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Granville–Soundararajan, Harper–Nikeghbali–Radziwiłł and Heap–Lindqvist independently established an asymptotic for the even natural moments of partial sums of random multiplicative functions defined over integers. Building on these works, we study the even natural moments of partial sums of Steinhaus random multiplicative functions defined over function fields. Using a combination of analytic arguments and combinatorial arguments, we obtain asymptotic expressions for all the even natural moments in the large field limit and large degree limit, as well as an exact expression for the fourth moment.
Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.
Methods
In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.
Results
In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).
Conclusions
This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.
Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods
T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results
PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).
Conclusions
PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.
The impact of chronic pain and opioid use on cognitive decline and mild cognitive impairment (MCI) is unclear. We investigated these associations in early older adulthood, considering different definitions of chronic pain.
Methods:
Men in the Vietnam Era Twin Study of Aging (VETSA; n = 1,042) underwent cognitive testing and medical history interviews at average ages 56, 62, and 68. Chronic pain was defined using pain intensity and interference ratings from the SF-36 over 2 or 3 waves (categorized as mild versus moderate-to-severe). Opioid use was determined by self-reported medication use. Amnestic and non-amnestic MCI were assessed using the Jak-Bondi approach. Mixed models and Cox proportional hazards models were used to assess associations of pain and opioid use with cognitive decline and risk for MCI.
Results:
Moderate-to-severe, but not mild, chronic pain intensity (β = −.10) and interference (β = −.23) were associated with greater declines in executive function. Moderate-to-severe chronic pain intensity (HR = 1.75) and interference (HR = 3.31) were associated with a higher risk of non-amnestic MCI. Opioid use was associated with a faster decline in verbal fluency (β = −.18) and a higher risk of amnestic MCI (HR = 1.99). There were no significant interactions between chronic pain and opioid use on cognitive decline or MCI risk (all p-values > .05).
Discussion:
Moderate-to-severe chronic pain intensity and interference related to executive function decline and greater risk of non-amnestic MCI; while opioid use related to verbal fluency decline and greater risk of amnestic MCI. Lowering chronic pain severity while reducing opioid exposure may help clinicians mitigate later cognitive decline and dementia risk.
Background: Attitudes toward aging influence many health outcomes, yet their relationship with cognition and Alzheimer’s disease (AD) remains unknown. To better understand their impact on cognition and AD risk, we examined whether positive attitudes predict better cognition and diminished risk on AD biomarkers. Methods: A subsample of older adults with a family history of AD (n=54; women=39) from the McGill PREVENT-AD cohort participated in this study. Participants completed the Attitudes to Ageing Questionnaire (AAQ-24), providing three scores: psychosocial loss, psychological growth and physical change. Participants underwent cognitive testing (Rey Auditory Verbal Learning Test, RAVLT; Delis-Kaplan Executive Function System-Color Word Interference Test, D-KEFS-CWIT), and AD blood-based biomarker assessments (p-tau217, Aβ42/40). Regression models tested associations, adjusting for covariates (age, sex, education, depression, APOE4), and were Bonferroni corrected. Results: Positive attitudes were associated with better recall and recognition (RAVLT) and improved word reading, colour naming, switching, and inhibition (D-KEFS-CWIT) (p<0.00077), while negative attitudes showed the opposite pattern. Negative attitudes were correlated with lower Aβ42/40 ratios, while positive attitudes were linked to lower p-tau217 (p<0.0167). Conclusions: These findings demonstrate that positive attitudes predict better cognition and a lower risk profile for AD biomarkers, suggesting that life outlook may be an early disease feature or a risk factor.
Current evidence underscores a need to transform how we do clinical research, shifting from academic-driven priorities to co-led community partnership focused programs, accessible and relevant career pathway programs that expand opportunities for career development, and design of trainings and practices to develop cultural competence among research teams. Failures of equitable research translation contribute to health disparities. Drivers of this failed translation include lack of diversity in both researchers and participants, lack of alignment between research institutions and the communities they serve, and lack of attention to structural sources of inequity and drivers of mistrust for science and research. The Duke University Research Equity and Diversity Initiative (READI) is a program designed to better align clinical research programs with community health priorities through community engagement. Organized around three specific aims, READI-supported programs targeting increased workforce diversity, workforce training in community engagement and cultural competence, inclusive research engagement principles, and development of trustworthy partnerships.
This article examines the practice of post-mortem examination in the Royal Navy during the French Revolutionary and Napoleonic Wars (1793–1815). The professional medical logbooks kept by ship’s surgeons as part of their mandated practice reveal that they turned to pathological anatomy to diagnose their patients – a technique typically associated with French anatomy during this period. I show that these post-mortem dissections blended medicine and surgery together by correlating clinical signs and symptoms of disease with pathological manifestations of disease in the bodies after death. This article also considers the medical culture that existed on these ships that enabled this research, specifically how captains, officers and crew responded to, and interpreted, such medical enquiry on board. By resituating the naval ship as a site of medical experimentation and enquiry, I explore how naval surgeons participated in medical research within the Royal Navy and used the ship space to engage in pathological anatomy before their British civilian counterparts flocked to French hospitals after the wars.
Geochemical and 40Ar/39Ar age analyses of a new exposure of a previously destroyed volcanic ash locality within the Airport Terrace above the Middle Popo Agie River in Lander, Wyoming, allows us to re-establish it as Lava Creek A from the last major eruption of the Yellowstone caldera, with a weighted mean age of 628.2 ± 4.1 ka. Confirmation of the ash as Lava Creek more firmly establishes correlation of the terrace with the WR-7 terraces along the Wind River that contain Lava Creek ash and with outwash correlated to the Sacagawea Ridge type moraine at Dinwoody Lakes. By projecting the Airport Terrace gradient upstream, we show that it grades to the previously mapped terminus of the Sacagawea Ridge valley glacier. Additionally, 10Be boulder-exposure ages of ca. 521, ca. 554, and ca. 556 ka from Sacagawea Ridge moraines in nearby canyons support more closely constraining the Sacagawea Ridge glaciation here to Marine Oxygen Isotope Stage 16, which corresponds with recent evidence for an advance of the Laurentide Ice Sheet at this time in the U.S. midcontinent.
Current clinical guidelines for people at risk of heart disease in Australia recommend nutrition intervention in conjunction with pharmacotherapy(1). However, Australians living in rural and remote regions have less access to medical nutritional therapy (MNT) provided by Accredited Practising Dietitians (APDs) than their urban counterparts(2). The aim of the HealthyRHearts study was to trial the delivery of MNT by APDs using telehealth to eligible patients of General Practitioners (GPs) located in small to large rural towns in the Hunter New England region(3) of New South Wales, Australia. The study design was a 12-month pragmatic randomised controlled trial. The key outcome was reduced total cholesterol. The study was place-based, meaning many of the research team and APDs were based rurally, to ensure the context of the GPs and patients was already known. Eligible participants were those assessed as moderate-to-high risk of CVD by their GP. People in the intervention group received five MNT consults (totalling two hours) delivered via telehealth by APDs, and also answered a personalised nutrition questionnaire to guide their priorities and to support personalised dietary behaviour change during the counselling. Both intervention and control groups received usual care from their GP and were provided access to the Australian Eating Survey (Heart version), a 242-item online food frequency questionnaire with technology-supported personalised nutrition reports that evaluated intake relative to heart healthy eating principles. Of the 192 people who consented to participate, 132 were eligible due to their moderate-to-high risk. Pre-post participant medication use with a registered indication(4) for hypercholesterolemia, hypertension and glycemic control were documented according to class and strength (defined daily dose: DDD)(5). Nine GP practices (with 91 participants recruited) were randomised to the intervention group and seven practices (41 participants) were randomised to control. Intervention participants attended 4.3 ± 1.4 out of 5 dietetic consultations offered. Of the132 people with baseline clinical chemistry, 103 also provided a 12-month sample. Mean total cholesterol at baseline was 4.97 ± 1.13 mmol/L for both groups, with 12-m reduction of 0.26 ± 0.77 for intervention and 0.28 ± 0.79 for control (p = 0.90, unadjusted value). Median (IQR) number of medications for the intervention group was 2 (1–3) at both baseline and 12 months (p = 0.78) with 2 (1–3) and 3 (2–3) for the control group respectively. Combined DDD of all medications was 2.1 (0.5–3.8) and 2.5 (0.75–4.4) at baseline and 12 months (p = 0.77) for the intervention group and 2.7 (1.5–4.0) and 3.0 (2.0–4.5) for the control group (p = 0.30). Results suggest that medications were a significant contributor to the management of total cholesterol. Further analysis is required to evaluate changes in total cholesterol attributable to medication prescription relative to the MNT counselling received by the intervention group.
Traditional foods are increasingly being incorporated into modern diets. This is largely driven by consumers seeking alternative food sources that have superior nutritional and functional properties. Within Australia, Aboriginal and Torres Strait Islander peoples are looking to develop their traditional foods for commercial markets. However, supporting evidence to suggest these foods are safe for consumption within the wider general population is limited. At the 2022 NSA conference a keynote presentation titled ‘Decolonising food regulatory frameworks to facilitate First Peoples food sovereignty’ was presented. This presentation was followed by a manuscript titled ‘Decolonising food regulatory frameworks: Importance of recognising traditional culture when assessing dietary safety of traditional foods’, which was published in the conference proceedings journal(1). These pieces examined the current regulatory frameworks that are used to assess traditional foods and proposed a way forward that would allow Traditional Custodians to successfully develop their foods for modern markets. Building upon the previously highlighted works, this presentation will showcase best practice Indigenous engagement and collaboration principles in the development of traditionally used food products. To achieve this, we collaborated with a collective of Gamilaraay peoples who are looking to reignite their traditional grain practices and develop grain-based food products. To meet the current food safety regulatory requirements, we needed to understand how this grain would fit into modern diets, which included understanding the history of use, elucidating the nutritional and functional properties that can be attributed to the grain, and developing a safety dossier(2) so that the Traditional Custodians can confidently take their product to market. To aid the Traditional Custodians in performing their due diligence, we have systemically analysed the dietary safety of the selected native grain and compared it side-by-side with commonly consumed wheat in a range of in vitro bioassays and chemical analyses. From a food safety perspective, we show that the native grain is equivalent to commonly consumed wheat. The native grain has been shown to be no more toxic than wheat within our biological screening systems. Chemical analysis showed that the level of contaminants are below tolerable limits, and we were not able to identify any chemical classes of concern. Our initial findings support the history of safe use and suggest that the tested native grain species would be no less safe than commonly consumed wheat. This risk assessment and previously published nutritional study(3) provides an overall indication that the grain is nutritionally superior and viable for commercial development. The learnings from this project can direct the future risk assessment of traditional foods and therefore facilitate the safe market access of a broader range of traditionally used foods. Importantly, the methods presented are culturally safe and financially viable for the small businesses hoping to enter the market.
Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.
Methods
We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).
Results
Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.
Conclusions
Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.
Objectives/Goals: We will conduct a 12-week pilot randomized controlled trial (RCT) to test the feasibility, acceptability, and preliminary efficacy of a staged-intensity whole foods intervention on hemoglobin A1c (HbA1c) change in adults, diet quality change (via the 2020 healthy eating index [HEI-2020]) in adults and offspring, and diet adherence and social determinants of health (SDOH) considerations via focus groups. Methods/Study Population: In this two-arm, parallel RCT, 30 adults with prediabetes (25–59 years) and their offspring (6–18 years) will be randomized to receive the 1) 12-week whole foods intervention which includes a 2-week feeding period (all foods/recipies provided), a 6-week customizable feeding period (3 dinners/recipies weekly), and a 4-week maintenance period (no food/recipies). The control group will receive standard of care (i.e., single RD-led diet counseling session). Primary outcomes include feasibility (≥80% retention and completion of study outcome measures) and acceptability (≥75% adult self-reported diet satisfaction). Intervention effects include 1) HbA1c change at 12-weeks in adults and 2) adult/offspring HEI-2020 scores assessed via diet records. Focus groups will assess influences of SDOH on diet adherence. Results/Anticipated Results: We have received Institutional Review Board approval, and recruitment is planned for January 2025. We will enroll 30 families from the greater Nashville, TN area. An intent-to-treat analysis will be conducted to test the preliminary effects of the whole foods diet intervention on the 12-week change in HbA1c (adults only) and 2020-HEI diet quality scores during the intervention period (adults and offspring). Focus groups will be conducted to understand how individual and family needs/preferences and SDOH may be perceived barriers or facilitators of diet adherence. Data generated from this study will be used to guide a fully powered RCT of our whole foods intervention to assess long-term effects on additional diabetes and metabolic outcomes and assessment of SDOH influences to support long-term adherence. Discussion/Significance of Impact: A healthy diet pattern is an effective nonpharmacological solution to prevent T2D, but only if it can be maintained. A family-centered whole foods diet pattern that uses “food as medicine” and considers how individual and family needs/preferences, and SDOHs could be an effective and sustainable multigenerational solution to prevent T2D in families.
Archimedes screw generators are a small-scale, eco-friendly hydropower technology. Despite their promise as a sustainable energy technology, the design specifics of the technology are not well documented in the published literature. Existing performance prediction models often fail to accurately forecast power loss, particularly as it relates to the outlet of the screw generator. To address this, a comprehensive computational fluid dynamic model was developed and evaluated using both laboratory-scale experiments and real-world data. This yielded an extensive dataset that covered wide variations in design parameters. The dataset was then used to inform the development and evaluation of an outlet power loss prediction model. The resulting model significantly improved the accuracy of overall performance predictions, reducing average error to 13.68 % compared with nominal experimental data – a substantial improvement over previous models, which averaged around 42.55 % error for the same test cases. Notably, the new model achieved an absolute error of 5 % or less in over 26 % of comparison points, marking a remarkable advancement by predicting outlet power loss by more than 28.8 %.
This paper studies a situation wherein a set of voters choose between two alternatives in the presence of a payoff externality. Specifically, regardless of her intrinsic preference, a voter's payoff is maximized should she vote for the alternative that garners a majority of the votes cast. Are votes coordinated on a single alternative? Using laboratory experiments, we examine voting patterns in sequential voting and simultaneous voting elections. Across both election types, we also vary the amount of information that an individual voter has regarding the intrinsic preferences of the other voters. Our main findings are as follows. In the “low” information treatment, sequential voting elections facilitate coordinated voting. However, in the “high” information treatment, voting patterns are not dependent on how the election is structured.
Low vitamin D associated with high parathyroid hormone (PTH) is common in HIV infection. We determined the association between total 25(OH)D and PTH in adolescents living with HIV, in Zambia and Zimbabwe. Adolescents (11–19 years) perinatally infected with HIV and established on antiretroviral therapy for ≥ 6 months were recruited into a cross-sectional study. Socio-demographic and clinical characteristics were recorded, anthropometry measured and fasted serum concentrations of 1,25(OH)2D, total 25(OH)D and intact PTH measured. The association between total 25(OH)D and PTH was examined using natural cubic spline regression. 842 participants (female: 53·2%) with a median age of 15·5 (IQR: 13·2–17·9) years were enrolled. Median antiretroviral therapy duration was 9·8 (IQR: 6·3–12·3) years, and 165/841 had an HIV viral-load >60 copies/ml. Stunting (height-for-age z-score <–2) and underweight (weight-for-age z-score <–2) were observed in 29·9 and 30·0%, respectively. Three-quarters reported daily Ca intakes <150 mg/d. The mean (sd) concentrations of total 25(OH)D and 1,25(OH)2D were 66·1(16·5) nmol/l and 210·6 (70·4) pmol/l, respectively, and median PTH level was 4·3 (IQR: 3·3–5·5) pmol/l. There was an inverse non-linear relationship between total 25(OH)D and PTH, 25(OH)D levelling off at 74·6 nmol/l (95 % CI: 74·5, 75·2). Results were consistent in those taking tenofovir disoproxil fumarate and virally unsuppressed participants. In this population with extremely low habitual Ca intakes, the lack of association between 25(OH)D and PTH when 25(OH)D exceeded 75 nmol/l potentially suggests that levels of 25(OH)D >75 nmol/l may need to be achieved to improve bone health; investigation is needed in future research studies.
Most people with mental illness in low and middle-income countries (LMICs) do not receive biomedical treatment, though many seek care from traditional healers and faith healers. We conducted a qualitative study in Buyende District, Uganda, using framework analysis. Data collection included interviews with 24 traditional healers, 20 faith healers, and 23 biomedical providers, plus 4 focus group discussions. Interviews explored treatment approaches, provider relationships, and collaboration potential until theoretical saturation was reached. Three main themes emerged: (1) Biomedical providers’ perspectives on traditional and faith healers; (2) Traditional and faith healers’ views on biomedical providers; and (3) Collaboration opportunities and barriers. Biomedical providers viewed faith healers positively but traditional healers as potentially harmful. Traditional and faith healers valued biomedical approaches while feeling variably accepted. Interest in collaboration existed across groups but was complicated by power dynamics, economic concerns, and differing mental illness conceptualizations. Traditional healers and faith healers routinely referred patients to biomedical providers, though reciprocal referrals were rare. The study reveals distinct dynamics among providers in rural Uganda, with historical colonial influences continuing to shape relationships and highlighting the need for integrated, contextually appropriate mental healthcare systems.