-3·11] for men; 3·48 [3·41-3·56] for women) and disabled people who were limited a little (HR 1·88 [1·84-1·92] for men; 2·03 [1·98-2·08] for women) than among non-disabled people. Adjustment for residence type, geography, sociodemographics, and health conditions reduced but did not eliminate the associations between disability and death involving COVID-19 (HR 1·35 [1·32-1·38] for men who were limited a lot; 1·21 [1·18-1·23] for men who were limited a little; 1·55 [1·51-1·59] for women who were limited a lot; and 1·28 [1·25-1·31] for women who were limited a little). INTERPRETATION: Given the association between disability and mortality involving COVID-19, verification of these findings and consideration of recommendations for protective measures are now required. FUNDING: None.

Keeping Pace with Your Eating: Visual Feedback Affects Eating Rate in Humans.

Deliberately eating at a slower pace promotes satiation and eating quickly has been associated with a higher body mass index. Therefore, understanding factors that affect eating rate should be given high priority. Eating rate is affected by the physical/textural properties of a food, by motivational state, and by portion size and palatability. This study explored the prospect that eating rate is also influenced by a hitherto unexplored cognitive process that uses ongoing perceptual estimates of the volume of food remaining in a container to adjust intake during a meal. A 2 (amount seen; 300 ml or 500 ml) x 2 (amount eaten; 300 ml or 500 ml) between-subjects design was employed (10 participants in each condition). In two 'congruent' conditions, the same amount was seen at the outset and then subsequently consumed (300 ml or 500 ml). To dissociate visual feedback of portion size and actual amount consumed, food was covertly added or removed from a bowl using a peristaltic pump. This created two additional 'incongruent' conditions, in which 300 ml was seen but 500 ml was eaten or vice versa. We repeated these conditions using a savoury soup and a sweet dessert. Eating rate (ml per second) was assessed during lunch. After lunch we assessed fullness over a 60-minute period. In the congruent conditions, eating rate was unaffected by the actual volume of food that was consumed (300 ml or 500 ml). By contrast, we observed a marked difference across the incongruent conditions. Specifically, participants who saw 300 ml but actually consumed 500 ml ate at a faster rate than participants who saw 500 ml but actually consumed 300 ml. Participants were unaware that their portion size had been manipulated. Nevertheless, when it disappeared faster or slower than anticipated they adjusted their rate of eating accordingly. This suggests that the control of eating rate involves visual feedback and is not a simple reflexive response to orosensory stimulation.

Variation in the Oral Processing of Everyday Meals Is Associated with Fullness and Meal Size; A Potential Nudge to Reduce Energy Intake?

Laboratory studies have demonstrated that experimental manipulations of oral processing can have a marked effect on energy intake. Here, we explored whether variations in oral processing across a range of unmodified everyday meals could affect post-meal fullness and meal size. In Study 1, female participants (N = 12) attended the laboratory over 20 lunchtime sessions to consume a 400-kcal portion of a different commercially available pre-packaged meal. Prior to consumption, expected satiation was assessed. During each meal, oral processing was characterised using: (i) video-recordings of the mouth and (ii) real-time measures of plate weight. Hunger and fullness ratings were elicited pre- and post-consumption, and for a further three hours. Foods that were eaten slowly had higher expected satiation and delivered more satiation and satiety. Building on these findings, in Study 2 we selected two meals (identical energy density) from Study 1 that were equally liked but maximised differences in oral processing. On separate days, male and female participants (N = 24) consumed a 400-kcal portion of either the "fast" or "slow" meal followed by an ad libitum meal (either the same food or a dessert). When continuing with the same food, participants consumed less of the slow meal. Further, differences in food intake during the ad libitum meal were not compensated at a subsequent snacking opportunity an hour later. Together, these findings suggest that variations in oral processing across a range of unmodified everyday meals can affect fullness after consuming a fixed portion and can also impact meal size. Modifying food form to encourage increased oral processing (albeit to a lesser extent than in experimental manipulations) might represent a viable target for food manufacturers to help to nudge consumers to manage their weight.

Effects of eating rate on satiety: A role for episodic memory?

Eating slowly is associated with a lower body mass index. However, the underlying mechanism is poorly understood. Here, our objective was to determine whether eating a meal at a slow rate improves episodic memory for the meal and promotes satiety. Participants (N=40) consumed a 400ml portion of tomato soup at either a fast (1.97ml/s) or a slow (0.50ml/s) rate. Appetite ratings were elicited at baseline and at the end of the meal (satiation). Satiety was assessed using; i) an ad libitum biscuit 'taste test' (3h after the meal) and ii) appetite ratings (collected 2h after the meal and after the ad libitum snack). Finally, to evaluate episodic memory for the meal, participants self-served the volume of soup that they believed they had consumed earlier (portion size memory) and completed a rating of memory 'vividness'. Participants who consumed the soup slowly reported a greater increase in fullness, both at the end of the meal and during the inter-meal interval. However, we found little effect of eating rate on subsequent ad libitum snack intake. Importantly, after 3h, participants who ate the soup slowly remembered eating a larger portion. These findings show that eating slowly promotes self-reported satiation and satiety. For the first time, they also suggest that eating rate influences portion size memory. However, eating slowly did not affect ratings of memory vividness and we found little evidence for a relationship between episodic memory and satiety. Therefore, we are unable to conclude that episodic memory mediates effects of eating rate on satiety.