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Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum. MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.
Globally, there is seasonal variation in tuberculosis (TB) incidence, yet the biological and behavioural or social factors driving TB seasonality differ across countries. Understanding season-specific risk factors that may be specific to the UK could help shape future decision-making for TB control. We conducted a time-series analysis using data from 152,424 UK TB notifications between 2000 and 2018. Notifications were aggregated by year, month, and socio-demographic covariates, and negative binomial regression models fitted to the aggregate data. For each covariate, we calculated the size of the seasonal effect as the incidence risk ratio (IRR) for the peak versus the trough months within the year and the timing of the peak, whilst accounting for the overall trend. There was strong evidence for seasonality (p < 0.0001) with an IRR of 1.27 (95% CI 1.23–1.30). The peak was estimated to occur at the beginning of May. Significant differences in seasonal amplitude were identified across age groups, ethnicity, site of disease, latitude and, for those born abroad, time since entry to the UK. The smaller amplitude in older adults, and greater amplitude among South Asians and people who recently entered the UK may indicate the role of latent TB reactivation and vitamin D deficiency in driving seasonality.
Many paediatric studies report that patients must be established on aspirin therapy for a minimum of 5 days to achieve adequate response. This is not always practical especially in critical settings. Prospective identification of patients that are unresponsive to aspirin sooner could potentially prevent thrombotic events.
Aims:
The aim of this study was to investigate prospectively if the first dose of aspirin is effective in decreasing platelet aggregation, and thromboxane formation and if this can be measured after 2 hours in paediatric cardiology patients. A secondary aim was to identify a cut-off for a novel marker of aspirin responsiveness the maximum amplitude with arachidonic acid, which could potentially dramatically reduce the blood volume required. Third, we aimed to prospectively identify potentially non-responsive patients by spiking a sample of their blood ex vivo with aspirin.
Results:
The majority (92.3%) of patients were responsive, when measured 2 hours post first dose of aspirin. Non-response or inadequate response (7.7%) can also be identified at 2 hours after taking the first dose of aspirin. Additionally, we have shown a novel way to reduce blood sample volume requirements by measurement of the maximum amplitude with arachidonic acid as a marker of response, particularly for monitoring.
Conclusions:
These findings of rapid efficacy in the majority of patients offer assurance in a sound, practical way to attending clinicians, patients, and families.
The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity.
Methods
We utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case–control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection.
Results
In UKB, reductions in network efficiency were observed in MDD cases globally (d = −0.076, pFDR = 0.033), across all tiers (d = −0.069 to −0.079, pFDR = 0.020), and in hubs (d = −0.080 to −0.113, pFDR = 0.013–0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample.
Conclusion
Our results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.
In the UK and Republic of Ireland, the European badger (Meles meles) is considered the most significant wildlife reservoir of the bacterium Mycobacterium bovis, the cause of bovine tuberculosis (bTB). To expand options for bTB surveillance and disease control, the Animal and Plant Health Agency developed a bespoke physical restraint cage to facilitate collection of a small blood sample from a restrained, conscious badger in the field. A key step, prior to pursuing operational deployment of the novel restraint cage, was an assessment of the relative welfare impacts of the approach. We used an established welfare assessment model to elicit expert opinion during two workshops to compare the impacts of the restraint cage approach with the only current alternative for obtaining blood samples from badgers in the field, which involves administration of a general anaesthetic. Eleven panellists participated in the workshops, comprising experts in the fields of wildlife biology, animal welfare science, badger capture and sampling, and veterinary science. Both approaches were assessed to have negative welfare impacts, although in neither case were overall welfare scores higher than intermediate, never exceeding 5–6 out of a possible 8. Based on our assessments, the restraint cage approach is no worse for welfare compared to using general anaesthesia and possibly has a lower overall negative impact on badger welfare. Our results can be used to integrate consideration of badger welfare alongside other factors, including financial cost and efficiency, when selecting a field method for blood sampling free-living badgers.
To cope with homonegativity-generated stress, gay, bisexual and other men who have sex with men (GBM) use more mental health services (MHS) compared with heterosexual men. Most previous research on MHS among GBM uses data from largely white HIV-negative samples. Using an intersectionality-based approach, we evaluated the concomitant impact of racialization and HIV stigma on MHS use among GBM, through the mediating role of perceived discrimination (PD).
Methods
We used baseline data from 2371 GBM enrolled in the Engage cohort study, collected between 2017 and 2019, in Montreal, Toronto and Vancouver, using respondent-driven sampling. The exposure was GBM groups: Group 1 (n = 1376): white HIV-negative; Group 2 (n = 327): white living with HIV; Group 3 (n = 577): racialized as non-white HIV-negative; Group 4 (n = 91): racialized as non-white living with HIV. The mediator was interpersonal PD scores measured using the Everyday Discrimination Scale (5-item version). The outcome was MHS use (yes/no) in the prior 6 months. We fit a three-way decomposition of causal mediation effects utilizing the imputation method for natural effect models. We obtained odds ratios (ORs) for pure direct effect (PDE, unmediated effect), pure indirect effect (PIE, mediated effect), mediated interaction effect (MIE, effect due to interaction between the exposure and mediator) and total effect (TE, overall effect). Analyses controlled for age, chronic mental health condition, Canadian citizenship, being cisgender and city of enrolment.
Results
Mean PD scores were highest for racialized HIV-negative GBM (10.3, SD: 5.0) and lowest for white HIV-negative GBM (8.4, SD: 3.9). MHS use was highest in white GBM living with HIV (GBMHIV) (40.4%) and lowest in racialized HIV-negative GBM (26.9%). Compared with white HIV-negative GBM, white GBMHIV had higher TE (OR: 1.71; 95% CI: 1.27, 2.29) and PDE (OR: 1.68; 95% CI: 1.27, 2.24), and racialized HIV-negative GBM had higher PIE (OR: 1.09; 95% CI: 1.02, 1.17). Effects for racialized GBMHIV did not significantly differ from those of white HIV-negative GBM. MIEs across all groups were comparable.
Conclusions
Higher MHS use was observed among white GBMHIV compared with white HIV-negative GBM. PD positively mediated MHS use only among racialized HIV-negative GBM. MHS may need to take into account the intersecting impact of homonegativity, racism and HIV stigma on the mental health of GBM.
To determine the reach, adoption, implementation and effectiveness of an intervention to increase children’s vegetable intake in long day care (LDC).
Design:
A 12-week pragmatic cluster randomised controlled trial, informed by the multiphase optimisation strategy (MOST), targeting the mealtime environment and curriculum. Children’s vegetable intake and variety was measured at follow-up using a modified Short Food Survey for early childhood education and care and analysed using a two-part mixed model for non-vegetable and vegetable consumers. Outcome measures were based on the RE-AIM framework.
Setting:
Australian LDC centres.
Participants:
Thirty-nine centres, 120 educators and 719 children at follow-up.
Results:
There was no difference between intervention and waitlist control groups in the likelihood of consuming any vegetables when compared with non-vegetable consumers for intake (OR = 0·70, (95 % CI 0·34–1·43), P = 0·32) or variety (OR = 0·73 (95 % CI 0·40–1·32), P = 0·29). Among vegetable consumers (n 652), there was no difference between groups in vegetable variety (exp(b): 1·07 (95 % CI:0·88–1·32, P = 0·49) or vegetable intake (exp(b): 1·06 (95 % CI: 0·78, 1·43)), P = 0·71) with an average of 1·51 (95 % CI 1·20–1·82) and 1·40 (95 % CI 1·08–1·72) serves of vegetables per day in the intervention and control group, respectively. Intervention educators reported higher skills for promoting vegetables at mealtimes, and knowledge and skills for teaching the curriculum, than control (all P < 0·001). Intervention fidelity was moderate (n 16/20 and n 15/16 centres used the Mealtime environment and Curriculum, respectively) with good acceptability among educators. The intervention reached 307/8556 centres nationally and was adopted by 22 % eligible centres.
Conclusions:
The pragmatic self-delivered online intervention positively impacted educator’s knowledge and skills and was considered acceptable and feasible. Intervention adaptations, using the MOST cyclic approach, could improve intervention impact on children’ vegetable intake.
Older adults have low levels of mental health literacy relating to anxiety which may contribute to delaying or not seeking help. Lifestyle interventions, including physical activity (PA), have increasing evidence supporting their effectiveness in reducing anxiety. The COVID-19 pandemic also highlighted the potential for technology to facilitate healthcare provision. This study aimed to investigate perspectives of older adults about their understanding of anxiety, possible use of PA interventions to reduce anxiety, and whether technology could help this process.
Methods:
The INDIGO trial evaluated a PA intervention for participants aged 60 years and above at risk of cognitive decline and not meeting PA guidelines. Twenty-nine of the INDIGO trial completers, including some with anxiety and/or cognitive symptoms, attended this long-term follow-up study including semi-structured qualitative interviews. Transcripts were analyzed thematically.
Results:
There was quite a diverse understanding of anxiety amongst participants. Some participants were able to describe anxiety as involving worry, uncertainty and fear, as well as relating it to physical manifestations and feeling out of control. Others had less understanding of the concept of anxiety or found it confusing. Participants generally believed that PA could potentially reduce anxiety and thought that this could occur through a “mindfulness” and/or “physiological” process. Technology use was a more controversial topic with some participants quite clearly expressing a dislike or distrust of technology or else limited access or literacy in relation to technology. Participants who were supportive of using technology described that it could help with motivation, information provision and health monitoring. Wearable activity monitors were described favorably, with online platforms and portable devices also being options.
Conclusion:
Our results highlight the importance of increasing information and education about anxiety to older adults. This may increase awareness of anxiety and reduce delays in seeking help or not seeking help at all. Findings also emphasize the need for clinicians to support understanding of anxiety in older adults that they are seeing and provide information and education where needed. It is likely that PA interventions to reduce anxiety, with the option of a technology component with support, will be acceptable to most older adults.
Children need to be repeatedly and consistently exposed to a variety of vegetables from an early age to achieve an increase in vegetable intake. A focus on enjoyment and learning to like eating vegetables at an early age is critical to forming favourable lifelong eating habits. Coordinated work is needed to ensure vegetables are available and promoted in a range of settings, using evidence-based initiatives, to create an environment that will support children’s acceptance of vegetables. This will help to facilitate increased intake and ultimately realise the associated health benefits. The challenges and evidence base for a new approach are described.
Homeless shelter residents and staff may be at higher risk of SARS-CoV-2 infection. However, SARS-CoV-2 infection estimates in this population have been reliant on cross-sectional or outbreak investigation data. We conducted routine surveillance and outbreak testing in 23 homeless shelters in King County, Washington, to estimate the occurrence of laboratory-confirmed SARS-CoV-2 infection and risk factors during 1 January 2020–31 May 2021. Symptom surveys and nasal swabs were collected for SARS-CoV-2 testing by RT-PCR for residents aged ≥3 months and staff. We collected 12,915 specimens from 2,930 unique participants. We identified 4.74 (95% CI 4.00–5.58) SARS-CoV-2 infections per 100 individuals (residents: 4.96, 95% CI 4.12–5.91; staff: 3.86, 95% CI 2.43–5.79). Most infections were asymptomatic at the time of detection (74%) and detected during routine surveillance (73%). Outbreak testing yielded higher test positivity than routine surveillance (2.7% versus 0.9%). Among those infected, residents were less likely to report symptoms than staff. Participants who were vaccinated against seasonal influenza and were current smokers had lower odds of having an infection detected. Active surveillance that includes SARS-CoV-2 testing of all persons is essential in ascertaining the true burden of SARS-CoV-2 infections among residents and staff of congregate settings.
OBJECTIVES/GOALS: Congenital anomalies (CA) are common, but the cause is often unknown. The interplay between known environmental teratogens, such as medication use in pregnancy, and genetic predisposition impacts CA risk, but such interactions are poorly understood. We test the hypothesis that pharmacogenomic (PGx) variation impacts CA risk. METHODS/STUDY POPULATION: We performed a drug absorption, distribution, metabolism, and excretion (ADME) gene-wide association study (GWAS), which tests for a possible association between ADME gene single nucleotide polymorphisms and individuals with CAs. This analysis was performed in BioVU and utilized billing codes to identify 5,845 cases, individuals with at least one CA, and 50,059 controls of genetically European ancestry. Using Plink software we analyzed 5,398 SNPs in 292 ADME genes across cases and controls. Results from this analysis drove us to further investigate the association between CA risk and SLC22A1-3. Next, we performed PrediXcan analyses to estimate the association between genetically predicted gene expression (GPGE) of SLC22A1-3 genes across all available tissues in the GTEx resource and CA risk. RESULTS/ANTICIPATED RESULTS: The ADME GWAS identified multiple variants on chromosome 6 in the region of SCL22A1-3 that were associated with the risk for CAs. The most significant variants were rs2048327, rs2292334, rs3088442, rs1810126, rs376563, and rs7758229, p DISCUSSION/SIGNIFICANCE: The combination of the known crucial pharmacological roles of OCT1-3 and the results of our ADME GWAS / PrediXcan analyses demonstrates that PGx burden, specifically variation in the SLC22A1-3 genes, influences the risk of developing CAs. This new understanding has the potential to personalize care for pregnant individuals to reduce the risk of CAs.
To explore patterns of post-malnutrition growth (PMGr) during and after treatment for severe malnutrition and describe associations with survival and non-communicable disease (NCD) risk 7 years post-treatment.
Design:
Six indicators of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score and height-for-age z-score (HAZ). Three categorisation methods included no categorisation, quintiles and latent class analysis (LCA). Associations with mortality risk and seven NCD indicators were analysed.
Setting:
Secondary data from Blantyre, Malawi between 2006 and 2014.
Participants:
A cohort of 1024 children treated for severe malnutrition (weight-for-length z-score < 70 % median and/or MUAC (mid-upper arm circumference) < 110 mm and/or bilateral oedema) at ages 5–168 months.
Results:
Faster weight gain during treatment (g/d) and after treatment (g/kg/day) was associated with lower risk of death (adjusted OR 0·99, 95 % CI 0·99, 1·00; and adjusted OR 0·91, 95 % CI 0·87, 0·94, respectively). In survivors (mean age 9 years), it was associated with greater hand grip strength (0·02, 95 % CI 0·00, 0·03) and larger HAZ (6·62, 95 % CI 1·31, 11·9), both indicators of better health. However, faster weight gain was also associated with increased waist:hip ratio (0·02, 95 % CI 0·01, 0·03), an indicator of later-life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/d during treatment and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder.
Conclusions:
A complex pattern of benefits and risks is associated with faster PMGr. Both initial weight deficit and rate of weight gain have important implications for future health.
Early environmental experience can have significant effects on an animal's ability to adapt to challenges in later life. Prior experience of specific situations may facilitate the development of behavioural skills which can be applied in similar situations to later life. In addition, exposure to a more complex environment may enhance cognitive development (eg increased synaptic density), which can then speed the acquisition of new behavioural responses when faced with novel challenges (Grandin 1989).
Dropout from psychotherapy for borderline personality disorder (BPD) is a notorious problem. We investigated whether treatment, treatment format, treatment setting, substance use exclusion criteria, proportion males, mean age, country, and other variables influenced dropout.
Methods
From Pubmed, Embase, Cochrane, Psycinfo and other sources, 111 studies (159 treatment arms, N = 9100) of psychotherapy for non-forensic adult patients with BPD were included. Dropout per quarter during one year of treatment was analyzed on participant level with multilevel survival analysis, to deal with multiple predictors, nonconstant dropout chance over time, and censored data. Multiple imputation was used to estimate quarter of drop-out if unreported. Sensitivity analyses were done by excluding DBT-arms with deviating push-out rules.
Results
Dropout was highest in the first quarter of treatment. Schema therapy had the lowest dropout overall, and mentalization-based treatment in the first two quarters. Community treatment by experts had the highest dropout. Moreover, individual therapy had lowest dropout, group therapy highest, with combined formats in-between. Other variables such as age or substance-use exclusion criteria were not associated with dropout.
Conclusion
The findings do not support claims that all treatments are equal, and indicate that efforts to reduce dropout should focus on early stages of treatment and on group treatment.
This paper provides an overview and appraisal of the International Design Engineering Annual (IDEA) challenge - a virtually hosted design hackathon run with the aim of generating a design research dataset that can provide insights into design activities at virtually hosted hackathons. The resulting dataset consists of 200+ prototypes with over 1300 connections providing insights into the products, processes and people involved in the design process. The paper also provides recommendations for future deployments of virtual hackathons for design research.
Prototyping is a vital activity in product development. For reasons of time, cost and level of definition, low fidelity representations of products are used to advance understanding and progress design. With the advent of Mixed Reality prototyping, the ways in which abstractions of different fidelities can be created have multiplied, but there is no guidance on how best to specify this abstraction. In this paper, a taxonomy of the dimensions of product fidelity is proposed so that both designers and researchers can better understand how fidelity can be managed to maximise prototype value.
Theories of early cooperation in human society often draw from a small sample of ethnographic studies of surviving populations of hunter–gatherers, most of which are now sedentary. Borneo hunter–gatherers (Punan, Penan) have seldom figured in comparative research because of a decades-old controversy about whether they are the descendants of farmers who adopted a hunting and gathering way of life. In 2018 we began an ethnographic study of a group of still-nomadic hunter–gatherers who call themselves Punan Batu (Cave Punan). Our genetic analysis clearly indicates that they are very unlikely to be the descendants of neighbouring agriculturalists. They also preserve a song language that is unrelated to other languages of Borneo. Dispersed travelling groups of Punan Batu with fluid membership use message sticks to stay in contact, co-operate and share resources as they journey between rock shelters and forest camps. Message sticks were once widespread among nomadic Punan in Borneo, but have largely disappeared in sedentary Punan villages. Thus the small community of Punan Batu offers a rare glimpse of a hunting and gathering way of life that was once widespread in the forests of Borneo, where prosocial behaviour extended beyond the face-to-face community, facilitating successful collective adaptation to the diverse resources of Borneo's forests.
Plasma oxidation for 14C sampling utilizes low-pressure (133 Pa), low-energy (<50 W), and low- temperature (<50°C) Ar- and O2-plasmas generating CO2 for AMS dating. O2-plasmas on empty chambers remove organic contamination. When clean, a new specimen is inserted and Ar-plasmas dislodge adsorbed atmospheric CO2 from surfaces. Finally, O2-plasmas oxidize organic materials to CO2 for AMS analysis. During some Ar-plasmas we observed anomalous pressure increases and unexpectedly high CO2. Residual gas analysis detected water, hydrogen and oxygen species with Ar and CO2 indicating water plasmas that produced excited oxygen species that prematurely oxidized specimen organic matter. Evolution of excess CO2 during Ar cleaning compromises the ability to affirm that atmospheric CO2 was removed. Standards, TIRI Belfast Pine and VIRI I Whalebone, were dated to determine whether water-induced oxidation was a confounding influence in dating. TIRI wood was sampled twice, once a water-soaked specimen in an Ar plasma and once with water-vapor-plasma only. The TIRI dates agreed with six earlier dates on usual specimens. A colloidal extract from VIRI I whale bone was also sampled and dated twice using both water–plasma oxidation in an Ar-plasma and in an O2-plasma. Dating agreement suggests that water plasmas do not pose undue risks of contamination.