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Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 effector memory (TEM) and central memory (TCM) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here, we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4 T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the TCM and TEM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bullock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 + effector memory (T EM ) and central memory (T CM ) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4 + T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the T CM and T EM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age.

The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb-treated macaques. Viral control was correlated with the reprogramming of CD8 + T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.

Background: Colorectal cancer is diagnosed in approximately 500,000 patients each year in Europe, leading to a high number of patients having to cope with the consequences of resection for colorectal cancer. As treatment options tend to grow, more information on the effects of these treatments is needed to engage in shared decision-making. This study aims to explore the impact of resection for colorectal cancer on patients' daily life., Methods: Patients (≥18 years of age) who underwent an oncological colorectal resection between 2018 and 2021 were selected. Purposeful sampling was used to include patients who differed in age, comorbidity conditions, types of (neo)adjuvant therapy, postoperative complications and the presence/absence of a stoma. Semi-structured interviews were conducted, guided by a topic guide. Interviews were fully transcribed and subsequently thematically analysed using the framework approach. Analyses were carried out using the following predefined themes: (1) daily life and activities; (2) psychological functioning; (3) social functioning; (4) sexual functioning; and (5) healthcare experiences., Results: Sixteen patients with a follow-up period of between 0.6 and 4.4 years after surgery were included in this study. Participants reported several challenges experienced because of poor bowel function, a stoma, chemotherapy-induced neuropathy, fear of recurrence and sexual dysfunction. However, they reported these as not interfering much with daily life., Conclusion: Colorectal cancer treatment leads to several challenges and treatment-related health deficits. This is often not recognized by generic patient-reported outcome measures, but the findings on treatment-related health deficits presented in this study contain valuable insights which might contribute to improving colorectal cancer care, shared decision making and value-based health care., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

New variants of SARS-CoV-2 show remarkable heterogeneity in their relative fitness over both time and space. In this paper we extend the tools available for estimating the selection strength for new SARS-CoV-2 variants to a hierarchical, mixed-effects, renewal equation model. This formulation allows us to estimate selection effects at the global level while incorporating both measured and unmeasured heterogeneity among countries. Applying this model to the spread of Omicron in forty countries, we find evidence for very strong but very heterogeneous selection effects. To test whether this heterogeneity is explained by differences in the immune landscape, we considered several measures of vaccination rates and recent population-level infection as covariates, finding moderately strong, statistically significant effects. We also found a significant positive correlation between the selection advantage of Delta and Omicron at the country level, suggesting that other region-specific explanatory variables of fitness differences do exist. Our method is implemented in the Stan programming language, can be run on standard consumer-grade computing resources, and will be straightforward to apply to future variants., (© The Author(s) 2022. Published by Oxford University Press.)

1. Musk xylene (1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene) is used as a fragrance component in toiletries, detergents and skin care products. Musk xylene is widely distributed in the environment and has been identified as a persistent contaminant in fish and in mothers' milk. Experimental data in man indicate a slow elimination of musk xylene and a potential for accumulation. Nitroarenes may be biotransformed to the respective amines. Some aromatic amines are known to be tumorigenic in animals and in man. Quantitation of the binding of those aromatic amines to haemoglobin has been proposed as a biomarker of internal exposure. 2. To determine bioavailability, metabolic reduction and haemoglobin binding of musk xylene in man, we investigated the presence of musk xylene metabolites bound to haemoglobin in blood samples from rat and from 10 human volunteers not knowingly exposed to musk xylene. 3. Haemoglobin from the blood samples was isolated, and bound metabolites were liberated as amines by alkaline hydrolysis. In haemoglobin samples from all individuals, 1-tert-butyl-3,5-dimethyl-4-amino-2,6-dinitrobenzene and, after chemical derivatization, the corresponding N-perfluoropropyl amide were identified by GC/MS using electron-impact and electron-capture mass spectrometry. 4. The amounts of 1-tert-butyl-3,5-dimethyl-4-amino-2,6-dinitrobenzene bound to haemoglobin in the human blood samples ranged from 13 to 46 fmol/mg haemoglobin. 5. These data demonstrate that musk xylene is bioavailable in man. The use of haemoglobin binding as a biomarker for nitromusk exposure in the general population warrants further studies.

Recent progress in biomonitoring allows measurement of internal exposure of individuals ranging from occupational and life style exposures to environmental levels. Ten specific hemoglobin adducts generated by polycyclic and monocyclic nitro-arenes were measured in coke oven workers and residents living on ground contaminated with explosive wastes, respectively. Consistently, adducts were found in most 'exposed' as well as control individuals, interindividual variation being great. Adduct levels in the majority of exposed individuals were within the range of reference values (95 percentile). Although hemoglobin adduct levels do not directly reflect genotoxic potential and potency of the parent compounds, they correlate with the biologically active dose. On the basis of such target doses, the contribution of specific exposures relative to 'background' and to related chemicals can be assessed. The impact of 'relative risk' on risk perception and risk management is to provide a rationale for the application of the ALARA principle (As Low As Reasonably Achievable).

In a study performed by primary health doctors among 10- and 11-year-olds in Zoetermeer (the Netherlands), 72% of the children were found to possess four healthy permanent first molars. The examination was exclusively based on visual inspection by means of mouth mirrors.

The aim of this study was to compare pit-and fissure sealants with fluoride treatments in their effectiveness to inhibit or reduce the progression of enamel lesions, particularly in the fissure region. The effects of fissure probing as used in diagnosis were compared with in the same protocol. Using a combination of image analysis of X-ray pictures of full crowns and a light microscopic evaluation of cross-sections provided information on the three dimensional spread of enamel demineralization. Pit-and-fissure sealants were superior in protecting enamel against progression of demineralization, as long as the walls of the fissures were well covered. The protection against demineralization offered by fluoride was mainly restricted to the smooth enamel surfaces; in fissures no protection could be measured. Surface defects of the enamel caused by probing or abrasion aided the progress of the lesion.

By using an explorer on demineralized fissures, an entrance may be created through which cariogenic micro-organisms and their metabolic products can directly penetrate into the softened subsurface. The effect of probing on the rate of formation and growth of lesions was quantified in vitro.

The role of Ca2+ in alpha-MSH action on melanophores was studied, in vitro, with a bioassay on ventral tail-fin pieces from tadpoles of Xenopus laevis. Melanosome dispersion induced by alpha-MSH required 1-2 mM extracellular Ca2+. Gradual lowering of the extracellular Ca2+ levels produced a concentration-dependent inhibition of the alpha-MSH response; complete inhibition was obtained in a Ca2+-free medium containing 10-4 M EGTA. In Mg2+-free medium, normal dispersion was observed. The Ca2+ antagonists verapamil (10-4 M), methoxy-verapamil (10-4 M) and La3+ (10-3 M) inhibited the dispersion induced by 3 X 10-9 M alpha-MSH, whereas ruthenium red (10-3 M) was without effect. The ionophore A23187 mimicked the effect of the hormone. Melanosome movement per se was evidently independent of Ca2+, because cAMP and dibutyryl-cAMP induced a full dispersion in the absence of Ca2+. These results show that extracellular Ca2+ is specifically required for alpha-MSH action on tail-fin melanophores in vitro and suggests a Ca2+ influx concomitant with the action of the hormone. Possible intra- and extra-cellular Ca2+ sites are discussed.