Impacts of ambient air quality on acute asthma hospital admissions during the COVID-19 pandemic in Oxford City, UK: a time-series study.

OBJECTIVES: The study aims to investigate the short-term associations between exposure to ambient air pollution (nitrogen dioxide (NO2), particulate matter pollution-particles with diameter<2.5 µm (PM2.5) and PM10) and incidence of asthma hospital admissions among adults, in Oxford, UK. DESIGN: Retrospective time-series study. SETTING: Oxford City (postcode areas OX1-OX4), UK. PARTICIPANTS: Adult population living within the postcode areas OX1-OX4 in Oxford, UK from 1 January 2015 to 31 December 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: Hourly NO2, PM2.5 and PM10 concentrations and meteorological data for the period 1 January 2015 to 31 December 2020 were analysed and used as exposures. We used Poisson linear regression analysis to identify independent associations between air pollutant concentrations and asthma admissions rate among the adult study population, using both single (NO2, PM2.5, PM10) and multipollutant (NO2 and PM2.5, NO2 and PM10) models, where they adjustment for temperature and relative humidity. RESULTS: The overall 5-year average asthma admissions rate was 78 per 100 000 population during the study period. The annual average rate decreased to 46 per 100 000 population during 2020 (incidence rate ratio 0.58, 95% CI 0.42 to 0.81, p<0.001) compared to the prepandemic years (2015-2019). In single-pollutant analysis, we observed a significantly increased risk of asthma admission associated with each 1 µg/m3 increase in monthly concentrations of NO2 4% (95% CI 1.009% to 1.072%), PM2.5 3% (95% CI 1.006% to 1.052%) and PM10 1.8% (95% CI 0.999% to 1.038%). However, in the multipollutant regression model, the effect of each individual pollutant was attenuated. CONCLUSIONS: Ambient NO2 and PM2.5 air pollution exposure increased the risk of asthma admissions in this urban setting. Improvements in air quality during COVID-19 lockdown periods may have contributed to a substantially reduced acute asthma disease burden. Large-scale measures to improve air quality have potential to protect vulnerable people living with chronic asthma in urban areas.

Nonclassical monocytes potentiate anti-tumoral CD8+ T cell responses in the lungs.

CD8+ T cells drive anti-cancer immunity in response to antigen-presenting cells such as dendritic cells and subpopulations of monocytes and macrophages. While CD14+ classical monocytes modulate CD8+ T cell responses, the contributions of CD16+ nonclassical monocytes to this process remain unclear. Herein we explored the role of nonclassical monocytes in CD8+ T cell activation by utilizing E2-deficient (E2-/-) mice that lack nonclassical monocytes. During early metastatic seeding, modeled by B16F10-OVA cancer cells injected into E2-/- mice, we noted lower CD8+ effector memory and effector T cell frequencies within the lungs as well as in lung-draining mediastinal lymph nodes in the E2-/- mice. Analysis of the myeloid compartment revealed that these changes were associated with depletion of MHC-IIloLy6Clo nonclassical monocytes within these tissues, with little change in other monocyte or macrophage populations. Additionally, nonclassical monocytes preferentially trafficked to primary tumor sites in the lungs, rather than to the lung-draining lymph nodes, and did not cross-present antigen to CD8+ T cells. Examination of the lung microenvironment in E2-/- mice revealed reduced CCL21 expression in endothelial cells, which is chemokine involved in T cell trafficking. Our results highlight the previously unappreciated importance of nonclassical monocytes in shaping the tumor microenvironment via CCL21 production and CD8+ T cell recruitment.

The spectrum of eating environments encountered in free living adults documented using a passive capture food intake wearable device.

Introduction: The aim of this feasibility and proof-of-concept study was to examine the use of a novel wearable device for automatic food intake detection to capture the full range of free-living eating environments of adults with overweight and obesity. In this paper, we document eating environments of individuals that have not been thoroughly described previously in nutrition software as current practices rely on participant self-report and methods with limited eating environment options. Methods: Data from 25 participants and 116 total days (7 men, 18 women, Mage = 44 ± 12 years, BMI 34.3 ± 5.2 kg/mm2), who wore the passive capture device for at least 7 consecutive days (≥12h waking hours/d) were analyzed. Data were analyzed at the participant level and stratified amongst meal type into breakfast, lunch, dinner, and snack categories. Out of 116 days, 68.1% included breakfast, 71.5% included lunch, 82.8% included dinner, and 86.2% included at least one snack. Results: The most prevalent eating environment among all eating occasions was at home and with one or more screens in use (breakfast: 48.1%, lunch: 42.2%, dinner: 50%, and snacks: 55%), eating alone (breakfast: 75.9%, lunch: 89.2%, dinner: 74.3%, snacks: 74.3%), in the dining room (breakfast: 36.7%, lunch: 30.1%, dinner: 45.8%) or living room (snacks: 28.0%), and in multiple locations (breakfast: 44.3%, lunch: 28.8%, dinner: 44.8%, snacks: 41.3%). Discussion: Results suggest a passive capture device can provide accurate detection of food intake in multiple eating environments. To our knowledge, this is the first study to classify eating occasions in multiple eating environments and may be a useful tool for future behavioral research studies to accurately codify eating environments.

Impact assessment of a raw coal ban on maternal and child health outcomes in Ulaanbaatar: a protocol for an interrupted time series study.

INTRODUCTION: Despite a decade of policy actions, Ulaanbaatar's residents continue to be exposed to extreme levels of air pollution, a major public health concern, especially for vulnerable populations such as pregnant women and children. In May 2019, the Mongolian government implemented a raw coal ban (RCB), prohibiting distribution and use of raw coal in households and small businesses in Ulaanbaatar. Here, we present the protocol for an interrupted time series (ITS; a strong quasi-experimental study design for public health interventions) that aims to assess the effectiveness of this coal ban policy on environmental (air quality) and health (maternal and child) outcomes. METHODS AND ANALYSIS: Routinely collected data on pregnancy and child respiratory health outcomes between 2016 and 2022 in Ulaanbaatar will be collected retrospectively from the four main hospitals providing maternal and/or paediatric care as well as the National Statistics Office. Hospital admissions data for childhood diarrhoea, an unrelated outcome to air pollution exposure, will be collected to control for unknown or unmeasured coinciding events. Retrospective air pollution data will be collected from the district weather stations and the US Embassy. An ITS analysis will be conducted to determine the RCB intervention impact on these outcomes. Prior to the ITS, we have proposed an impact model based on a framework of five key factors, which were identified through literature search and qualitative research to potentially influence the intervention impact assessment. ETHICS AND DISSEMINATION: Ethical approval has been obtained via the Ministry of Health, Mongolia (No.445) and University of Birmingham (ERN_21-1403). To inform relevant stakeholders of our findings, key results will be disseminated on both (inter)national and population levels through publications, scientific conferences and community briefings. These findings are aimed to provide evidence for decision-making in coal pollution mitigation strategies in Mongolia and similar settings throughout the world.

Audience immersion: validating attentional and physiological measures against self-report.

When an audience member becomes immersed, their attention shifts towards the media and story, and they allocate cognitive resources to represent events and characters. Here, we investigate whether it is possible to measure immersion using continuous behavioural and physiological measures. Using television and film clips, we validated dual-task reaction times, heart rate, and skin conductance against self-reported narrative engagement. We find that reaction times to a secondary task were strongly positively correlated with self-reported immersion: slower reaction times were indicative of greater immersion, particularly emotional engagement. Synchrony in heart rate across participants was associated with self-reported attentional and emotional engagement with the story, although we found no such relationship with skin conductance. These results establish both dual-task reaction times and heart rate as candidate measures for the real-time, continuous, assessment of audience immersion.

Persistence of social isolation and mortality: 10-year follow-up of the Guangzhou Biobank Cohort study.

Although social isolation has been associated with higher mortality risk, the associations of persistence of social isolation with mortality are unclear. We investigated the prospective associations of intermittent and persistent social isolation with all-cause and cause-specific mortality, considering the social contact types (face-to-face and non-face-to-face). 30,518 participants were recruited in 2003-2008 initially and 18,104 participants with re-assessed social isolation information in 2008-2012 were followed up to Dec 2019 in Guangzhou Biobank Cohort Study (GBCS). During an average of 9.7 years of follow-up, 2,119 deaths occurred. The isolation at baseline survey, isolation at second survey and persistent isolation were positively associated with all-cause mortality in the minimal adjusted model (adjusted hazard ratio (AHR) =1.24, 95% CI 1.12-1.38, 1.11, 1.00-1.23 and 1.23, 1.05-1.43, respectively). Totally 47.2% of the risk was explained by health status, SEP, and biological, behavioural and psychological factors. Persistent isolation from face-to-face with co-inhabitants, versus no isolation, was associated with higher risks of all-cause (HR=1.40, 1.09-1.81) and CVD (subdistribution hazard ratio (SHR)=1.92, 1.31-2.81) mortality in fully adjusted model. Our study showed that intermittent and persistent isolation were generally associated with higher risks of mortality, and the risks were even higher in those with persistent face-to-face isolation with co-inhabitants.

Prevalence of atrial fibrillation in Northern Sri Lanka: a study protocol for a cross-sectional household survey.

INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia globally. It is associated with a fivefold risk in stroke, but early diagnosis and effective treatment can reduce this risk. AF is often underdiagnosed, particularly in low-income and middle-income countries (LMICs) where screening for AF is not always feasible or considered common practice in primary care settings. Epidemiological data on AF in LMICs is often incomplete particularly in vulnerable populations. This LMIC research collaborative aims to identify the prevalence of AF in the Northern Sri Lankan community. METHODS AND ANALYSIS: A cross-sectional household survey piloted and codesigned through a series of community engagement events will be administered in all five districts in Northern Province, Sri Lanka. A multistage cluster sampling approach will be used starting at district level, then the Divisional Secretariats followed by Grama Niladhari divisions. Twenty households will be selected from each cluster. The study aims to recruit 10 000 participants aged 50 years or older, 1 participant per household. Demographic and socioeconomic characteristics, well-being and lifestyle and anthropometric measurements will be collected using a digital data platform (REDCap, Research Electronic Data Capture) by trained data collectors. Participants will be screened for AF using a fingertip single-lead ECG via a smartphone application (AliveCor) with rhythm strips reviewed by a consultant cardiologist. Prevalence of AF and risk factors will be established at province and district-levels. Adjusted ORs and population attributable fractions for AF risk factors will be determined. ETHICS AND DISSEMINATION: This study was approved by the Ethics Review Committee of Faculty of Medicine at University of Jaffna. Written informed consent will be obtained from all participants. Findings will be disseminated through publication in a peer-reviewed journal and presentations at conferences. The findings will enable early treatment for new AF diagnoses and inform interventions to improve community-based management of AF in LMICs.

Association of Hand Grip Strength with Mild Cognitive Impairment in Middle-Aged and Older People in Guangzhou Biobank Cohort Study.

Background: Lower hand grip strength has been linked to cognitive impairment, but studies in older Chinese are limited. We examined the association of hand grip strength with cognitive function in a large sample of older Chinese. Methods: 6806 participants aged 50+ years from the Guangzhou Biobank Cohort Study (GBCS) were included. Relative grip strength was calculated by absolute handgrip strength divided by the body mass index (BMI). Cognitive function was assessed using the Delayed Word Recall Test (DWRT, from 0 to 10) and the Mini Mental State Examination (MMSE, from 0 to 30), with higher scores indicating better cognition. Results: After adjusting for multiple potential confounders, lower absolute grip strength and relative grip strength were significantly associated with lower DWRT (all p < 0.05) in all participants. No significant interaction effects between sex and handgrip strength on cognitive impairment were found (p from 0.27 to 0.87). No significant association between handgrip strength and total MMSE scores was found in the total sample or by sex (p from 0.06 to 0.50). Regarding the individual components of MMSE, lower absolute and relative grip strength were significantly associated with lower scores of the recall memory performance in all participants (p from 0.003 to 0.04). Conclusion: We have shown for the first time a positive association of grip strength with recall memory performance, but not general cognitive function in older people, which warrants further investigation.

Emulation of epidemics via Bluetooth-based virtual safe virus spread: experimental setup, software, and data

We describe an experimental setup and a currently running experiment for evaluating how physical interactions over time and between individuals affect the spread of epidemics. Our experiment involves the voluntary use of the Safe Blues Android app by participants at The University of Auckland (UoA) City Campus in New Zealand. The app spreads multiple virtual safe virus strands via Bluetooth depending on the social and physical proximity of the subjects. The evolution of the virtual epidemics is recorded as they spread through the population. The data is presented as a real-time (and historical) dashboard. A simulation model is applied to calibrate strand parameters. Participants locations are not recorded, but participants are rewarded based on the duration of participation within a geofenced area, and aggregate participation numbers serve as part of the data. Once the experiment is complete, the data will be made available as an open-source anonymized dataset. This paper outlines the experimental setup, software, subject-recruitment practices, ethical considerations, and dataset description. The paper also highlights current experimental results in view of the lockdown that started in New Zealand at 23:59 on August 17, 2021. The experiment was initially planned in the New Zealand environment, expected to be free of COVID and lockdowns after 2020. However, a COVID Delta strain lockdown shuffled the cards and the experiment is currently extended into 2022. Author summaryIn this paper, we describe the Safe Blues Android app experimental setup and a currently running experiment at the University of Auckland City Campus. This experiment is designed to evaluate how physical interactions over time and between individuals affect the spread of epidemics. The Safe Blues app spreads multiple virtual safe virus strands via Bluetooth based on the subjects unobserved social and physical proximity. The app does not record the participants locations, but participants are rewarded based on the duration of participation within a geofenced area, and aggregate participation numbers serve as part of the data. When the experiment is finished, the data will be released as an open-source anonymized dataset. The experimental setup, software, subject recruitment practices, ethical considerations, and dataset description are all described in this paper. In addition, we present our current experimental results in view of the lockdown that started in New Zealand at 23:59 on August 17, 2021. The information we provide here may be useful to other teams planning similar experiments in the future.

Daily associations between alcohol and sweets craving and consumption in early AUD recovery: Results from an ecological momentary assessment study.

INTRODUCTION: Alcohol cravings can predict relapse in persons with alcohol use disorder (AUD). Consuming sweets is a commonly recommend strategy to quell alcohol cravings in early recovery from AUD, yet research is equivocal on whether consuming sweets mitigates alcohol cravings or relapse risk. The current study used ecological momentary assessment (EMA) data to examine real-time alcohol cravings, sweet cravings, and consumption of sweets among adults in early recovery from AUD. METHODS: We used EMA methods to follow 25 adults (n = 14 women, 56%; M. age 40, S.D. 10.68) recently discharged from a partial hospitalization program for AUD for 21 days. Prompts were sent to the participants for completion four times per day via a mobile app. EMA data were disaggregated prior to analysis to examine between- and within-person effects. A series of three mixed linear models tested: 1) the contemporaneous effect of sweet and alcohol cravings, 2) alcohol cravings predicting sweet consumption later in the day, and 3) sweet consumption predicting alcohol craving later in the day. RESULTS: The results of the first model revealed alcohol cravings were associated with sweet cravings early in recovery. In the second model, no effect occurred between alcohol cravings earlier in the day predicting sweet consumption later in the day. The third model suggested consuming sweets earlier in the day predicted higher alcohol cravings later in the day. DISCUSSION: Sweet craving and consumption are associated with alcohol cravings among adults in early recovery from AUD. These findings suggest consuming sweets may increase alcohol cravings. If future studies can replicate this result, consuming sweets in early recovery may emerge as a potential risk for relapse in this population.

Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade.

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types of cancer over the past decade. The initial therapeutic hypothesis underlying the mechanism of anti-PD-1/PD-L1 ICB was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1hiCD8+ T cells by "releasing the brakes." However, recent studies have provided unprecedented insight into the complexity within the CD8+ T-cell pool in the tumor microenvironment (TME). Single-cell RNA sequencing and epigenetic profiling studies have identified novel cell surface markers, revealing heterogeneity within CD8+ T-cell states classified as unique. Moreover, these studies highlighted that following ICB, CD8+ T-cell states within and outside the TME possess a differential capacity to respond, mobilize to the TME, and seed an effective antitumor immune response. In aggregate, these recent developments have led to a reevaluation of our understanding of both the underlying mechanisms and the sites of action of ICB therapy. Here, we discuss the evidence for the reversibility of CD8+ T-cell exhaustion after ICB treatment and its implication for the further development of cancer immunotherapy.

Combinatorial immunotherapy induces tumor-infiltrating CD8+ T cells with distinct functional, migratory, and stem-like properties.

BACKGROUND: Programmed death (ligand) 1 (PD-(L)1) blockade and OX40/4-1BB costimulation have been separately evaluated in the clinic to elicit potent antitumor T cell responses. The precise mechanisms underlying single agent activity are incompletely understood. It also remains unclear if combining individual therapies leads to synergism, elicits novel immune mechanisms, or invokes additive effects. METHODS: We performed high-dimensional flow cytometry and single-cell RNA sequencing-based immunoprofiling of murine tumor-infiltrating lymphocytes (TILs) isolated from hosts bearing B16 or MC38 syngeneic tumors. This baseline infiltrate was compared to TILs after treatment with either anti-PD-(L)1, anti-OX40, or anti-4-1BB as single agents or as double and triple combinatorial therapies. Fingolimod treatment and CXCR3 blockade were used to evaluate the contribution of intratumoral versus peripheral CD8+ T cells to therapeutic efficacy. RESULTS: We identified CD8+ T cell subtypes with distinct functional and migratory signatures highly predictive of tumor rejection upon treatment with single agent versus combination therapies. Rather than reinvigorating terminally exhausted CD8+ T cells, OX40/4-1BB agonism expanded a stem-like PD-1loKLRG-1+Ki-67+CD8+ T cell subpopulation, which PD-(L)1 blockade alone did not. However, PD-(L)1 blockade synergized with OX40/4-1BB costimulation by dramatically enhancing stem-like TIL presence via a CXCR3-dependent mechanism. CONCLUSIONS: Our findings provide new mechanistic insights into the interplay between components of combinatorial immunotherapy, where agonism of select costimulatory pathways seeds a pool of stem-like CD8+ T cells more responsive to immune checkpoint blockade (ICB).

EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells.

Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.

CD8+ T Cell Exhaustion in Cancer.

A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.

Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment.

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.

Genetic variability of Edwardsiella piscicida isolates from Mississippi catfish aquaculture with an assessment of virulence in channel and channel × blue hybrid catfish.

The bacterium Edwardsiella piscicida causes significant losses in global aquaculture, particularly channel (Ictalurus punctatus) × blue (I. furcatus) hybrid catfish cultured in the south-eastern United States. Emergence of E. piscicida in hybrid catfish is worrisome given current industry trends towards increased hybrid production. The project objectives were to assess intraspecific genetic variability of E. piscicida isolates recovered from diseased channel and hybrid catfish in Mississippi; and determine virulence associations among genetic variants. Repetitive extragenic palindromic sequence-based PCR (rep-PCR) using ERIC I and II primers was used to screen 158 E. piscicida diagnostic case isolates. A subsample of 39 E. piscicida isolates, representing predominant rep-PCR profiles, was further characterized using BOX and (GTG)5 rep-PCR primers, virulence gene assessment and multilocus sequence analysis (MLSA) targeting housekeeping genes gyrb, pgi and phoU. The MLSA provided greater resolution than rep-PCR, revealing 5 discrete phylogroups that correlated similarly with virulence gene profiles. Virulence assessments using E. piscicida representatives from each MLSA group resulted in 14-day cumulative mortality ranging from 22% to 54% and 63 to 72% in channel and hybrid fingerlings, respectively. Across all phylogroups, mortality was higher in hybrid catfish (p < .05), supporting previous work indicating E. piscicida is an emerging threat to hybrid catfish aquaculture in the south-eastern United States.

Investigating Cooking Activity Patterns and Perceptions of Air Quality Interventions among Women in Urban Rwanda.

Household air pollution (HAP) from biomass cooking with traditional stoves is a major cause of morbidity and mortality in low-and-middle-income countries (LMICs) worldwide. Air quality interventions such as improved cookstoves (ICS) may mitigate HAP-related impacts; however, poor understanding of contextual socio-cultural factors such as local cooking practices have limited their widespread adoption. Policymakers and stakeholders require an understanding of local cooking practices to inform effective HAP interventions which meet end-user needs. A semi-structured questionnaire was administered to 36 women residing in biomass-cooking fuel households in Kigali, Rwanda to identify cooking activity patterns, awareness of HAP-related health risks and ICS intervention preferences. Overall, 94% of respondents exclusively used charcoal cooking fuel and 53% cooked one meal each day (range = 1-3 meals). Women were significantly more likely to cook outdoors compared to indoors (64% vs. 36%; p < 0.05). Over half of respondents (53%) were unaware of HAP-related health risks and 64% had no prior awareness of ICS. Participants expressed preferences for stove mobility (89%) and facility for multiple pans (53%) within an ICS intervention. Our findings highlight the need for HAP interventions to be flexible to suit a range of cooking patterns and preferred features for end-users in this context.

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer.

Tumor-associated macrophages (TAMs) are among the main contributors to immune suppression in the tumor microenvironment, however, TAM depletion strategies have yielded little clinical benefit. Here, we discuss the concept that TAMs are also key regulators of anti-PD(L)-1-mediated CD8 T cell-dependent immunity. Emerging data suggest that expression of the chemokine CXCL9 by TAMs regulates the recruitment and positioning of CXCR3-expressing stem-like CD8 T (Tstem) cells that underlie clinical responses to anti-PD(L)-1 treatment. We evaluate clinical and mechanistic studies that establish relationships between CXCL9-expressing TAMs, Tstem and antitumor immunity. Therapies that enhance anti-PD(L)-1 response rates must consider TAM CXCL9 expression. In this perspective, we discuss opportunities to enhance the frequency and function of CXCL9 expressing TAMs and draw on comparative analyzes from infectious disease models to highlight potential functions of these cells beyond Tstem recruitment.

Heart rate variability in patients with atrial fibrillation and hypertension.

BACKGROUND: Atrial fibrillation (AF) and hypertension are independently associated with impaired autonomic function determined using heart rate variability (HRV). As these conditions frequently co-exist, we sought to determine whether AF would worsen HRV in hypertensive patients. DESIGN: We studied HRV in AF (and hypertension) (n = 61) and hypertension control group (n = 33). The AF (and hypertension) group was subdivided into permanent AF (n = 30) and paroxysmal AF (n = 31) and re-studied. Time-domain, frequency-domain and nonlinear measures of HRV were determined. Permanent AF group (n = 30) was followed up after 8 weeks following optimisation of their heart rate and blood pressure (BP). RESULTS: Time-domain and nonlinear indices of HRV were higher in AF (and hypertension) group compared to hypertensive controls (P ≤ .01). Time-domain and nonlinear indices of HRV were higher in permanent AF group compared to paroxysmal AF (P ≤ .001). Permanent AF was an independent predictor of HRV on multivariable analysis (P = .006). Optimisation of heart rate and BP had no significant impact on HRV in permanent AF. CONCLUSIONS: AF, independent of hypertension, is characterised with marked HRV and is possibly related to vagal tone. HRV is higher in permanent AF compared to paroxysmal AF suggesting evident autonomic influence in the pathophysiology of permanent AF. Modulation of autonomic influence on cardiovascular system should be explored in future studies.

EZH2 as a Regulator of CD8+ T Cell Fate and Function.

Enhancer of zeste 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that mediates di- and trimethylation of histone 3 lysine 27 effectively precluding successful gene transcription at these loci. This class of epigenetic modifications facilitates the maintenance of tissue-specific cellular transcriptional programs as cells undergoing successive rounds of proliferation. CD8+ T cells are effective mediators of adaptive immunity and function to eliminate virus- and bacteria-infected cells as well as tumor cells. Upon recognition of cognate antigen, T cells undergo activation/proliferation to clear the target cells. The heterogeneous population of responding T cells formed during these proliferative events thus rely on epigenetic modifications to ensure identity and confer functional capabilities. In this review, we will focus on the role of the dynamic expression EZH2 in shaping the epigenetic landscape of CD8+ T cell fate and function, with a particular emphasis on infection and cancer. We also explore competing hypotheses pertaining to EZH2 function and the prospects of clinical EZH2 inhibitors in fine-tuning T cell responses.