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1.
Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence.
Reeves, DB, Bacchus-Souffan, C, Fitch, M, Abdel-Mohsen, M, Hoh, R, Ahn, H, Stone, M, Hecht, F, Martin, J, Deeks, SG, et al
Nature communications. 2023;(1):6145
Abstract
Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (TN), stem-cell- (TSCM), central- (TCM), transitional- (TTM), and effector-memory (TEM). HIV decreases in TTM and TEM but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant's year ~10 (in TN and TSCM) and ~104 (in TCM, TTM, TEM) proviruses are generated by proliferation while ~103 proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.
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Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial.
Aparicio, T, Bouché, O, Etienne, PL, Barbier, E, Mineur, L, Desgrippes, R, Guérin-Meyer, V, Hocine, F, Martin, J, Le Brun-Ly, V, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2023;(4):541-548
Abstract
BACKGROUND Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.
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3.
Latent generative landscapes as maps of functional diversity in protein sequence space.
Ziegler, C, Martin, J, Sinner, C, Morcos, F
Nature communications. 2023;(1):2222
Abstract
Variational autoencoders are unsupervised learning models with generative capabilities, when applied to protein data, they classify sequences by phylogeny and generate de novo sequences which preserve statistical properties of protein composition. While previous studies focus on clustering and generative features, here, we evaluate the underlying latent manifold in which sequence information is embedded. To investigate properties of the latent manifold, we utilize direct coupling analysis and a Potts Hamiltonian model to construct a latent generative landscape. We showcase how this landscape captures phylogenetic groupings, functional and fitness properties of several systems including Globins, β-lactamases, ion channels, and transcription factors. We provide support on how the landscape helps us understand the effects of sequence variability observed in experimental data and provides insights on directed and natural protein evolution. We propose that combining generative properties and functional predictive power of variational autoencoders and coevolutionary analysis could be beneficial in applications for protein engineering and design.
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4.
Obesity prevention practices in early care and education settings: an adaptive implementation trial.
Swindle, T, Rutledge, JM, Selig, JP, Painter, J, Zhang, D, Martin, J, Johnson, SL, Whiteside-Mansell, L, Almirall, D, Barnett-McElwee, T, et al
Implementation science : IS. 2022;(1):25
Abstract
BACKGROUND Despite the potential for Early Care and Education (ECE) settings to promote healthy habits, a gap exists between current practices and evidence-based practices (EBPs) for obesity prevention in childhood. METHODS We will use an enhanced non-responder trial design to determine the effectiveness and incremental cost-effectiveness of an adaptive implementation strategy for Together, We Inspire Smart Eating (WISE), while examining moderators and mediators of the strategy effect. WISE is a curriculum that aims to increase children's intake of carotenoid-rich fruits and vegetables through four evidence-based practices in the early care and education setting. In this trial, we will randomize sites that do not respond to low-intensity strategies to either (a) continue receiving low-intensity strategies or (b) receive high-intensity strategies. This design will determine the effect of an adaptive implementation strategy that adds high-intensity versus one that continues with low-intensity among non-responder sites. We will also apply explanatory, sequential mixed methods to provide a nuanced understanding of implementation mechanisms, contextual factors, and characteristics of sites that respond to differing intensities of implementation strategies. Finally, we will conduct a cost effectiveness analysis to estimate the incremental effect of augmenting implementation with high-intensity strategies compared to continuing low-intensity strategies on costs, fidelity, and child health outcomes. DISCUSSION We expect our study to contribute to an evidence base for structuring implementation support in real-world ECE contexts, ultimately providing a guide for applying the adaptive implementation strategy in ECE for WISE scale-up. Our work will also provide data to guide implementation decisions of other interventions in ECE. Finally, we will provide the first estimate of relative value for different implementation strategies in this setting. TRIAL REGISTRATION NCT05050539 ; 9/20/21.
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Exploring the effects of added sugar labels on food purchasing behaviour in Australian parents: An online randomised controlled trial.
Riesenberg, D, Peeters, A, Backholer, K, Martin, J, Ni Mhurchu, C, Blake, MR
PloS one. 2022;(8):e0271435
Abstract
BACKGROUND Evidence of the effects of front-of-pack added sugar labelling remains limited, especially for foods other than sugary drinks. More information is needed about which labels are likely to be most effective in reducing intended purchases of products with higher added sugar content in realistic contexts to inform policymakers' decisions. OBJECTIVE To determine the impact of added sugar labels on intended purchases of high sugar breakfast cereals, yoghurt, and non-alcoholic beverages. METHODS Australian parents who were regular purchasers of relevant product categories completed an online parallel randomised controlled trial from 31 August 2020 to 13 February 2021. Participants selected their intended purchase from 10 products in each of packaged beverages, breakfast cereal, and yoghurt categories after randomisation to one of seven added sugar labelling conditions in current use or under consideration by the Australian Government. Logistic regressions assessed differences between intervention and control conditions in the odds of intended purchases of a high sugar product. RESULTS 2825 eligible participants were randomised with 2582 valid surveys analysed (Control n = 367; 'Nutrition Information Panel (NIP) with Added Sugar' n = 364; 'Teaspoons of Sugar' n = 369; 'Warning' n = 371; 'Health Star Rating (HSR) using Total Sugar' n = 368; 'HSR with Added Sugar' n = 371; 'Sugar in the Ingredients List' n = 372). No consistent effects were found on intended purchases of high sugar products overall or within product categories for any of the tested labels compared to controls (overall, 'NIP with Added Sugar': OR 1.00 [95%CI 0.83,1.20]; 'Teaspoons of Sugar': 0.94[0.80,1.11]; 'Warning': 1.10[0.93,1.30]; 'HSR with Total Sugar': 1.01[0.85,1.21]; 'HSR with Added Sugar': 1.09[0.92,1.30]; 'Sugar in the Ingredients List': 1.01[0.85,1.21]). CONCLUSIONS Findings reinforce the importance of ensuring nutrition labelling policies are introduced as part of a suite of interventions to influence both consumer and manufacturer behaviour. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, ACTRN12620000858998. Registered 28 August 2020, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000858998.
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6.
Myocarditis and Cardiac Complications Associated With COVID-19 and mRNA Vaccination: A Pragmatic Narrative Review to Guide Clinical Practice.
Holland, DJ, Blazak, PL, Martin, J, Broom, J, Poulter, RS, Stanton, T
Heart, lung & circulation. 2022;(7):924-933
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Abstract
Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus is likely to remain endemic globally despite widespread vaccination. There is increasing concern for myocardial involvement and ensuing cardiac complications due to COVID-19, however, the available evidence suggests these risks are low. Pandemic publishing has resulted in rapid manuscript availability though pre-print servers. Subsequent article retractions, a lack of standardised definitions, over-reliance on isolated troponin elevation and the heterogeneity of studied patient groups (i.e. severe vs. symptomatic vs all infections) resulted in early concern for high rates of myocarditis in patients with and recovering from COVID-19. The estimated incidence of myocarditis in COVID-19 infection is 11 cases per 100,000 infections compared with an estimated 2.7 cases per 100,000 persons following mRNA vaccination. For substantiated cases, the clinical course of myocarditis related to COVID-19 or mRNA vaccination appears mild and self-limiting, with reports of severe/fulminant myocarditis being rare. There is limited data available on the management of myocarditis in these settings. Clinical guidance for appropriate use of cardiac investigations and monitoring in COVID-19 is needed for effective risk stratification and efficient use of cardiac resources in Australia. An amalgamation of national and international position statements and guidelines is helpful for guiding clinical practice. This paper reviews the current available evidence and guidelines and provides a summary of the risks and potential use of cardiac investigations and monitoring for patients with COVID-19.
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Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic oesophageal and gastrooesophageal carcinoma with dysphagia: a single arm phase II clinical trial (PALEO, sponsored by the Australasian Gastro-Intestinal Trials Group).
Day, F, Sridharan, S, Lynam, J, Gedye, C, Johnson, C, Fraser, A, Thompson, SR, Michael, M, Leong, T, Roy, A, et al
BMC cancer. 2022;(1):1324
Abstract
BACKGROUND Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. METHODS PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. DISCUSSION This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019.
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Behaviour Change Techniques in Weight Gain Prevention Interventions in Adults of Reproductive Age: Meta-Analysis and Meta-Regression.
Awoke, MA, Harrison, CL, Martin, J, Misso, ML, Lim, S, Moran, LJ
Nutrients. 2022;(1)
Abstract
Weight gain prevention interventions are likely to be more effective with the inclusion of behaviour change techniques. However, evidence on which behaviour change techniques (BCT) are most effective for preventing weight gain and improving lifestyle (diet and physical activity) is limited, especially in reproductive-aged adults. This meta-analysis and meta-regression aimed to identify BCT associated with changes in weight, energy intake and physical activity in reproductive-aged adults. BCT were identified using the BCT Taxonomy (v1) from each intervention. Meta-regression analyses were used to identify BCT associated with change in weight, energy intake and physical activity. Thirty-four articles were included with twenty-nine articles for the meta-analysis. Forty-three of the ninety-three possible BCT listed in the taxonomy were identified in the included studies. Feedback on behaviour and Graded tasks were significantly associated with less weight gain, and Review behaviour goals was significantly associated with lower energy intake. No individual BCT were significantly associated with physical activity. Our analysis provides further evidence for which BCT are most effective in weight gain prevention interventions. The findings support that the use of key BCT within interventions can contribute to successful weight gain prevention in adults of reproductive age.
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9.
Rhizosphere Bacterial Networks, but Not Diversity, Are Impacted by Pea-Wheat Intercropping.
Pivato, B, Semblat, A, Guégan, T, Jacquiod, S, Martin, J, Deau, F, Moutier, N, Lecomte, C, Burstin, J, Lemanceau, P
Frontiers in microbiology. 2021;:674556
Abstract
Plant-plant associations, notably cereal-legume intercropping, have been proposed in agroecology to better value resources and thus reduce the use of chemical inputs in agriculture. Wheat-pea intercropping allows to decreasing the use of nitrogen fertilization through ecological processes such as niche complementarity and facilitation. Rhizosphere microbial communities may account for these processes, since they play a major role in biogeochemical cycles and impact plant nutrition. Still, knowledge on the effect of intecropping on the rhizosphere microbiota remains scarce. Especially, it is an open question whether rhizosphere microbial communities in cereal-legume intercropping are the sum or not of the microbiota of each plant species cultivated in sole cropping. In the present study, we assessed the impact of wheat and pea in IC on the diversity and structure of their respective rhizosphere microbiota. For this purpose, several cultivars of wheat and pea were cultivated in sole and intercropping. Roots of wheat and pea were collected separately in intercropping for microbiota analyses to allow deciphering the effect of IC on the bacterial community of each plant species/cultivar tested. Our data confirmed the well-known specificity of the rhizosphere effect and further stress the differentiation of bacterial communities between pea genotypes (Hr and hr). As regards the intercropping effect, diversity and structure of the rhizosphere microbiota were comparable to sole cropping. However, a specific co-occurrence pattern in each crop rhizosphere due to intercropping was revealed through network analysis. Bacterial co-occurrence network of wheat rhizosphere in IC was dominated by OTUs belonging to Alphaproteobacteria, Bacteroidetes and Gammaproteobacteria. We also evidenced a common network found in both rhizosphere under IC, indicating the interaction between the plant species; this common network was dominated by Acidobacteria, Alphaproteobacteria, and Bacteroidetes, with three OTUs belonging to Acidobacteria, Betaproteobacteria and Chloroflexi that were identified as keystone taxa. These findings indicate more complex rhizosphere bacterial networks in intercropping. Possible implications of these conclusions are discussed in relation with the functioning of rhizosphere microbiota in intercropping accounting for its beneficial effects.
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10.
Cost-Effectiveness of a School-and Family-Based Childhood Obesity Prevention Programme in China: The "CHIRPY DRAGON" Cluster-Randomised Controlled Trial.
Zanganeh, M, Adab, P, Li, B, Pallan, M, Liu, WJ, Hemming, K, Lin, R, Liu, W, Martin, J, Cheng, KK, et al
International journal of public health. 2021;:1604025
Abstract
Objectives: Rapid socioeconomic and nutrition transitions in Chinese populations have contributed to the growth in childhood obesity. This study presents a cost-effectiveness analysis of a school- and family-based childhood obesity prevention programme in China. Methods: A trial-based economic evaluation assessed cost-effectiveness at 12 months. Forty schools with 1,641 children were randomised to either receive the multi-component (diet and physical activity) intervention or to continue with usual activities. Both public sector and societal perspectives were adopted. Costs and benefits in the form of quality-adjusted life years (QALYs) were compared and uncertainty was assessed using established UK and US thresholds. Results: The intervention cost was 35.53 Yuan (£7.04/US$10.01) per child from a public sector perspective and 536.95 Yuan (£106/US$151) from a societal perspective. The incremental cost-effectiveness ratio (ICER) was 272.7 Yuan (£54/US$77)/BMI z-score change. The ICER was 8,888 Yuan (£1,760/US$2,502) and 73,831 Yuan (£14,620/US$20,796) per QALY from a public sector and societal perspective, respectively and was cost-effective using UK (£20,000) and US (US$50,000) per QALY thresholds. Conclusion: A multi-component school-based prevention programme is a cost-effective means of preventing childhood obesity in China.