Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation.

Subcapsular sinus (SCS) macrophages capture antigens from lymph and present them intact for B cell encounter and follicular delivery. However, the properties of SCS macrophages are poorly defined. Here we show SCS macrophage development depended on lymphotoxin-alpha1beta2, and the cells had low lysosomal enzyme expression and retained opsonized antigens on their surface. Intravital imaging revealed immune complexes moving along macrophage processes into the follicle. Moreover, noncognate B cells relayed antigen opsonized by newly produced antibodies from the subcapsular region to the germinal center, and affinity maturation was impaired when this transport process was disrupted. Thus, we characterize SCS macrophages as specialized antigen-presenting cells functioning at the apex of an antigen transport chain that promotes humoral immunity

Sphingosine-1-phosphate receptor 2 restrains egress of γδ T cells from the skin.

Maintenance of a population of IL-17-committed γδ T cells in the dermis is important in promoting tissue immunity. However, the signals facilitating γδ T cell retention within the dermis remain poorly understood. Here, we find that sphingosine-1-phosphate receptor 2 (S1PR2) acts in a cell-intrinsic manner to oppose γδ T cell migration from the dermis to the skin draining lymph node (dLN). Migration of dermal γδ T cells to the dLN under steady-state conditions occurs in an S1PR1-dependent manner. S1PR1 and CD69 are reciprocally expressed on dermal γδ T cells, with loss of CD69 associated with increased S1PR1 expression and enhanced migration to the dLN. γδ T cells lacking both S1PR2 and CD69 are impaired in their maintenance within the dermis. These findings provide a mechanism for how IL-17+ γδ T cells establish residence within the dermis and identify a role for S1PR2 in restraining the egress of tissue-resident lymphocytes

Sex differences in circumstances and consequences of outdoor and indoor falls in older adults in the MOBILIZE Boston cohort study

Background: Despite extensive research on risk factors associated with falling in older adults, and current fall prevention interventions focusing on modifiable risk factors, there is a lack of detailed accounts of sex differences in risk factors, circumstances and consequences of falls in the literature. We examined the circumstances, consequences and resulting injuries of indoor and outdoor falls according to sex in a population study of older adults. Methods: Men and women 65 years and older (N = 743) were followed for fall events from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston prospective cohort study. Baseline measurements were collected by comprehensive clinical assessments, home visits and questionnaires. During the follow-up (median = 2.9 years), participants recorded daily fall occurrences on a monthly calendar, and fall circumstances were determined by a telephone interview. Falls were categorized by activity and place of falling. Circumstance-specific annualized fall rates were calculated and compared between men and women using negative binomial regression models. Results: Women had lower rates of outdoor falls overall (Crude Rate Ratio (RR): 0.72, 95% Confidence Interval (CI): 0.56-0.92), in locations of recreation (RR: 0.34, 95% CI: 0.17-0.70), during vigorous activity (RR: 0.38, 95% CI: 0.18-0.81) and on snowy or icy surfaces (RR: 0.55, 95% CI: 0.36-0.86) compared to men. Women and men did not differ significantly in their rates of falls outdoors on sidewalks, streets, and curbs, and during walking. Compared to men, women had greater fall rates in the kitchen (RR: 1.88, 95% CI: 1.04-3.40) and while performing household activities (RR: 3.68, 95% CI: 1.50-8.98). The injurious outdoor fall rates were equivalent in both sexes. Women’s overall rate of injurious indoor falls was nearly twice that of men’s (RR: 1.98, 95% CI: 1.44-2.72), especially in the kitchen (RR: 6.83, 95% CI: 2.05-22.79), their own home (RR: 1.84, 95% CI: 1.30-2.59) and another residential home (RR: 4.65, 95% CI: 1.05-20.66) or other buildings (RR: 2.29, 95% CI: 1.18-4.44). Conclusions: Significant sex differences exist in the circumstances and injury potential when older adults fall indoors and outdoors, highlighting a need for focused prevention strategies for men and women

Barriers to flexible sigmoidoscopy colorectal cancer screening in low uptake socio-demographic groups: A systematic review.

OBJECTIVE: To synthesise qualitative evidence related to barriers and facilitators of flexible sigmoidoscopy screening (FSS) intention and uptake, particularly within low socio-demographic uptake groups. FSS uptake is lower amongst women, lower socio-economic status (SES), and Asian ethnic groups within the United Kingdom (UK) and United States of America. METHODS: A total of 12 168 articles were identified from searches of four databases: EMBASE, MEDLINE, PsycINFO and Web of Science. Eligibility criteria included: individuals eligible to attend FSS and empirical peer-reviewed studies that analysed qualitative data. The Critical Appraisal Skills Program tool evaluated the methodological quality of included studies, and thematic synthesis was used to analyse the data. RESULTS: Ten qualitative studies met the inclusion criteria. Key barriers to FSS intention and uptake centred upon procedural anxieties. Women, including UK Asian women, reported shame and embarrassment, anticipated pain, perforation risk, and test preparation difficulties to elevate anxiety levels. Religious and cultural-influenced health beliefs amongst UK Asian groups were reported to inhibit FSS intention and uptake. Competing priorities, such as caring commitments, particularly impeded women's ability to attend certain FSS appointments. The review identified a knowledge gap concerning factors especially associated with FSS participation amongst lower SES groups. CONCLUSIONS: Studies mostly focussed on barriers and facilitators of intention to participate in FSS, particularly within UK Asian groups. To determine the barriers associated with FSS uptake, and further understand how screening intention translates to behaviour, it is important that future qualitative research is equally directed towards factors associated with screening behaviour

Does repeated influenza vaccination attenuate effectiveness? A systematic review and meta-analysis

BACKGROUND: Influenza vaccines require annual readministration; however, several reports have suggested that repeated vaccination might attenuate the vaccine's effectiveness. We aimed to estimate the reduction in vaccine effectiveness associated with repeated influenza vaccination. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and CINAHL Complete databases for articles published from Jan 1, 2016, to June 13, 2022, and Web of Science for studies published from database inception to June 13, 2022. For studies published before Jan 1, 2016, we consulted published systematic reviews. Two reviewers (EJ-G and EJR) independently screened, extracted data using a data collection form, assessed studies' risk of bias using the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) and evaluated the weight of evidence by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included observational studies and randomised controlled trials that reported vaccine effectiveness against influenza A(H1N1)pdm09, influenza A(H3N2), or influenza B using four vaccination groups: current season; previous season; current and previous seasons; and neither season (reference). For each study, we calculated the absolute difference in vaccine effectiveness (ΔVE) for current season only and previous season only versus current and previous season vaccination to estimate attenuation associated with repeated vaccination. Pooled vaccine effectiveness and ∆VE were calculated by season, age group, and overall. This study is registered with PROSPERO, CRD42021260242. FINDINGS: We identified 4979 publications, selected 681 for full review, and included 83 in the systematic review and 41 in meta-analyses. ΔVE for vaccination in both seasons compared with the current season was -9% (95% CI -16 to -1, I2=0%; low certainty) for influenza A(H1N1)pdm09, -18% (-26 to -11, I2=7%; low certainty) for influenza A(H3N2), and -7% (-14 to 0, I2=0%; low certainty) for influenza B, indicating lower protection with consecutive vaccination. However, for all types, A subtypes and B lineages, vaccination in both seasons afforded better protection than not being vaccinated. INTERPRETATION: Our estimates suggest that, although vaccination in the previous year attenuates vaccine effectiveness, vaccination in two consecutive years provides better protection than does no vaccination. The estimated effects of vaccination in the previous year are concerning and warrant additional investigation, but are not consistent or severe enough to support an alternative vaccination regimen at this time. FUNDING: WHO and the US National Institutes of Health

Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis

Objective biomarkers for the clinically heterogeneous adult-onset neurodegenerative disorder amyotrophic lateral sclerosis are crucial to facilitate assessing emerging therapeutics, and improve the diagnostic pathway in what is a clinically heterogeneous syndrome. With non-coding RNA transcripts including microRNA, piwi-RNA, and transfer RNA present in human biofluids, we sought to identify whether non-coding RNA in serum could be biomarkers for amyotrophic lateral sclerosis. Serum samples from our Oxford Study for Biomarkers in MND/ALS discovery cohort of amyotrophic lateral sclerosis patients (n=48), disease mimics (n=16), and age- and sex-matched healthy controls (n=24) were profiled for non-coding RNA expression using RNA-sequencing, which showed a wide range of non-coding RNA to be dysregulated. We confirmed significant alterations with reverse transcription-quantitative PCR in the expression of hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-92a-3p, hsa-piR-33151, TRV-AAC4-1.1, and TRA-AGC6-1.1. Furthermore, hsa-miR-206, a previously identified amyotrophic lateral sclerosis biomarker, showed a binary-like pattern of expression in our samples. Using the expression of these non-coding RNA, we were able to discriminate amyotrophic lateral sclerosis samples from healthy controls in our discovery cohort using a random forest analysis with 93.7% accuracy with promise in predicting progression rate of patients. Importantly, cross-validation of this novel signature using a new geographically distinct cohort of samples from the United Kingdom and Germany with both amyotrophic lateral sclerosis and control samples (n=156) yielded an accuracy of 73.9%. The high prediction accuracy of this non-coding RNA-based biomarker signature, even across heterogeneous cohorts, demonstrates the strength of our approach as a novel platform to identify and stratify amyotrophic lateral sclerosis patients

Variations in Community Prevalence and Determinants of Recreational and Utilitarian Walking in Older Age

Background:. Regular walking is critical to maintaining health in older age. We examined influences of individual and community factors on walking habits in older adults. Methods:. We analyzed walking habits among participants of a prospective cohort study of 745 community-dwelling men and women, mainly aged 70 years or older. We estimated community variations in utilitarian and recreational walking, and examined whether the variations were attributable to community differences in individual and environmental factors. Results:. Prevalence of recreational walking was relatively uniform while prevalence of utilitarian walking varied across the 16 communities in the study area. Both types of walking were associated with individual health and physical abilities. However, utilitarian walking was also strongly associated with several measures of neighborhood socioeconomic status and access to amenities while recreational walking was not. Conclusions:. Utilitarian walking is strongly influenced by neighborhood environment, but intrinsic factors may be more important for recreational walking. Communities with the highest overall walking prevalence were those with the most utilitarian walkers. Public health promotion of regular walking should take this into account

Fluctuation solution theory of pure fluids

Citation: Ploetz, E. A., Pallewela, G. N., & Smith, P. E. (2017). Fluctuation solution theory of pure fluids. Journal of Chemical Physics, 146(9), 13. doi:10.1063/1.4977040Fluctuation Solution Theory (FST) provides an alternative view of fluid thermodynamics in terms of pair fluctuations in the particle number and excess energy observed for an equivalent open system. Here we extend the FST approach to provide a series of triplet and quadruplet particle and excess energy fluctuations that can also be used to help understand the behavior of fluids. The fluctuations for the gas, liquid, and supercritical regions of three fluids (H2O, CO2, and SF6) are then determined from accurate equations of state. Many of the fluctuating quantities change sign on moving from the gas to liquid phase and, therefore, we argue that the fluctuations can be used to characterize gas and liquid behavior. Further analysis provides an approach to isolate contributions to the excess energy fluctuations arising from just the intermolecular interactions and also indicates that the triplet and quadruplet particle fluctuations are related to the pair particle fluctuations by a simple power law for large regions of the phase diagram away from the critical point. Published by AIP Publishing

Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for pure liquids

Citation: Ploetz, E. A., Karunaweera, S., & Smith, P. E. (2015). Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for pure liquids. Journal of Chemical Physics, 142(4), 14. doi:10.1063/1.4905562Fluctuation solution theory has provided an alternative view of many liquid mixture properties in terms of particle number fluctuations. The particle number fluctuations can also be related to integrals of the corresponding two body distribution functions between molecular pairs in order to provide a more physical picture of solution behavior and molecule affinities. Here, we extend this type of approach to provide expressions for higher order triplet and quadruplet fluctuations, and thereby integrals over the corresponding distribution functions, all of which can be obtained from available experimental thermodynamic data. The fluctuations and integrals are then determined using the International Association for the Properties of Water and Steam Formulation 1995 (IAPWS-95) equation of state for the liquid phase of pure water. The results indicate small, but significant, deviations from a Gaussian distribution for the molecules in this system. The pressure and temperature dependence of the fluctuations and integrals, as well as the limiting behavior as one approaches both the triple point and the critical point, are also examined. (C) 2015 AIP Publishing LLC