The investigation of proteomics, which describes the large-scale study of multiple proteins and their interconnected pathways, may enable a more comprehensive understanding of disease mechanisms due to the integral role of proteins in many biological processes (1). Circulating protein levels can be altered by diet, but current evidence on this is limited. We aimed to assess differences in the plasma proteome between people of different habitual dietary groups, defined by degree of animal food consumption.

We used data from the UK Biobank (2) of middle-aged (mostly 40 to 69 years) men and women recruited throughout the UK between 2006-2010. Relative concentrations of 2920 plasma proteins were quantified using the Olink Proximity Extension Assay in blood samples from 49,615 (54% women) participants. All participants completed a touchscreen questionnaire, which asked about their consumption of red and processed meat, poultry, fish, dairy and eggs, as well as ethnicity and lifestyle habits. We defined six diet groups among the white British participants, including 23,243 regular meat eaters (red and processed meat consumption >3 times/wk), 23,472 low meat eaters, 486 poultry eaters, 1081 fish eaters, 721 vegetarians, and 54 vegans, and two diet groups among the British Indians, including 391 meat eaters and 167 vegetarians. We used multivariable linear regressions adjusting for key socio-demographic and lifestyle confounders to assess the differences in individual protein concentrations between diet groups, with correction for multiple testing based on the effective number of independent tests.

We observed significant differences in many plasma proteins by diet group. In the white British population, 632 plasma proteins were significantly different in one or more pairwise comparisons between regular meat eaters and at least one of the other diet groups (p-value< 0.000037), including 266 proteins for vegetarians and 15 proteins for vegans. Of the biggest differences, compared with regular meat eaters, vegetarians (and other non-meat eaters) had significantly higher FGF21 (+0.40 SD), CKB (+0.34), GUCA2A (+0.33), FOLR1 (+0.32), IGFBP2 (+0.31) and DSG2 (+0.30); all groups except the vegans had lower HAVCR1 (also called KIM-1, -0.38 in vegetarians). Vegetarians also had significantly lower SELENOP (-0.46), while the vegans had lower FGFBP2 (-0.68). The observed differences were generally similar in direction in both ethnicities, but only two proteins were significantly different (SUMF2 and ATRAID, both of which were higher in vegetarians) when comparing British Indian vegetarians and meat eaters, likely owing to the relatively small number of British Indians in the study.

In this first comprehensive assessment of plasma proteins by diet group, we identified many differences in proteins between groups defined by animal food consumption. The variations in protein levels suggest differences in various biological activities, including gastrointestinal tract and kidney function, which may relate to differences in future disease risk.

Background: Late-onset Pompe disease (LOPD) is caused by a deficiency of acid α-glucosidase (GAA), leading to progressive muscle and respiratory decline. Cipaglucosidase alfa (cipa), a recombinant human GAA naturally enriched with bis-mannose-6-phosphate, exhibits improved muscle uptake but is limited by inactivation at near-neutral blood pH. Miglustat (mig), an enzyme stabiliser, binds competitively and reversibly to cipa, enhancing its stability and activity. Methods: In dose-finding studies, Gaa-/- mice were treated with cipa (20 mg/kg) +/- mig (10 mg/kg; equivalent human dose ~260 mg). Clinical study methodologies have been published (Schoser et al. Lancet Neurol 2021:20;1027–37; Schoser et al. J Neurol 2024:271;2810–23). Results: In Gaa-/- mice, cipa+mig improved muscle glycogen reduction more than cipa alone and grip strength to levels approaching wild-type mice. LOPD patients (n=11) treated with cipa alone showed dose-dependent decreases in hexose tetrasaccharide (Hex4) levels by ~15% from baseline, decreasing another ~10% with added mig (260 mg). In a head-to-head study, cipa+mig had a similar safety profile to alglucosidase alfa. Among 151 patients (three trials), mig-related adverse events occurred in 21 (13.9%), none serious. Conclusions: Mig stabilised cipa in circulation, improving cipa exposure, further reducing Hex4 levels and was well tolerated in clinical studies in patients with LOPD. Sponsored by Amicus Therapeutics, Inc.

Microbial, anoxygenic phototrophic ferrous iron (Fe(II)) oxidation (pFeOx) plays an important role in biological iron cycling. The uptake and oxidation of dissolved Fe(II) species (Fe2+aq) as an electron donor for pFeOx bacteria is well understood. In contrast, the oxidation of solid Fe(II)-bearing minerals by pFeOx is less well studied, with possible mechanisms including dissolution of the minerals followed by uptake and intracellular oxidation of Fe2+aq or extracellular electron transfer from solid Fe(II) minerals to the bacterial cells. We investigated the oxidation of the Fe(II)-bearing carbonate mineral siderite (FeCO3) by an anoxygenic phototrophic Fe(II) oxidiser Rhodopseudomonas palustris TIE-1. We aimed to explain if oxidation was controlled by chemical dissolution kinetics or whether direct electron transfer was involved. Controlled dissolution experiments using increasing dissolved bicarbonate concentrations (0–300 mM HCO3–), supported by geochemical modelling, demonstrated that R. palustris TIE-1 can oxidise up to 5-fold more Fe(II) when cells are in direct contact with siderite than would be expected if oxidation occurred through dissolution alone. These results suggest that anoxygenic phototrophic Fe(II)-oxidising bacteria have the capability to enhance carbonate dissolution or even access solid-phase Fe(II) in siderite as a source of electrons, especially when siderite dissolution is limited or suppressed by geochemical constraints.

Involving participants in the design of clinical trials should improve the overall success of a study. For this to occur, streamlined mechanisms are needed to connect the populations potentially impacted by a given study or health topic with research teams in order to inform trial design in a meaningful and timely manner. To address this need, we developed an innovative mechanism called the “ResearchMatch Expert Advice Tool” that quickly obtains volunteer perspectives from populations with specific health conditions or lived experiences using the national recruitment registry, ResearchMatch. This tool does not ask volunteers to participate in the trial but allows for wider community feedback to be gathered and translated into actionable recommendations used to inform the study’s design. We describe early use cases that shaped the current Expert Advice Tool workflow, how results from this tool were incorporated and implemented by studies, and feedback from volunteers and study teams regarding the tool’s usefulness. Additionally, we present a set of lessons learned during the development of the Expert Advice Tool that can be used by other recruitment registries seeking to obtain volunteer feedback on study design and operations.

Recruiting and retaining research participants is challenging because it often requires overcoming structural barriers and addressing how histories of mistrust and individuals’ lived experiences affect their research engagement. We describe a pilot workshop designed to educate clinical research professionals on using empathy skills to recognize and mitigate bias to improve recruitment and retention. In a post-workshop survey (22/31 participants completed), 94% agreed the workshop helped them practice perspective-taking, recognize implicit bias, and identify opportunities for empathy. Participants reported increased confidence in key recruitment and retention skills (p < 0.05). Future studies will evaluate whether this translates into improved recruitment.

Iron (Fe) minerals play a crucial role in biogeochemical cycles due to their ubiquity in nature, high adsorption capacity and redox activity towards many other elements. Mixed-valent Fe minerals are unique since they contain Fe(II) and Fe(III). For example, magnetite (Fe(II)Fe(III)2O4) nanoparticles (MNPs) can affect the availability and mobility of nutrients and contaminants. This is due to the high surface area to volume ratio and the presence of Fe(II) and Fe(III), allowing redox transformation of (in‑)organic contaminants. Recent studies have shown that magnetite can serve as an electron source and sink for Fe(II)-oxidizing and Fe(III)-reducing microorganisms, storing and releasing electrons; thus, it functions as a biogeobattery. However, the ability of MNPs to act as biogeobatteries over consecutive redox cycles and the consequences for mineral integrity and identity remain unknown. Here, we show MNPs working as biogeobatteries in two consecutive redox cycles over 41 days. MNPs were first oxidized by the autotrophic nitrate-reducing Fe(II)-oxidizing culture KS and subsequently reduced by the Fe(III)-reducing Geobacter sulfurreducens. In addition to reduced magnetite, we identified the Fe(II) mineral vivianite after reductions, suggesting partial reductive dissolution of MNPs and re-crystallization of Fe2+ with phosphate from the growth medium. Measurements of the Fe(II)/Fe(III) ratio revealed microbial oxidation and reduction for both the first redox cycle (oxidation: 0.29±0.014, reduction: 0.75±0.023) and the second redox cycle (oxidation: 0.30±0.015, reduction: 1.64±0.10). Relative changes in magnetic susceptibility (∆κ in %) revealed greater changes for the second oxidation (–8.7±1.99%) than the first (–3.9±0.19%) but more minor changes for the second reduction (+14.29±0.39%) compared to the first (+25.42±1.31%). Our results suggest that MNPs served as biogeobatteries but became less stable over time, which has significant consequences for associated contaminants, nutrients and bioavailability for Fe-metabolizing microorganisms.

During the menopausal transition, women often encounter a range of physical and psychological symptoms which negatively impact on health-related quality of life (HRQoL)(1). Diet quality has previously been identified as a modifiable factor associated with mitigating the severity of these symptoms in peri-menopausal and menopausal women(2). We therefore explored the independent associations between adherence to a Mediterranean diet (MedDiet) and the severity of menopausal symptoms in peri-menopausal and menopausal women living in Australia. We also explored the association between MedDiet adherence and HRQoL in this same cohort of women. We conducted a cross-sectional study of Australian peri-menopausal or menopausal women aged between 40 to 60 years. An 86-item self-administered questionnaire was used to assess the relationship between adherence to a MedDiet and severity of symptoms. MedDiet adherence was assessed using the Mediterranean Diet Adherence Screener (MEDAS), the Menopause Rating Scale (MRS) was used to assess the severity of menopausal symptoms related to somatic, psychological and urinary-genital symptoms and the 36-item short form survey instrument (SF-36) was used to assess HRQoL. Multivariable linear regression analysis (and 95% CI) was used to investigate the independent association between adherence to a MedDiet, severity of menopausal symptoms and HRQoL subscales using one unadjusted and five adjusted predictor models. A total of n = 207 participants (50.7 ± 4.3 years; BMI: 28.0 ± 7.4 kg/m2) were included in the final analyses. Participants reported low-moderate adherence to a MedDiet (5.2 ± 1.8; range: 1-11). We showed that MedDiet adherence was not associated with severity of menopausal symptoms. However, when assessing individual dietary constituents of the MEDAS, we showed that low consumption of sugar-sweetened beverages (<250ml per day) was inversely associated with joint and muscle complaints, independent of all covariates (β = −0.149; CI: −0.118, −0.022; P = 0.042). Furthermore, adherence to a MedDiet was positively associated with the physical function subscale of HRQoL (β = 0.173, CI: 0.001, 0.029; P = 0.031) and a low intake of red and processed meats (≤ 1 serve per day) was positively associated with the general health subscale (β = 0.296, CI: 0.005, 0.014; P = <0.001), independent of all covariates used in the fully adjusted model. Our results suggest that diet quality may be related to severity of menopausal symptoms and HRQoL in peri-menopausal and menopausal women. However, exploration of these findings using longitudinal analyses and robust clinical trials are needed to better elucidate these findings.

Food cravings are one of several important complexities between psychological and physiological triggers for food consumption. Cravings are commonly cited as contributing to over-consumption of hyperpalatable foods (sugary, salty, and fatty foods) and may be causal in obesity(1). The Mediterranean dietary pattern (MedDiet) is linked to reduced disease risk and improved health and wellbeing(2). Despite a lower intake of sugary and salty foods compared to a Western diet, free-living adults switching to the MedDiet find it satiating and achieve high adherence in Western countries. The MedDiet is known to improve mood and wellbeing, is high in fibre, monounsaturated fat and low in added sugar, and has a low glycaemic load, which could separately and synergistically reduce food cravings. The relationship between adherence to the MedDiet and food cravings has never been investigated. In the MedLey randomised controlled trial, we investigated the effects of a MedDiet on food cravings, compared with a habitual Australian diet (HabDiet)(3). Adherence to the MedDiet was scored out of 15 (maximum adherence). Participants completed three food cravings questionnaires at baseline and 6-months. The State questionnaire measures momentary cravings and has a maximum score of 75, indicating maximum food cravings. The Trait-reduced questionnaire measures general cravings and has a maximum score of score of 126, indicating more frequent and intense cravings for foods. The Food Cravings Inventory (FCI) measures cravings for four food domains: fatty foods, fast foods, sugary foods, and high carbohydrate (CHO) foods. MedDiet group (n = 58) responses were compared with the HabDiet group (n = 53) across visits using linear mixed effects modelling. Predicted differences were obtained for adherence scores of ≤8 (median adherence) and ≥9. Means ± SD or CIs are presented. Mean adherence increased from 7.1 ± 1.8 to 10.7 ± 1.48 in the MedDiet group (P<0.01), with no change in the HabDiet group (P = 1.00). Trait-reduced scores were not significantly different between groups at 6-months (P = 0.11), although there was a 5.57-point reduction within the MedDiet group (CI −12.56, −1.96, P = 0.04). State score was significantly lower in the MedDiet group than the HabDiet at 6-months (−4.4 (CI −7.53, −0.39), P = 0.03), and was significantly lower than at baseline (−5.9 (CI −9.33, −0.24,) P = 0.04). There were no differences between groups for the four domains of the FCI (P>0.05). Cravings for sugary foods was significantly reduced within the MedDiet group (−0.26 (CI −0.46, −0.05) P = 0.01). The predictive modelling suggested moving from an adherence score of 8 to 9 was associated with lower cravings for sugar (−0.03 ± 0.01, P = 0.03), fast food (−0.04 ± 0.02, P = 0.02) and CHO foods (−0.05 ± 0.02, P = 0.02). These results are suggestive that higher adherence to a MedDiet could reduce cravings compared to the Australian diet and suggest that the MedDiet may specifically reduce sugar cravings. Further investigation is warranted, through observational and intervention trials.

Imaging platforms for generating highly multiplexed histological images are being continually developed and improved. Significant improvements have also been made in the accuracy of methods for automated cell segmentation and classification. However, less attention has focused on the quantification and analysis of the resulting point clouds, which describe the spatial coordinates of individual cells. We focus here on a particular spatial statistical method, the cross-pair correlation function (cross-PCF), which can identify positive and negative spatial correlation between cells across a range of length scales. However, limitations of the cross-PCF hinder its widespread application to multiplexed histology. For example, it can only consider relations between pairs of cells, and cells must be classified using discrete categorical labels (rather than labeling continuous labels such as stain intensity). In this paper, we present three extensions to the cross-PCF which address these limitations and permit more detailed analysis of multiplex images: topographical correlation maps can visualize local clustering and exclusion between cells; neighbourhood correlation functions can identify colocalization of two or more cell types; and weighted-PCFs describe spatial correlation between points with continuous (rather than discrete) labels. We apply the extended PCFs to synthetic and biological datasets in order to demonstrate the insight that they can generate.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.