Dementia prevention: the Mendelian randomisation perspective.

Understanding the causes of Alzheimer's disease and related dementias remains a challenge. Observational studies investigating dementia risk factors are limited by the pervasive issues of confounding, reverse causation and selection biases. Conducting randomised controlled trials for dementia prevention is often impractical due to the long prodromal phase and the inability to randomise many potential risk factors. In this essay, we introduce Mendelian randomisation as an alternative approach to examine factors that may prevent or delay Alzheimer's disease. Mendelian randomisation is a causal inference method that has successfully identified risk factors and treatments in various other fields. However, applying this method to dementia risk factors has yielded unexpected findings. Here, we consider five potential explanations and provide recommendations to enhance causal inference from Mendelian randomisation studies on dementia. By employing these strategies, we can better understand factors affecting dementia risk.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Effects of in-store marketing on food and beverage purchases: a longitudinal study of households with children.

OBJECTIVE: Most food retailers display foods in prominent locations as a marketing strategy (i.e. 'placement promotions'). We examined the extent to which households with children change their food and beverage purchases in response to these promotions. DESIGN: We analysed a novel dataset of all products promoted in two supermarkets from 2016 to 2017, including promotion dates and locations (e.g. aisle endcaps and front registers). We linked promotions to all purchases from the supermarkets from 2016 to 2017 by a cohort of households with children. We calculated the number of weekly promotions in each of thirteen food and beverage groups (e.g. bread; candy) and used fixed effects regressions to estimate associations between number of weekly promotions and households' weekly food purchases, overall and by Supplemental Nutrition Assistance Program (SNAP) participation. SETTING: Two large supermarkets in Maine, USA. PARTICIPANTS: Eight hundred and twenty-one households with children. RESULTS: Most promotions (74 %) were for less healthy foods. The most promoted food groups were sweet and salty snacks (mean = 131·0 promotions/week), baked goods (mean = 68·2) and sugar-sweetened beverages (mean = 41·6). Households generally did not change their food group purchases during weeks when they were exposed to more promotions for those groups, except that a 1-sd increase in endcap candy promotions (about 1 promotion/week) was associated with $0·19/week (about 14·5 %) increase in candy purchases among SNAP nonparticipants (adjusted P < 0·001). CONCLUSIONS: In-store placement promotions for food groups were generally not associated with purchases of promoted food groups, perhaps because exposure to unhealthy food marketing was consistently high. Substantial changes to in-store food marketing may be needed to promote healthier purchases.

Artificial intelligence for dementia genetics and omics.

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible omics signatures that differentiate between dementia subtypes? Can high-dimensional omics data identify improved biomarkers? How can genetics inform our understanding of causal status of dementia risk factors? And which biological processes are altered by dementia-related genetic variation? Artificial intelligence (AI) and machine learning approaches give us powerful new tools in helping us to tackle these challenges, and we review possible solutions and examples of best practice. However, their limitations also need to be considered, as well as the need for coordinated multidisciplinary research and diverse deeply phenotyped cohorts. Ultimately AI approaches improve our ability to interrogate genetics and omics data for precision dementia medicine. HIGHLIGHTS: We have identified five key challenges in dementia genetics and omics studies. AI can enable detection of undiscovered patterns in dementia genetics and omics data. Enhanced and more diverse genetics and omics datasets are still needed. Multidisciplinary collaborative efforts using AI can boost dementia research.

How Selection Over Time Contributes to the Inconsistency of the Association Between Sex/Gender and Cognitive Decline Across Cognitive Aging Cohorts.

The association between sex/gender and aging-related cognitive decline remains poorly understood because of inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to differential selection by dropout and death between men and women. We aimed to evaluate the impact of selection by dropout and death on the association between sex/gender and cognitive decline. We first compared the statistical methods most frequently used for longitudinal data, targeting either population estimands (marginal models fitted by generalized estimating equations) or subject-specific estimands (mixed/joint models fitted by likelihood maximization) in 8 studies of aging: 6 population-based studies (the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (1996-2009), Personnes Âgées QUID (PAQUID; 1988-2014), the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study (2003-2016), the Three-City Study (Bordeaux only; 1999-2016), the Washington Heights-Inwood Community Aging Project (WHICAP; 1992-2017), and the Whitehall II Study (2007-2016)) and 2 clinic-based studies (the Alzheimer's Disease Neuroimaging Initiative (ADNI; 2004-2017) and a nationwide French cohort study, MEMENTO (2011-2016)). We illustrate differences in the estimands of the association between sex/gender and cognitive decline in selected examples and highlight the critical role of differential selection by dropout and death. Using the same estimand, we then contrast the sex/gender-cognitive decline associations across cohorts and cognitive measures suggesting a residual differential sex/gender association depending on the targeted cognitive measure (memory or animal fluency) and the initial cohort selection. We recommend focusing on subject-specific estimands in the living population for assessing sex/gender differences while handling differential selection over time.

Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function.

BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding. METHODS: We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N = 8,293), Alzheimer's disease (71,880 cases/383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051). RESULTS: Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR = 1.09 95%CI: 1.01 to 1.19, p = 0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR = 1.04 95% CI: 0.99 to 1.09, p = 0.08), Eotaxin (OR = 1.08 95% CI: 0.99 to 1.17, p = 0.10), GROa (CXCL1) (OR = 1.04 95% CI: 0.99 to 1.10, p = 0.15), MIG (CXCL9) (OR = 1.17 95% CI: 0.97 to 1.41, p = 0.10), IL-8 (Wald ratio: OR = 1.21 95% CI: 0.97 to 1.51, p = 0.09) and IL-2 (Wald Ratio: OR = 1.21 95% CI: 0.94 to 1.56, p = 0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR = 1.05 95% CI: 0.98 to 1.13, p = 0.14), IL-8 (OR = 1.21 95% CI: 1.07 to 1.37, p = 0.003) and MCP1 (OR = 1.07 95% CI: 1.03 to 1.13, p = 0.003) were associated with lower fluid intelligence, and IL-4 (OR = 0.86 95%CI: 0.79 to 0.98, p = 0.02) with higher. CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.

Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. METHODS: ALSPAC offspring's total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. RESULTS: Mean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. CONCLUSION: Results suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life.

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle.

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.

Rural patients highly satisfied with gynaecological oncology care via telehealth.

BACKGROUND: Introduction of telehealth for gynaecological oncology consultations aims to improve access to specialised care for rural and remote Queensland women with gynaecological malignancies. AIMS: This survey examines patient satisfaction with gynaecological oncology consultations via telehealth after introduction of the service in Far North Queensland in 2017. MATERIALS AND METHODS: Patients who accessed the gynaecological oncology telehealth service at Cairns Hospital from January 2019 to June 2020 were invited to participate in the study. Demographic details and results of a satisfaction survey were investigated. The questionnaire included 16 statements measured on a five-point Likert scale and three open-ended questions, which were coded into related responses and predominant themes developed. RESULTS: Fifty-three patients completed the study. The mean satisfaction score across all questions was 90.5% (standard deviation 8.7%). The lowest overall patient score was 77.5% and the highest was 100%. Themes emerging from the open questions were emotions experienced by women, communication, relationship building and acceptability of the service. CONCLUSIONS: Patients were highly satisfied with the telehealth service. Our findings encourage further development and research into telehealth care models for surgical disciplines such as gynaecological oncology.

Investigating the impact of cigarette smoking behaviours on DNA methylation patterns in adolescence.

Smoking usually begins in adolescence, and early onset of smoking has been linked to increased risk of later life disease. There is a need to better understand the biological impact of cigarette smoking behaviours in adolescence. DNA methylation profiles related to smoking behaviours and cessation in adulthood have been previously identified, but alterations arising from smoking initiation have not been thoroughly investigated. We aimed to investigate DNA methylation in the Avon Longitudinal Study of Parents and Children in relation to (1) different smoking measures, (2) time since smoking initiation and frequency of smoke exposure and (3) latent classes of smoking behaviour. Using 2620 CpG sites previously associated with cigarette smoking, we investigated DNA methylation change in relation to own smoking measures, smoke exposure duration and frequency, and using longitudinal latent class analysis of different smoking behaviour patterns in 968 adolescents. Eleven CpG sites located in seven gene regions were differentially methylated in relation to smoking in adolescence. While only AHRR (cg05575921) showed a robust pattern of methylation in relation to weekly smoking, several CpGs showed differences in methylation among individuals who had tried smoking compared with non-smokers. In relation to smoke exposure duration and frequency, cg05575921 showed a strong dose-response relationship, while there was evidence for more immediate methylation change at other sites. Our findings illustrate the impact of cigarette smoking behaviours on DNA methylation at some smoking-responsive CpG sites, even among individuals with a short smoking history.

EBNA1 inhibitors have potent and selective antitumor activity in xenograft models of Epstein-Barr virus-associated gastric cancer.

BACKGROUND AND AIMS: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~ 10% of all gastric cancers (GC). Epstein-Barr virus nuclear antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. METHODS: We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. RESULTS: Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. CONCLUSIONS: EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC.

Pregnant women's experiences of social distancing behavioural guidelines during the Covid-19 pandemic 'lockdown' in the UK, a qualitative interview study.

BACKGROUND: Covid-19 triggered the rapid roll-out of mass social distancing behavioural measures for infection control. Pregnant women were categorised as 'at risk' requiring extra vigilance with behavioural guidelines. Their understanding and ability to adhere to recommendations was unknown. OBJECTIVES: To complete a behavioural analysis of the determinants of recommended social distancing behaviour in pregnant women, according to the 'capability, opportunity, motivation and behaviour' ('COM-B') model to inform the development of recommendations/materials to support pregnant women in understanding and adhering to behavioural guidelines. DESIGN: Qualitative interview study with pregnant women in the Bristol area (UK). METHODS: Semi-structured telephone/videoconference interviews were conducted following a topic guide informed by the COM-B model, transcribed verbatim and subjected to framework analysis. Infographic materials were iteratively produced with stakeholder consultation, to support pregnant women. RESULTS: Thirty-one women participated (selected for demographic range). Women reported adhering to social distancing recommendations and intended to continue. COM-B analysis identified gaps in understanding around risk, vulnerability, and the extent of required social distancing, as well as facilitators of social distancing behaviour (e.g. social support, motivation to stay safe, home environment/resources). Additional themes around detrimental mental health effects and changes to maternity healthcare from the social distancing measures were identified. Infographic resources (plus midwife report) addressing women's key concerns were produced and disseminated. CONCLUSIONS: The COM-B model provided useful details of determinants of pregnant women's adherence to social distancing behaviours. The confusion of what being 'at risk' meant and varying interpretation of what was expected indicates a need for greater clarity around categories and guidance. The loss of maternity care and negative mental health effects of social distancing suggest a growing area of unmet health needs to be addressed in future.

Exposure to multiple childhood social risk factors and adult body mass index trajectories from ages 20 to 64 years.

BACKGROUND: While childhood social risk factors appear to be associated with adult obesity, it is unclear whether exposure to multiple childhood social risk factors is associated with accelerated weight gain during adulthood. METHODS: We used the Medical Research Council National Survey of Health and Development, a British population-based birth cohort study of participants born in 1946, height and weight were measured by nurses at ages 36, 43, 53 and 60-64 and self-reported at 20 and 26 years. The 9 childhood socioeconomic risk factors and 8 binary childhood psychosocial risk factors were measured, with 13 prospectively measured at age 4 years (or at 7 or 11 years if missing) and 3 were recalled when participants were age 43. Multilevel modelling was used to examine the association between the number of childhood social risk factors and changes in body mass index (BMI) with age. RESULTS: Increasing exposure to a higher number of childhood socioeconomic risk factors was associated with higher mean BMI across adulthood for both sexes and with a faster increase in BMI from 20 to 64 years, among women but not men. Associations remained after adjustment for adult social class. There was no evidence of an association between exposure to childhood psychosocial risk factors and mean BMI in either sex at any age. CONCLUSIONS: Strategies for the prevention and management of weight gain across adulthood may need to tailor interventions in consideration of past exposure to multiple socioeconomic disadvantages experienced during childhood.

Psychosocial adversity and socioeconomic position during childhood and epigenetic age: analysis of two prospective cohort studies.

Psychosocial adversity in childhood (e.g. abuse) and low socioeconomic position (SEP) can have significant lasting effects on social and health outcomes. DNA methylation-based biomarkers are highly correlated with chronological age; departures of methylation-predicted age from chronological age can be used to define a measure of age acceleration, which may represent a potential biological mechanism linking environmental exposures to later health outcomes. Using data from two cohorts of women Avon Longitudinal Study of Parents and Children, (ALSPAC), N = 989 and MRC National Survey of Health and Development, NSHD, N = 773), we assessed associations of SEP, psychosocial adversity in childhood (parental physical or mental illness or death, parental separation, parental absence, sub-optimal maternal bonding, sexual, emotional and physical abuse and neglect) and a cumulative score of these psychosocial adversity measures, with DNA methylation age acceleration in adulthood (measured in peripheral blood at mean chronological ages 29 and 47 in ALSPAC and buccal cells at age 53 in NSHD). Sexual abuse was strongly associated with age acceleration in ALSPAC (sexual abuse data were not available in NSHD), e.g. at the 47-year time point sexual abuse associated with a 3.41 years higher DNA methylation age (95% CI 1.53 to 5.29) after adjusting for childhood and adulthood SEP. No associations were observed between low SEP, any other psychosocial adversity measure or the cumulative psychosocial adversity score and age acceleration. DNA methylation age acceleration is associated with sexual abuse, suggesting a potential mechanism linking sexual abuse with adverse outcomes. Replication studies with larger sample sizes are warranted.

Digital Behavior Change Interventions for Younger Children With Chronic Health Conditions: Systematic Review.

BACKGROUND: The prevalence of chronic health conditions in childhood is increasing, and behavioral interventions can support the management of these conditions. Compared with face-to-face treatment, the use of digital interventions may be more cost-effective, appealing, and accessible, but there has been inadequate attention to their use with younger populations (children aged 5-12 years). OBJECTIVE: This systematic review aims to (1) identify effective digital interventions, (2) report the characteristics of promising interventions, and (3) describe the user's experience of the digital intervention. METHODS: A total of 4 databases were searched (Excerpta Medica Database [EMBASE], PsycINFO, Medical Literature Analysis and Retrieval System Online [MEDLINE], and the Cochrane Library) between January 2014 and January 2019. The inclusion criteria for studies were as follows: (1) children aged between 5 and 12 years, (2) interventions for behavior change, (3) randomized controlled trials, (4) digital interventions, and (5) chronic health conditions. Two researchers independently double reviewed papers to assess eligibility, extract data, and assess quality. RESULTS: Searches run in the databases identified 2643 papers. We identified 17 eligible interventions. The most promising interventions (having a beneficial effect and low risk of bias) were 3 targeting overweight or obesity, using exergaming or social media, and 2 for anxiety, using web-based cognitive behavioral therapy (CBT). Characteristics of promising interventions included gaming features, therapist support, and parental involvement. Most were purely behavioral interventions (rather than CBT or third wave), typically using the behavior change techniques (BCTs) feedback and monitoring, shaping knowledge, repetition and substitution, and reward. Three papers included qualitative data on the user's experience. We developed the following themes: parental involvement, connection with a health professional is important for engagement, technological affordances and barriers, and child-centered design. CONCLUSIONS: Of the 17 eligible interventions, digital interventions for anxiety and overweight or obesity had the greatest promise. Using qualitative methods during digital intervention development and evaluation may lead to more meaningful, usable, feasible, and engaging interventions, especially for this underresearched younger population. The following characteristics could be considered when developing digital interventions for younger children: involvement of parents, gaming features, additional therapist support, behavioral (rather than cognitive) approaches, and particular BCTs (feedback and monitoring, shaping knowledge, repetition and substitution, and reward). This review suggests a model for improving the conceptualization and reporting of behavioral interventions involving children and parents.

Recruiting Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis to Internet-Delivered Therapy: Internal Pilot Within a Randomized Controlled Trial.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in adolescents is common and disabling. Teenagers in the United Kingdom are more likely to recover if they access specialist care, but most do not have access to a local specialist CFS/ME service. Delivering treatment remotely via the internet could improve access to treatment. OBJECTIVE: This study aims to assess (1) the feasibility of recruitment and retention into a trial of internet-delivered specialist treatment for adolescents with CFS/ME and (2) the acceptability of trial processes and 2 web-based treatments (to inform continuation to full trial). METHODS: This study is an internal pilot for the initial 12 months of a full randomized controlled trial (RCT), with integrated qualitative methods (analysis of recruitment consultations and participant and clinician interviews). Recruitment and treatment were delivered remotely from a specialist pediatric CFS/ME treatment service within a hospital in South West United Kingdom. Adolescents (aged 11-17 years) from across the United Kingdom with a diagnosis of CFS/ME and no access to local specialist treatment were referred by their general practitioner to the treatment center. Eligibility assessment and recruitment were conducted via remote methods (telephone and on the web), and participants were randomized (via a computer-automated system) to 1 of 2 web-based treatments. The trial intervention was Fatigue in Teenagers on the InterNET in the National Health Service, a web-based modular CFS/ME-specific cognitive behavioral therapy program (designed to be used by young people and their parents or caregivers) supported by individualized clinical psychologist electronic consultations (regular, scheduled therapeutic message exchanges between participants and therapist within the platform). The comparator was Skype-delivered activity management with a CFS/ME clinician (mainly a physiotherapist or occupational therapist). Both treatments were intended to last for up to 6 months. The primary outcomes were (1) the number of participants recruited (per out-of-area referrals received between November 1, 2016, to October 31, 2017) and the proportion providing 6-month outcome data (web-based self-report questionnaire assessing functioning) and (2) the qualitative outcomes indicating the acceptability of trial processes and treatments. RESULTS: A total of 89 out of 150 (59.3% of potentially eligible referrals) young people and their parents or caregivers were recruited, with 75 out of 89 (84.2%) providing 6-month outcome data. Overall, web-based treatment was acceptable; however, participants and clinicians described both the advantages and disadvantages of remote methods. No serious adverse events were reported. CONCLUSIONS: Recruiting young people (and their parents or caregivers) into an RCT of web-based treatment via remote methods is feasible and acceptable. Delivering specialist treatment at home via the internet is feasible and acceptable, although some families prefer to travel across the United Kingdom for face-to-face treatment. TRIAL REGISTRATION: ISRCTN 18020851; http://www.isrctn.com/ISRCTN18020851. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-018-2500-3.

Can linguistic analysis be used to identify whether adolescents with a chronic illness are depressed?

Comorbid depression is common in adolescents with chronic illness. We aimed to design and test a linguistic coding scheme for identifying depression in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), by exploring features of e-consultations within online cognitive behavioural therapy treatment. E-consultations of 16 adolescents (aged 11-17) receiving FITNET-NHS (Fatigue in teenagers on the interNET in the National Health Service) treatment in a national randomized controlled trial were examined. A theoretically driven linguistic coding scheme was developed and used to categorize comorbid depression in e-consultations using computerized content analysis. Linguistic coding scheme categorization was subsequently compared with classification of depression using the Revised Children's Anxiety and Depression Scale published cut-offs (t-scores ≥65, ≥70). Extra linguistic elements identified deductively and inductively were compared with self-reported depressive symptoms after unblinding. The linguistic coding scheme categorized three (19%) of our sample consistently with self-report assessment. Of all 12 identified linguistic features, differences in language use by categorization of self-report assessment were found for "past focus" words (mean rank frequencies: 1.50 for no depression, 5.50 for possible depression, and 10.70 for probable depression; p < .05) and "discrepancy" words (mean rank frequencies: 16.00 for no depression, 11.20 for possible depression, and 6.40 for probable depression; p < .05). The linguistic coding profile developed as a potential tool to support clinicians in identifying comorbid depression in e-consultations showed poor value in this sample of adolescents with CFS/ME. Some promising linguistic features were identified, warranting further research with larger samples.

Respiratory Tract Infections in Children in the Community: Prospective Online Inception Cohort Study.

PURPOSE: Describe the duration of symptoms, proportion of parents seeking primary care consultations, and costs for respiratory tract infections (RTIs) of children in the community. METHODS: Community-based, online, prospective inception cohort study. General practitioners from socioeconomically diverse practices posted study invitations to parents of 10,310 children aged ≥3 months and <15 years. RESULTS: One parent of 485 (4.7%) children in 331 families consented, completed baseline data and symptom diaries, and agreed to medical record review. Compared with nonresponders, responding parent's children were younger (aged 4 vs 6 years) and less socioeconomically deprived. Between February and July 2016, 206 parents reported 346 new RTIs in 259 children. Among the 197 first RTIs reported per family, it took 23 days for 90% (95% CI, 85%-94%) of children to recover. Median symptom duration was longer: in children with primary care consultations (9 days) vs those without consultations (6 days, P = 0.06); children aged <3 years (11 days) vs >3 years (7 days, P <.01); and among children with reported lower RTI symptoms (12 days) vs those with only upper RTI symptoms (8 days, P <.001). Sixteen (8.1%; 95% CI, 4.7%-12.8%) of 197 children had primary care consultations at least once (total 19 consultations), and a similar proportion had time off school or nursery. Sixty of 188 (32%; 95% CI, 25%-39%) parents reported paying for medications for their child's illness. CONCLUSIONS: Parents can be advised that RTI symptoms last up to 3 weeks. Policy makers should be aware that parents may seek primary care support in at least 1 in 12 illnesses.

Reducing Primary Care Attendance Intentions for Pediatric Respiratory Tract Infections.

PURPOSE: The aim of this study was to evaluate a theory and evidence-based, parent-targeted online intervention, combining microbiological local syndromic surveillance data, symptom information, and home-care advice, to reduce primary care attendance for self-limiting, low-risk pediatric respiratory tract infections (RTIs). METHODS: The effect of this novel intervention on primary care attendance intentions was evaluated in an online experimental study. A representative sample of mothers (n = 806) was randomly assigned to receive the intervention material before (intervention) or after (control) answering questions concerning attendance intentions for an RTI illness scenario and mediating factors. Both groups provided feedback on the material. Group comparisons, linear regression, and path analyses were conducted. RESULTS: Intervention participants reported lower attendance intentions compared with control participants (d = 0.69, 95% CI, 0.55-0.83), an effect that remained when controlling for demographic and clinical characteristics (B = -1.62, 95% CI, -1.97 to -1.30). The path model highlighted that the intervention effect (B = -0.33, 95% CI, -0.40 to -0.26) was mostly indirect and mediated by infection and antibiotic knowledge, symptom severity concerns, and social norm perceptions concerning attendance. Information on when to attend was rated as the most important intervention component 227 times, followed by symptoms rated 186 times. Information on circulating viruses was rated as least important 274 times. CONCLUSIONS: The intervention was effective in reducing primary care attendance intentions by increasing knowledge, lowering attendance motivation, and reducing the need for additional resources. The contribution of individual intervention components and effects on behavioral outcomes requires further testing.

Association of work-related and leisure-time physical activity with workplace food purchases, dietary quality, and health of hospital employees.

BACKGROUND: While leisure-time physical activity (PA) has been associated with reduced risk of cardiometabolic disease, less is known about the relationship between work-related PA and health. Work-related PA is often not a chosen behavior and may be associated with lower socioeconomic status and less control over job-related activities. This study examined whether high work-related PA and leisure-time PA reported by hospital employees were associated with healthier dietary intake and reductions in cardiometabolic risk. METHODS: This was a cross-sectional analysis of 602 hospital employees who used workplace cafeterias and completed the baseline visit for a health promotion study in 2016-2018. Participants completed the International Physical Activity Questionnaire and clinical measures of weight, blood pressure, HbA1c, and lipids. Healthy Eating Index (HEI) scores were calculated from two 24-h dietary recalls, and a Healthy Purchasing Score was calculated based on healthfulness of workplace food/beverage purchases. Regression analyses examined Healthy Purchasing Score, HEI, and obesity, hypertension, hyperlipidemia, and diabetes/prediabetes by quartile of work-related PA, leisure-time PA, and sedentary time. RESULTS: Participants' mean age was 43.6 years (SD = 12.2), 79.4% were female, and 81.1% were white. In total, 30.3% had obesity, 20.6% had hypertension, 26.6% had prediabetes/diabetes, and 32.1% had hyperlipidemia. Median leisure-time PA was 12.0 (IQR: 3.3, 28.0) and median work-related PA was 14.0 (IQR: 0.0, 51.1) MET-hours/week. Higher leisure-time PA was associated with higher workplace Healthy Purchasing Score and HEI (p's < 0.01) and lower prevalence of obesity, diabetes/prediabetes, and hyperlipidemia (p's < 0.05). Work-related PA was not associated with Healthy Purchasing Score, HEI, or cardiometabolic risk factors. Increased sedentary time was associated with lower HEI (p = 0.02) but was not associated with the workplace Healthy Purchasing Score. CONCLUSIONS: Employees with high work-related PA did not have associated reductions in cardiometabolic risk or have healthier dietary intake as did employees reporting high leisure-time PA. Workplace wellness programs should promote leisure-time PA and healthy food choices for all employees, but programs may need to be customized and made more accessible to meet the unique needs of employees who are physically active at work. TRIAL REGISTRATION: This trial was prospectively registered with clinicaltrials.gov (Identifier: NCT02660086) on January 21, 2016. The first participant was enrolled on September 16, 2016.