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Summary: Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

Impaired post-thaw CD34 cell (postCD34) viability in autologous haematopoietic stem cell transplant (ASCT) could indicate delayed engraftment where multiple factors might complicate the relationship. Despite of a couple of unconfirmed reports of a negative correlation of platelet concentration with postCD34 viability, how platelets might be involved in the relationship is largely unknown. Therefore, this question was addressed in this retrospective study of 82 ASCT patients with a total of 150 collections of peripheral blood stem cells in New Zealand. A significant negative correction between platelet concentration and postCD34 recovery (r = -0.18, p = 0.028) was observed overall, but upon further analysis only confirmed in the subset with graft platelets 1500-2000 ×10 9 /L. Importantly, the postCD34 recovery was clearly reduced in the subgroups with either the lowest or the highest platelet concentration. The lowest subgroup was enriched with collections from patients with Hodgkin or non-Hodgkin lymphoma, whereas the highest subgroup from patients with multiple myeloma, both with clearly male preponderance. We hypothesized that graft platelet concentrations probably indicated CD34 cell state (e.g. cell cycle and cell adhesion highly related to platelet functions) that sustained when platelet concentrations were within a niche range but went out of kilter otherwise., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Following consumption of a meal, circulating glucose concentrations can rise and then fall briefly below the basal/fasting concentrations. This phenomenon is known as reactive hypoglycaemia but to date no researcher has explored potential inter-individual differences in response to meal consumption., Objective: We conducted a secondary analysis of existing data to examine inter-individual variability of reactive hypoglycaemia in response to breakfast consumption., Methods: Using a replicate crossover design, 12 healthy, physically active men (age: 18-30 y, body mass index: 22.1 to 28.0 kg⋅m - 2 ) completed two identical control (continued overnight fasting) and two breakfast (444 kcal; 60% carbohydrate, 17% protein, 23% fat) conditions in randomised sequences. Blood glucose and lactate concentrations, serum insulin and non-esterified fatty acid concentrations, whole-body energy expenditure, carbohydrate and fat oxidation rates, and appetite ratings were determined before and 2 h after the interventions. Inter-individual differences were explored using Pearson's product-moment correlations between the first and second replicates of the fasting-adjusted breakfast response. Within-participant covariate-adjusted linear mixed models and a random-effects meta-analytical approach were used to quantify participant-by-condition interactions., Results: Breakfast consumption lowered 2-h blood glucose by 0.44 mmol/L (95%CI: 0.76 to 0.12 mmol/L) and serum NEFA concentrations, whilst increasing blood lactate and serum insulin concentrations (all p < 0.01). Large, positive correlations were observed between the first and second replicates of the fasting-adjusted insulin, lactate, hunger, and satisfaction responses to breakfast consumption (all r > 0.5, 90%CI ranged from 0.03 to 0.91). The participant-by-condition interaction response variability (SD) for serum insulin concentration was 11 pmol/L (95%CI: 5 to 16 pmol/L), which was consistent with the τ-statistic from the random-effects meta-analysis (11.7 pmol/L, 95%CI 7.0 to 22.2 pmol/L) whereas effects were unclear for other outcome variables (e.g., τ-statistic value for glucose: 0 mmol/L, 95%CI 0.0 to 0.5 mmol/L)., Conclusions: Despite observing reactive hypoglycaemia at the group level, we were unable to detect any meaningful inter-individual variability of the reactive hypoglycaemia response to breakfast. There was, however, evidence that 2-h insulin responses to breakfast display meaningful inter-individual variability, which may be explained by relative carbohydrate dose ingested and variation in insulin sensitivity of participants., (© 2024. The Author(s).)

Apidaecin 1b (Api), the first characterized Type II Proline-rich antimicrobial peptide (PrAMP), is encoded in the honey bee genome. It inhibits bacterial growth by binding in the nascent peptide exit tunnel of the ribosome after the release of the completed protein and trapping the release factors. By genome mining, we have identified 71 PrAMPs encoded in insect genomes as pre-pro-polyproteins. Having chemically synthesized and tested the activity of 26 peptides, we demonstrate that despite significant sequence variation in the N-terminal sequence, the majority of the PrAMPs that retain the conserved C-terminal sequence of Api are able to trap the ribosome at the stop codons and induce stop codon readthrough-all hallmarks of Type II PrAMP mode of action. Some of the characterized PrAMPs exhibit superior antibacterial activity in comparison with Api. The newly solved crystallographic structures of the ribosome complexed with Api and with the more active peptide Fva1 from the stingless bee demonstrate the universal placement of the PrAMPs' C-terminal pharmacophore in the post-release ribosome despite variations in their N-terminal sequence., (© 2024. The Author(s).)

Study Objectives: Using the necessary replicate-crossover design, we investigated whether there is inter-individual variability in home-assessed sleep in response to acute exercise., Methods: Eighteen healthy men (mean(SD): 26(6) years) completed two identical control (8-h laboratory rest, 08:45-16:45) and two identical exercise (7-h laboratory rest; 1-h laboratory treadmill run [62(7)% peak oxygen uptake], 15:15-16:15) trials in randomised sequences. Wrist-worn actigraphy (MotionWatch 8) measured home-based sleep (total sleep time, actual wake time, sleep latency, sleep efficiency) two nights before (nights 1-2) and three nights after (nights 3-5) the exercise/control day. Pearson's correlation coefficients quantified the consistency of individual differences between the replicates of control-adjusted exercise responses to explore: (1) immediate (night 3 minus night 2); (2) delayed (night 5 minus night 2); and (3) overall (average post-intervention minus average pre-intervention) exercise-related effects. Within-participant linear mixed models and a random-effects between-participant meta-analysis estimated participant-by-trial response heterogeneity., Results: For all comparisons and sleep outcomes, the between-replicate correlations were non-significant, ranging from trivial-to-moderate (r range = -0.44 to 0.41, P≥0.065). Participant-by-trial interactions were trivial. Individual differences SDs were small, prone to uncertainty around the estimates indicated by wide 95% confidence intervals and did not provide support for true individual response heterogeneity. Meta-analyses of the between-participant, replicate-averaged condition effect revealed that, again, heterogeneity (τ) was negligible for most sleep outcomes., Conclusion: Control-adjusted sleep in response to acute exercise was inconsistent when measured on repeated occasions. Inter-individual differences in sleep in response to exercise were small compared to the natural (trial-to-trial) within-subject variability in sleep outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Objectives: To quantify the test-retest reliability of 3 patient-reported outcome measures of pain for people living with phantom limb pain (PLP) and assess the impact of test-retest errors on future research and clinical decisions., Methods: Thirty-nine participants (30 males), mean (SD) age: 55 (16), mean (SD) years postamputation: 6.8 (8.3), reported their PLP levels on a visual analogue scale (VAS) for pain intensity, the revised short-form McGill Pain Questionnaire (SF-MPQ-2), and a pain diary, on 2 occasions 7 to 14 days apart. Mean systematic change, within-subjects SD, limits of agreement (LOA), coefficient of variation, and the intraclass correlation coefficient (ICC) were quantified alongside their respective 95% confidence intervals (95% CIs)., Results: Systematic learning effects (mean changes) were not clinically relevant across the VAS, SF-MPQ-2, and pain diary. Within-subject SDs (95% CI) were 11.8 (9.6-15.3), 0.9 (0.7-1.2), and 8.6 (6.9-11.5), respectively. LOA (95% CI) were 32.6 (26.5-42.4), 2.5 (2-3.3), and 23.9 (19.2-31.8), respectively. ICCs (95% CI) were 0.8 (0.6-0.9), 0.8 (0.7-0.9), and 0.9 (0.8-0.9), respectively, but may have been inflated by sample heterogeneity. The test-retest errors allowed detection of clinically relevant effect sizes with feasible sample sizes in future studies, but individual errors were large., Discussion: For people with PLP, a pain intensity VAS, the SF-MPQ-2, and a pain diary show an acceptable level of intersession reliability for use in future clinical trials with feasible sample sizes. Nevertheless, the random error observed for all 3 of the pain outcome measures suggests they should be interpreted with caution in case studies and when monitoring individuals' clinical status and progress., Competing Interests: D.M. and C.R. are named inventors of a medical device for the management of phantom limb pain. They may benefit financially if the device is commercialized. This work was undertaken as part of the PhD by A.G., which was primarily funded by Teesside University but also received additional funding from Medi-Direct Ltd. who were involved in the development of the aforementioned medical device for the management of phantom limb pain. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe -/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe -/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.

Machine learning tasks involving biomedical signals frequently grapple with issues such as limited data availability, imbalanced datasets, labeling complexities, and the interference of measurement noise. These challenges often hinder the optimal training of machine learning algorithms. Addressing these concerns, we introduce BioDiffusion, a diffusion-based probabilistic model optimized for the synthesis of multivariate biomedical signals. BioDiffusion demonstrates excellence in producing high-fidelity, non-stationary, multivariate signals for a range of tasks including unconditional, label-conditional, and signal-conditional generation. Leveraging these synthesized signals offers a notable solution to the aforementioned challenges. Our research encompasses both qualitative and quantitative assessments of the synthesized data quality, underscoring its capacity to bolster accuracy in machine learning tasks tied to biomedical signals. Furthermore, when juxtaposed with current leading time-series generative models, empirical evidence suggests that BioDiffusion outperforms them in biomedical signal generation quality.

Background: Injuries are common in adult recreational athletes. Exercise-based injury prevention programmes offer the potential to reduce the risk of injury and have been a popular research topic. Yet, syntheses and meta-analyses on the effects of exercise-based injury prevention programmes for adult recreational athletes are lacking., Objectives: We aimed to synthesise and quantify the pooled intervention effects of exercise-based injury prevention programmes delivered to adults who participate in recreation sports., Methods: Studies were eligible for inclusion if they included adult recreational athletes (aged > 16 years), an exercise-based intervention and used a randomised controlled trial design. Exclusion criteria were studies without a control group, studies using a non-randomised design and studies including participants who were undertaking activity mandatory for their occupation. Eleven literature databases were searched from earliest record, up to 9 June, 2022. The Physiotherapy Evidence Database (PEDro) scale was used to assess the risk of bias in all included studies. Reported risk statistics were synthesised in a random-effects meta-analysis to quantify pooled treatment effects and associated 95% confidence intervals and prediction intervals., Results: Sixteen studies met the criteria. Risk statistics were reported as risk ratios [RRs] (n = 12) or hazard ratios [HRs] (n = 4). Pooled estimates of RRs and HRs were 0.94 (95% confidence interval 0.80-1.09) and 0.65 (95% confidence interval 0.39-1.08), respectively. Prediction intervals were 0.80-1.09 and 0.16-2.70 for RR and HR, respectively. Heterogeneity was very low for RR studies, but high for HR studies (tau = 0.29, I 2  = 81%). There was evidence of small study effects for RR studies, evidenced by funnel plot asymmetry and Egger's test for small study bias: - 0.99 (CI - 2.08 to 0.10, p = 0.07)., Conclusions: Pooled point estimates were suggestive of a reduced risk of injury in intervention groups. Nevertheless, these risk estimates were insufficiently precise, too heterogeneous and potentially compromised by small study effects to arrive at any robust conclusion. More large-scale studies are required to clarify whether exercise-based injury prevention programmes are effective in adult recreational athletes., Clinical Trial Registration: The protocol for this review was prospectively registered in the PROSPERO database (CRD42021232697)., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Using a replicated crossover design, we quantified the response heterogeneity of postprandial cardiovascular disease risk marker responses to acute exercise., Methods: Twenty men (mean (SD) age, 26 (6) yr; body mass index, 23.9 (2.4) kg·m -2 ) completed four 2-d conditions (two control, two exercise) in randomized orders. On days 1 and 2, participants rested and consumed two high-fat meals over 9 h. Participants ran for 60 min (61 (7)% of peak oxygen uptake) on day 1 (6.5 to 7.5 h) of both exercise conditions. Time-averaged total area under the curve (TAUC) for triacylglycerol, glucose, and insulin were calculated from 11 venous blood samples on day 2. Arterial stiffness and blood pressure responses were calculated from measurements at baseline on day 1 and at 2.5 h on day 2. Consistency of individual differences was explored by correlating the two replicates of control-adjusted exercise responses for each outcome. Within-participant covariate-adjusted linear mixed models quantified participant-by-condition interactions and individual response SDs., Results: Acute exercise reduced mean TAUC-triacylglycerol (-0.27 mmol·L -1 ·h; Cohen's d = 0.29, P = 0.017) and TAUC-insulin (-25 pmol·L -1 ·h; Cohen's d = 0.35, P = 0.022) versus control, but led to negligible changes in TAUC-glucose and the vascular outcomes (Cohen's d ≤ 0.36, P ≥ 0.106). Small-to-moderate, but nonsignificant, correlations were observed between the two response replicates ( r = -0.42 to 0.15, P ≥ 0.066). We did not detect any individual response heterogeneity. All participant-by-condition interactions were P ≥ 0.137, and all individual response SDs were small with wide 95% confidence intervals overlapping zero., Conclusions: Large trial-to-trial within-subject variability inhibited detection of consistent interindividual variability in postprandial metabolic and vascular responses to acute exercise., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)