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Abstract Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG Co‐A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20‐month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4‐hydroxy‐6‐methyl‐2‐pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3‐hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.

The laser interferometer space antenna (LISA) is a future space-based interferometric gravitational-wave detector consisting of three spacecraft in a triangular configuration. The interferometric measurements of path length changes between satellites will be performed on optical benches in the satellites. Angular misalignments of the interfering beams couple into the length measurement and represent a significant noise source. Imaging systems will be used to reduce this tilt-to-length coupling. We designed and constructed an optical test bed to experimentally investigate tilt-to-length coupling. It consists of two separate structures, a minimal optical bench and a telescope simulator. The minimal optical bench comprises the science interferometer where the local laser is interfered with light from a remote spacecraft. In our experiment, a simulated version of this received beam is generated on the telescope simulator. The telescope simulator provides a tilting beam, a reference interferometer and an additional static beam as a phase reference. The tilting beam can either be a flat-top beam or a Gaussian beam. We avoid tilt-to-length coupling in the reference interferometer by using a small photo diode placed at an image of the beam rotation point. We show that the test bed is operational with an initial measurement of tilt-to-length coupling without imaging systems. Furthermore, we show the design of two different imaging systems whose performance will be investigated in future experiments. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating B cells play a significant role in tumor development, progression, and prognosis, yet a comprehensive classification system is lacking. To address this gap, we present a pan-cancer single-cell RNA sequencing (scRNA-seq) atlas of tumor-infiltrating B and plasma cells across a large sample cohort. We identify key B cell subset signatures, revealing distinct subpopulations and highlighting the heterogeneity and functional diversity of these cells in the tumor microenvironment. We explore associations between B cell subsets and checkpoint inhibitor therapy responses, finding subset-specific effects on overall response. Additionally, we examine B and T cell crosstalk, identifying unique ligand-receptor pairs for specific B cell subsets, spatially validated. This comprehensive dataset serves as a valuable resource, providing a detailed atlas that enhances the understanding of B cell complexity in tumors and opens new avenues for research and therapeutic strategies., Competing Interests: Declaration of interests K.L. has the following disclosures (unrelated to this work): patent on indel burden and CPI response pending, patent on ctDNA minimal residual disease calling methods; speaker fees from Roche Tissue Diagnostics and Ellipses Pharma; research funding from CRUK TDL/Ono/LifeArc alliance and Genesis Therapeutics; and consulting roles with Monopteros Therapeutics, Kynos Therapeutics, SAGA Diagnostics, and Tempus Labs, Inc. Also unrelated to this work, K.L. is currently employed by Isomorphic Labs. J.L.R. has the following disclosures (unrelated to this work): patents filed for cancer early detection and consulting role for Achilles Therapeutics plc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adolescence is an important period of increasing independence, when adolescents experience changing influences of family and friends on their diets as they transition into adulthood. We conducted a scoping review to map the literature on interpersonal determinants of diet quality and eating behaviors among individuals aged 13-30 years. We searched seven literature databases, and following screening, 329 papers were included. Determinants were grouped according to sub-categories of the Determinants of Nutrition and Eating framework: family structure (n = 122), social influences (n = 121), parental behaviors (n = 90), family food culture (n = 83), social support (n = 69), parental feeding styles (n = 24), parental attitudes/beliefs (n = 8), and parental resources/risk factors (n = 6), and we added two new sub-categories: parenting style (n = 74) and partner behaviors (n = 6). Fruit/vegetable (n = 143) and sugar-sweetened beverage (n = 102) intake were the most commonly measured diet outcomes, and breakfast consumption (n = 41) and fast food/takeaway intake (n = 39) the most commonly examined eating behaviors. This review highlights the gaps in the literature, both across the determinant sub-categories and also the relative paucity of longitudinal evidence and lack of evidence in emerging adults, particularly outside of university settings. Future research should focus on these areas to provide stronger evidence to support better design of interventions for this age group., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: When collecting data from human participants, it is often important to minimise the length of questionnaire-based measures. This makes it possible to ensure that the data collection is as engaging as possible, while it also reduces response burden, which may protect data quality. Brevity is especially important when assessing eating disorders and related phenomena, as minimising questions pertaining to shame-ridden, unpleasant experiences may in turn minimise any negative affect experienced whilst responding., Methods: We relied on item response theory to shorten three eating disorder and body dysmorphia measures, while aiming to ensure that the information assessed by the scales remained as close to that assessed by the original scales as possible. We further tested measurement invariance, correlations among different versions of the same scales as well as different measures, and explored additional properties of each scale, including their internal consistency. Additionally, we explored the performance of the 3-item version of the modified Weight Bias Internalisation Scale and compared it to that of the 11-item version of the scale., Results: We introduce a 5-item version of the Eating Disorder Examination Questionnaire, a 3-item version of the SCOFF questionnaire, and a 3-item version of the Dysmorphic Concern Questionnaire. The results revealed that, across a sample of UK adults (N = 987, ages 18-86, M = 45.21), the short scales had a reasonably good fit. Significant positive correlations between the longer and shorter versions of the scales and their significant positive, albeit somewhat weaker correlations to other, related measures support their convergent and discriminant validity. The results followed a similar pattern across the young adult subsample (N = 375, ages 18-39, M = 28.56)., Conclusions: These results indicate that the short forms of the tested scales may perform similarly to the full versions., (© 2024. The Author(s).)

Objective: Pure tone audiometry (PTA) is the gold standard for hearing assessment. However, it requires access to specialized equipment. Smartphone audiometry applications (apps) have been developed to perform automated threshold audiometry and could allow patients to perform self-administered screening or monitoring. This study aimed to assess the validity and feasibility of patients using apps to self-assess hearing thresholds at home, with comparison to PTA., Methods: A multi-center, prospective randomized study was conducted amongst patients undergoing PTA in clinics. Participants were randomly allocated to one of four publicly-available apps designed to measure pure tone thresholds. Participants used an app once in optimal sound-treated conditions and a further three times at home. Ear-specific frequency-specific thresholds and pure tone average were compared using Pearson correlation coefficient. The percentage of app hearing tests with results within ±10 dB of PTA was calculated. Patient acceptability was assessed via an online survey., Results: One hundred thirty-nine participants submitted data. The results of two at-home automated smartphone apps correlated strongly/very strongly with PTA average and their frequency-specific median was within ±10 dB accuracy. Smartphone audiometry performed in sound-treated and home conditions were very strongly correlated. The apps were rated as easy/very easy to use by 90% of participants and 90% would be happy/very happy to use an app to monitor their hearing., Conclusion: Judicious use of self-performed smartphone audiometry was both valid and feasible for two of four apps. It could provide frequency-specific threshold estimates at home, potentially allowing assessments of patients remotely or monitoring of fluctuating hearing loss., Level of Evidence: 2 Laryngoscope, 134:2864-2870, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

We study the relationship between proximity to fast food restaurants and weight gain from late childhood to early adolescence. We use the Millennium Cohort Study, a UK-wide nationally representative longitudinal study, linked with granular geocoded food outlet data to measure the presence of fast food outlets around children's homes and schools from ages 7 to 14. We find that proximity to fast food outlets is associated with increased weight (body mass index, overweight, obese, body fat, weight), but only among those with maternal education below degree level. Within this sample, those with lower levels of emotional regulation are at heightened risk of weight gain., (© 2023 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Background: The number and proportion of children conceived through medically assisted reproduction (MAR) is steadily increasing yet the evidence on their mental health in adolescence is inconclusive. Two main mechanisms with opposite effects can explain differences in mental health outcomes by conception mode: while more advantaged parental characteristics could positively influence it, higher parental stress could have a negative influence., Methods: Linear and logistic estimations on a longitudinal population-based birth cohort study of 9,897 individuals to investigate whether adolescents conceived through MAR are more likely than naturally conceived (NC) children to experience mental health problems at age 17, as reported by adolescents themselves and their parents. We test whether this association is confounded and/or mediated by parental background characteristics collected when the cohort member was around 9 months old (maternal age, maternal education level, ethnicity, income quintile), family structure variables measured in adolescence (number of siblings in the household at age 15, parental household structure at age 14) or maternal distress at age 14., Results: Children conceived naturally and through MAR self-reported similar mental health outcomes. The only differences between MAR and NC adolescents are in the parental reports, with parents who conceived through MAR reporting their children had 3.82 (95% CI: 1.140 to 11.54) and 2.35 (95% CI: 1.145 to 4.838) higher odds of falling within the high category of SDQ total difficulties and emotional symptoms scales, respectively. The results did not change on adjustment for mediators, such as maternal distress, number of siblings in the household and parental household structure., Conclusions: The results reveal a lack of or small differences in MAR adolescents' mental health outcomes compared to children who were conceived naturally. While the results based on the parental reports could suggest that MAR adolescents are at higher risk of suffering from mental health problems, the differences are small and not supported by adolescents' own reports. The difference between MAR and NC adolescent's parental report might reflect differences in parental concern, their relationship or closeness and can help to reconcile the mixed findings of previous studies., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Decades of research shows that sexual minority youth (SMY) display heightened risk for mental health problems, although the onset of such disparities remains unclear. The Millennium Cohort Study is the largest nationally representative longitudinal study of adolescents in the United Kingdom. In this study, participants ( N = 10,047, 50% female) self-reported their sexual identity at age 17 and had parent-reported mental health data, from the Strengths and Difficulties Questionnaire, reported across five waves at ages 5, 7, 11, 14, and 17. Multilevel linear spline models, stratified by sex, were used to examine mental health trajectories between sexual identity groups (completely heterosexual, mostly heterosexual, SMY). SMY showed heightened peer problems from the baseline assessment at age five, increasing over time, and heightened emotional problems from age 11, increasing over time. Mostly heterosexual youth showed heightened emotional problems at age 11 in males, and at age 17 in females. Findings are discussed in light of the literature on minority stress and gender conformity in youth. The use of parent-reported mental health data means that estimates are likely to be conservative. We conclude that interventions supporting SMY should start early and be available throughout adolescence.

It is often important to minimise the time participants in social science studies spend on completing questionnaire-based measures, reducing response burden, and increasing data quality. Here, we investigated the performance of the short versions of some widely used depression, anxiety, and psychological distress scales and compared them to the performance of longer versions of these scales (PHQ-2 vs PHQ-9, GAD-2 vs GAD-7, Malaise-3 vs Malaise-9, K6 vs K10). Across a sample of UK adults (N = 987, ages 18-86), we tested the existing factor structure and accuracy of the scales through confirmatory factor analyses and exploration of the total information functions, observing adequate model fit indices across the measures. Measurement invariance was tested across birth sex and age groups to explore whether any differences in measurement properties or measurement bias may exist, finding support for the invariance of most measures. We conducted bivariate correlations across the measures as a way of obtaining evidence of the equivalence in the rank-ordering of short vs long scales. The results followed a similar pattern across the young adult subsample (N = 375, ages 18-39) as in the overall sample. Overall, these results indicate that the short forms of the tested scales may perform similarly to the full versions. Where brevity is important, researchers may opt to use the shorter versions of the scales based on these data., Competing Interests: Declaration of competing interest The authors disclose no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Developmental researchers often use a multi-informant approach to measure adolescent behaviour and adjustment, but informant discrepancies are common. In general population samples, it is often found that parents report more positive and less negative outcomes than adolescents themselves. This study aimed to investigate factors associated with informant discrepancy, including adolescent sex, and parental level of psychological distress and education., Methods: Informant discrepancy on the Strengths and Difficulties Questionnaire was investigated using a Latent Difference Score (LDS) approach, which estimates the true difference between parent and adolescent reports in a structural equation model. The sample were parent-adolescent dyads from the seventh wave of the UK Millennium Cohort Study (N = 6947, 49.3% female, aged 17 years)., Results: Parents reported lower levels of difficulties (emotion symptoms, peer problems, conduct problems), and higher levels of pro-social behaviour than adolescents themselves. Conditional effects were found, as discrepancy was greater amongst parent-daughter dyads for emotion and peer problems, and greater amongst parent-son dyads for conduct problems and pro-social behaviour. Parent-adolescent discrepancy was also greater generally if parents had a lower level of psychological distress or a higher level of education., Conclusions: In a large general population sample from the UK, it was found that adolescents tended to report more negative and less positive outcomes than parents reported about them. Conditional effects were found at the parent and adolescent level suggesting that specific informant biases are likely to impact the measurement of adolescent behaviour and adjustment across reporters., (© 2023. The Author(s).)

Background: This paper examined whether distinct life-course trajectories of psychological distress from adolescence to midlife were associated with poorer mental health outcomes during the pandemic., Methods: We present a secondary analysis of two nationally representative British birth cohorts, the 1958 National Child Development Study (NCDS) and 1970 British Cohort Study (BCS70). We used latent variable mixture models to identify pre-pandemic longitudinal trajectories of psychological distress and a modified Poisson model with robust standard errors to estimate associations with psychological distress, life satisfaction and loneliness at different points during the pandemic., Results: Our analysis identified five distinct pre-pandemic trajectories of psychological distress in both cohorts. All trajectories with prior symptoms of psychological distress irrespective of age of onset, severity and chronicity were associated with a greater relative risk of poorer mental health outcomes during the pandemic and the probability of poorer mental health associated with psychological distress trajectories remained fairly constant. The relationship was not fully attenuated when most recent pre-pandemic psychological distress and other midlife factors were controlled for., Conclusions: Whilst life-course trajectories with any prior symptoms of psychological distress put individuals at greater risk of poor mental health outcomes during the pandemic, those with chronic and more recent occurrences were at highest risk. In addition, prior poor mental health during the adult life-course may mean individuals are less resilient to shocks, such as pandemics. Our findings show the importance of considering heterogeneous mental health trajectories across the life-course in the general population in addition to population average trends.

This study uses longitudinal data from the UK Millennium Cohort Study (N = 13,277) to examine the childhood and early adolescence factors that predict weapon involvement in middle adolescence, which in this study is exemplified by having carried or used a weapon. It finds that childhood experiences of low family income and domestic abuse between parents predict weapon involvement at age 17 years. Other predictors include childhood externalizing problems and self-harm in early adolescence. Further early adolescent behaviors and experiences that predict weapon involvement are own substance use, peer substance use, school exclusion, and high levels of electronic gaming. These findings provide concrete areas for targeting risk factors both in childhood and the early adolescent period, with an indication that early intervention and prevention are likely to reduce the need for later action., (© 2022 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK., Methods: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis., Results: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I 2 : 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I 2 : 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I 2 : 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I 2 : 47%) but not men (0.84; 95% CI: 0.67-1.05; I 2 : 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I 2 : 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I 2 : 0%)., Conclusions: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics., (© 2022. The Author(s).)

Background: The COVID-19 pandemic has led to major economic disruptions. In March 2020, the UK implemented the Coronavirus Job Retention Scheme - known as furlough - to minimize the impact of job losses. We investigate associations between change in employment status and mental and social wellbeing during the early stages of the pandemic., Methods: Data were from 25,670 respondents, aged 17-66, across nine UK longitudinal studies. Furlough and other employment changes were defined using employment status pre-pandemic and during the first lockdown (April-June 2020). Mental and social wellbeing outcomes included psychological distress, life satisfaction, self-rated health, social contact, and loneliness. Study-specific modified Poisson regression estimates, adjusting for socio-demographic characteristics and pre-pandemic mental and social wellbeing, were pooled using meta-analysis. Associations were also stratified by sex, age, education, and household composition., Results: Compared to those who remained working, furloughed workers were at greater risk of psychological distress (adjusted risk ratio, ARR = 1.12; 95%CI: 0.97, 1.29), low life satisfaction (ARR = 1.14; 95%CI: 1.07, 1.22), loneliness (ARR = 1.12; 95%CI: 1.01, 1.23), and poor self-rated health (ARR = 1.26; 95%CI: 1.05, 1.50). Nevertheless, compared to furloughed workers, those who became unemployed had greater risk of psychological distress (ARR = 1.30; 95%CI: 1.12, 1.52), low life satisfaction (ARR = 1.16; 95%CI: 0.98, 1.38), and loneliness (ARR = 1.67; 95%CI: 1.08, 2.59). Effects were not uniform across all sub-groups., Conclusions: During the early stages of the pandemic, those furloughed had increased risk of poor mental and social wellbeing, but furloughed workers fared better than those who became unemployed, suggesting that furlough may have partly mitigated poorer outcomes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards., Experimental Design: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations)., Results: Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849., Conclusions: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic., Methods: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education., Results: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep., Conclusions: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours., (© 2022. The Author(s).)

Importance: How population mental health has evolved across the COVID-19 pandemic under varied lockdown measures is poorly understood, and the consequences for health inequalities are unclear., Objective: To investigate changes in mental health and sociodemographic inequalities from before and across the first year of the COVID-19 pandemic in 11 longitudinal studies., Design, Setting, and Participants: This cohort study included adult participants from 11 UK longitudinal population-based studies with prepandemic measures of psychological distress. Analyses were coordinated across these studies, and estimates were pooled. Data were collected from 2006 to 2021., Exposures: Trends in the prevalence of poor mental health were assessed in the prepandemic period (time period 0 [TP 0]) and at 3 pandemic TPs: 1, initial lockdown (March to June 2020); 2, easing of restrictions (July to October 2020); and 3, a subsequent lockdown (November 2020 to March 2021). Analyses were stratified by sex, race and ethnicity, education, age, and UK country., Main Outcomes and Measures: Multilevel regression was used to examine changes in psychological distress from the prepandemic period across the first year of the COVID-19 pandemic. Psychological distress was assessed using the 12-item General Health Questionnaire, the Kessler 6, the 9-item Malaise Inventory, the Short Mood and Feelings Questionnaire, the 8-item or 9-item Patient Health Questionnaire, the Hospital Anxiety and Depression Scale, and the Centre for Epidemiological Studies-Depression across different studies., Results: In total, 49 993 adult participants (12 323 [24.6%] aged 55-64 years; 32 741 [61.2%] women; 4960 [8.7%] racial and ethnic minority) were analyzed. Across the 11 studies, mental health deteriorated from prepandemic scores across all 3 pandemic periods, but there was considerable heterogeneity across the study-specific estimated effect sizes (pooled estimate for TP 1: standardized mean difference [SMD], 0.15; 95% CI, 0.06-0.25; TP 2: SMD, 0.18; 95% CI, 0.09-0.27; TP 3: SMD, 0.21; 95% CI, 0.10-0.32). Changes in psychological distress across the pandemic were higher in women (TP 3: SMD, 0.23; 95% CI, 0.11, 0.35) than men (TP 3: SMD, 0.16; 95% CI, 0.06-0.26) and lower in individuals with below-degree level education at TP 3 (SMD, 0.18; 95% CI, 0.06-0.30) compared with those who held degrees (SMD, 0.26; 95% CI, 0.14-0.38). Increased psychological distress was most prominent among adults aged 25 to 34 years (SMD, 0.49; 95% CI, 0.14-0.84) and 35 to 44 years (SMD, 0.35; 95% CI, 0.10-0.60) compared with other age groups. No evidence of changes in distress differing by race and ethnicity or UK country were observed., Conclusions and Relevance: In this study, the substantial deterioration in mental health seen in the UK during the first lockdown did not reverse when lockdown lifted, and a sustained worsening was observed across the pandemic period. Mental health declines have been unequal across the population, with women, those with higher degrees, and those aged 25 to 44 years more affected than other groups.

Background: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable., Aims: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing., Method: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies., Results: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03)., Conclusions: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

We use longitudinal data across a key developmental period, spanning much of childhood and adolescence (age 5 to 17, years 2006-2018) from the UK Millennium Cohort Study, a nationally representative study with an initial sample of just over 19,000. We first examine the extent to which inequalities in overweight, obesity, BMI and body fat over this period are consistent with the evolution of inequalities in health behaviours, including exercise and healthy diet markers (i.e., skipping breakfast) (n = 7,220). We next study the links between SES, health behaviours and adiposity (BMI, body fat), using rich models that account for the influence of a range of unobserved factors that are fixed over time. In this way, we improve on existing estimates measuring the relationship between SES and health behaviours on the one hand and adiposity on the other. The advantage of the individual fixed effects models is that they exploit within-individual changes over time to help mitigate biases due to unobserved fixed characteristics (n = 6,883). We observe stark income inequalities in BMI and body fat in childhood (age 5), which have further widened by age 17. Inequalities in obesity, physical activity, and skipping breakfast are observed to widen from age 7 onwards. Ordinary Least Square estimates reveal the previously documented SES gradient in adiposity, which is reduced slightly once health behaviours including breakfast consumption and physical activity are accounted for. The main substantive change in estimates comes from the fixed effects specification. Here we observe mixed findings on the SES associations, with a positive association between income and adiposity and a negative association with wealth. The role of health behaviours is attenuated but they remain important, particularly for body fat., Competing Interests: None., (© 2021 The Authors.)

Background: This study investigates the sex, ethnic and socioeconomic inequalities in emotional difficulties over childhood and adolescence using longitudinal cohort studies in the UK and Australia. Estimating cross-national differences contributes to understanding of the consistency of inequalities in mental health across contexts., Methods: Data from 19,748 participants in two contemporary representative samples in Australia (Growing Up in Australia: The Longitudinal Study of Australian Children, n = 4,975) and UK (Millennium Cohort Study, n = 14,773) were used. Emotional difficulties were assessed using the parent-reported Strengths and Difficulties Questionnaire at ages 4/5, 6/7, 11/12 and 14/15 years and the self-reported Short Moods and Feelings Questionnaire at age 14/15. Latent Growth Curve Modelling was used to examine mental health over time., Results: There were significant increases in emotional difficulties in both countries over time. Emotional difficulties were higher in Australian children at all ages. The gender gap in self-reported depressive symptoms at age 14/15 was larger in the UK (8% of UK and 13% of Australian boys were above the depression cut-off, compared with 23% of girls). Ethnic minority children had higher emotional difficulties at age 4/5 years in both countries, but over time this difference was no longer observed in Australia. In the UK, this reversed whereby at ages 11/12 and 14/15 ethnic minority children had lower symptoms than their White majority peers. Socioeconomic differences were more marked based on parent education and employment status in Australia and by parent income in the UK. UK children, children from White majority ethnicity and girls evidenced steeper worsening of symptoms from age 4/5 to 14/15 years., Conclusions: Even in two fairly similar countries (i.e. English-speaking, high-income, industrialised), the observed patterns of inequalities in mental health symptoms based on sociodemographics are not the same. Understanding country and context-specific drivers of different inequalities provides important insights to help reduce disparities in child and adolescent mental health., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

In a large (n = 10 103), nationally representative sample of 17-year-olds 16.1% had experienced high psychological distress in the past 30 days, 24.1% had self-harmed in the previous 12 months and 7.4% had ever attempted suicide. Females, White adolescents, sexual minorities and those from more socioeconomically disadvantaged families had worse mental health outcomes; with the exceptions of no detected differences in attempted suicide by ethnicity and in self-harm by socioeconomic position. Findings include a narrower gender gap in self-harm at age 17 (males 20.1%, females 28.2%) compared with at age 14 (males 8.5%; females 22.8%) and 2-4 times higher prevalence in sexual minority adolescents (39.3% high distress, 55.8% self-harmed, 21.7% attempted suicide compared with 13.4%, 20.5% and 5.8%, respectively, in heterosexual adolescents).

A DNA bank has been created from the Millennium Cohort Study (MCS) saliva samples. A total of 23,336 samples are available, from 9,259 cohort members (4,630 males and 4,629 females), 8,898 mothers and 5,179 fathers. There are 4,533 mother, child, father 'triads'. This paper describes the collection of the saliva samples from cohort members and their biological parents in the MCS. It analyses response rates and predictors of response, and details the DNA extraction, genotyping and imputation procedures performed on the data.

Background: Childhood socioeconomic position (SEP) is robustly associated with cognitive function later in life. However, it is unclear whether this reflects a direct relationship, or an indirect association via modifiable factors such as educational attainment and occupation. We sought to clarify these associations using retrospectively harmonised data from three ongoing British birth cohorts., Methods: We analysed data from the 1946 National Survey of Health and Development (n=2283), the 1958 National Child Development Study (n=9385) and the 1970 British Cohort Study (n=7631). Retrospective harmonisation was used to derive equivalent indicators of cognition, SEP, education and occupation across the three cohorts. Structural equation modelling was used to examine the association between childhood SEP and mid-life cognitive function, via childhood cognitive ability, educational attainment and mid-life occupation., Results: Across all three cohorts, no direct pathways were observed between childhood SEP and mid-life cognitive function. Rather, this association was indirect via the three temporally ordered mediators. In addition, the direct pathway between childhood cognition and adult cognitive function was weaker in the two younger studies., Conclusions: Across three British birth cohorts, we found that the association between early life SEP and mid-life cognitive function was fully mediated by childhood cognitive ability, educational attainment and occupational status. Furthermore, the association between early cognitive ability and mid-life cognitive function has decreased in younger generations. Therefore, cognitive function in adulthood may be influenced by modifiable factors and societal change., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

This paper examines the relationship between parents' and children's language skills for a nationally representative birth cohort born in the United Kingdom-the Millennium Cohort Study (MCS). We investigate both socioeconomic and ethnic differentials in children's vocabulary scores and the role of differences in parents' vocabulary scores in accounting for these. We find large vocabulary gaps between highly educated and less educated parents, and between ethnic groups. Nevertheless, socioeconomic and ethnic gaps in vocabulary scores are far wider among the parents than among their children. Parental vocabulary is a powerful mediator of inequalities in offspring's vocabulary scores at age 14, and also a powerful driver of change in language skills between the ages of five and 14. Once we account for parental vocabulary, no ethnic minority group of young people has a negative "vocabulary gap" compared to whites., (© 2020 The Authors. The British Journal of Sociology published by John Wiley & Sons Ltd on behalf of London School of Economics and Political Science.)

The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), examining phenotype and T cell receptor (TCR) repertoire, seeking correlations with timing of relapse. Compared to healthy donors (HD), we observed an increase in regulatory T cells (CD4+FoxP3+, Tregs) with reduction in CD4 T cells, leading to lower CD4:8 ratios. Compared to paired pre-treatment marrow, both CD4 and CD8 compartments showed a reduction in naïve, and increase in effector memory subsets, suggestive of a more differentiated phenotype. This was supported by increased levels of several immune-regulatory and activation proteins (ICOS, PD-1, LAG-3, CTLA-4 and GzmB) when compared with HD. Unsupervised analysis identified a patient subgroup with shorter PFS (p=0.031) whose BM contained increased Tregs, and higher immune-regulatory markers (ICOS, PD-1, LAG-3) on effector T cells. Using single feature analysis, higher frequencies of marrow PD-1+ on CD4+FoxP3- cells and Ki67+ on CD8 cells were independently associated with early relapse. Finally, studying paired pre-treatment and post-ASCT BM (n=5), we note reduced abundance of TCR sequences at day+100, with a greater proportion of expanded sequences indicating a more focused persistent TCR repertoire. Our findings indicate that, following induction chemotherapy and ASCT, marrow T cells demonstrate increased activation and differentiation, with TCR repertoire focusing. Pending confirmation in larger series, higher levels of immune-regulatory proteins on T cell effectors at day+100 may indicate early relapse., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Alrasheed, Khandelwal, Fitzsimons, Richards, Wilson, Chavda, Henry, Conde, De Massy, Chin, Galas-Filipowicz, Herrero, Chain, Quezada and Yong.)

We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising in vivo activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. This binding promotes an overall stress response and results in ubiquitination and proteasomal degradation of Keap1 and downstream activation of the Nrf2 pathway. Using positron emission tomography (PET) imaging with the PET-tracer 2-[ 18 F]fluoro-2-deoxy-d-glucose (FDG), we confirm that OBT is able to penetrate the brain and functionally target brain tumors. Finally, we show that an OBT analog with improved pharmacological properties, including enhanced potency, stability, and solubility, retains the antineoplastic properties in a xenograft mouse model.

Most epidemiological studies examine how risk factors relate to average difference in outcomes (linear regression) or odds of a binary outcome (logistic regression); they do not explicitly examine whether risk factors are associated differentially across the distribution of the health outcome investigated. This paper documents a phenomenon found repeatedly in the minority of epidemiological studies which do this (via quantile regression): associations between a range of established risk factors and body mass index (BMI) are progressively stronger in the upper ends of the BMI distribution. In this paper, we document this finding and provide illustrative evidence of it in the 1958 British birth cohort study. Associations of low childhood socio-economic position, high maternal weight, low childhood general cognition and adult physical inactivity with higher BMI are larger at the upper end of the BMI distribution, on both absolute and relative scales. For example, effect estimates for socio-economic position and childhood cognition were around three times larger at the 90th compared with 10th quantile, while effect estimates for physical inactivity were increasingly larger from the 50th to 90th quantiles, yet null at lower quantiles. We provide potential explanations for these findings and discuss implications. Risk factors may have larger causal effects among those in worse health, and these effects may not be discovered when health is only examined in average terms. In such scenarios, population-based approaches to intervention may have larger benefits than anticipated when assuming equivalent benefit across the population. Further research is needed to understand why effect estimates differ across the BMI outcome distribution and to investigate whether differential effects exist for other physical and mental health outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Iron deficiency anaemia (IDA) is common in older adults and associated with a range of adverse outcomes. Differentiating iron deficiency from other causes of anaemia is important to ensure appropriate investigations and treatment. It is possible to make the diagnosis reliably using simple blood tests. Clinical evaluation and assessment are required to help determine the underlying cause and to initiate appropriate investigations. IDA in men and post-menopausal females is most commonly due to occult gastrointestinal blood loss until proven otherwise, although there is a spectrum of underlying causative pathologies. Investigation decisions should take account of the wishes of the patient and their competing comorbidities, individualising the approach. Management involves supplementation using oral or intravenous (IV) iron then consideration of treatment of the underlying cause of deficiency. Future research areas are outlined including the role of Hepcidin and serum soluble transferrin receptor measurement, quantitative faecal immunochemical testing, alternative dosing regimens and the potential role of IV iron preparations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Maternal heavy alcohol use during pregnancy is harmful to offspring's health and adjustment. However, findings from studies on lower levels of prenatal drinking are mixed; a few even predict positive cognitive and psychosocial outcomes. Given that alcohol is a neurotoxin and teratogen, scholars question developmental benefits and point to residual confounding as a potential explanation, particularly as light drinkers are positively selected with respect to health and socioeconomic status. Using prospective, intergenerational data from the nationally-representative Millennium Cohort Study (MCS) in the United Kingdom, we studied associations between mother's drinking during pregnancy and children's cognitive and psychosocial outcomes at ages 3, 5, 7, 11, and 14 years (n = 10,454). We included early life confounders (e.g., maternal education, health, smoking) and mother's cognitive ability, and assessed robustness of relationships across outcomes and alternate drinking classifications. Results of a series of multivariable regression models found no association between light drinking and cognitive and psychosocial outcomes up to and including the age of 14, after controlling for key confounders. Light drinking during pregnancy was linked to higher socioeconomic advantages (e.g., mothers' higher education, professional/managerial occupation, home ownership, cognitive scores), which together accounted for positive associations between light drinking and children's outcomes. Mother's cognitive ability was an especially important confounder., (Copyright © 2019 Elsevier Ltd. All rights reserved.)