Search

Background:Cooking and heating in households contribute importantly to air pollution exposure worldwide. However, there is insufficient investigation of measured fine particulate matter (PM2.5) exposure levels, variability, seasonality, and inter-spatial dynamics associated with these behaviours.Methods:We undertook parallel measurements of personal, household (kitchen and living room), and community PM2.5in summer (May-September 2017) and winter (November 2017-Janauary 2018) in ∼480 participants from one urban and two rural communities in China. These recorded ∼61,000-81,000 person-hours of processed data per microenvironment. Age- and sex-adjusted geometric means of PM2.5were calculated by key participant characteristics, overall and by season. Spearman correlation coefficients between PM2.5levels across different microenvironments were computed.Findings:Overall, 25.1% reported use of solid fuel for both cooking and heating. Solid fuel users had ∼90% higher personal and kitchen 24-hour average PM2.5exposure than clean fuel users. Similarly, they also had a greater increase (∼75% vs ∼20%) in personal and household PM2.5from summer to winter, whereas community levels of PM2.5were 2-3 times higher in winter regardless of fuel use. Compared with clean fuel users, solid fuel users had markedly higher weighted annual average PM2.5exposure at personal (77.8 [95% CI 71.1-85.2] vs ∼40 µg/m3), kitchen (103.7 [91.5-117.6] vs ∼50 µg/m3) and living room (62.0 [57.1-67.4] vs ∼40 µg/m3) microenvironments. There was a remarkable diurnal variability in PM2.5exposure among the participants, with 5-minute moving average 700-1,200µg/m3in typical meal times. Personal PM2.5was moderately correlated with living room (Spearman r: 0.64-0.66) and kitchen (0.52-0.59) levels, but only weakly correlated with community levels, especially in summer (0.15-0.34) and among solid fuel users (0.11-0.31).Conclusion:Solid fuel use for cooking and heating was associated with substantially higher personal and household PM2.5exposure than clean fuel users. Household PM2.5appeared a better proxy of personal exposure than community PM2.5in this setting.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens.Significance:Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521

Supplementary Table from An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth

Supplementary Figure from An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth

Background Existing evidence on long-term ambient air pollution (AAP) exposure and risk of cardio-respiratory diseases in China is mainly on mortality, and based on area average concentrations from fixed-site monitors for individual exposures. Substantial uncertainty persists, therefore, about the shape and strength of the relationship when assessed using more personalised individual exposure data. We aimed to examine the relationships between AAP exposure and risk of cardio-respiratory diseases using predicted local levels of AAP. Methods A prospective study included 50,407 participants aged 30–79 years from Suzhou, China, with concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), fine (PM2.5), and inhalable (PM10) particulate matter, ozone (O3) and carbon monoxide (CO) and incident cases of cardiovascular disease (CVD) (n = 2,563) and respiratory disease (n = 1,764) recorded during 2013–2015. Cox regression models with time-dependent covariates were used to estimate adjusted hazard ratios (HRs) for diseases associated with local-level concentrations of AAP exposure, estimated using Bayesian spatio–temporal modelling. Results The study period of 2013–2015 included a total of 135,199 person-years of follow-up for CVD. There was a positive association of AAP, particularly SO2 and O3, with risk of major cardiovascular and respiratory diseases. Each 10 µg/m3 increase in SO2 was associated with adjusted hazard ratios (HRs) of 1.07 (95% CI: 1.02, 1.12) for CVD, 1.25 (1.08, 1.44) for COPD and 1.12 (1.02, 1.23) for pneumonia. Similarly, each 10 µg/m3 increase in O3 was associated with adjusted HR of 1.02 (1.01, 1.03) for CVD, 1.03 (1.02, 1.05) for all stroke, and 1.04 (1.02, 1.06) for pneumonia. Conclusions Among adults in urban China, long-term exposure to ambient air pollution is associated with a higher risk of cardio-respiratory disease.

Indoor air purifiers are increasingly marketed for their health benefits, but their cardiovascular effects remain unclear. We systematically reviewed and meta-analysed randomized controlled trials (RCTs) on the cardiovascular effects of indoor air purification interventions in humans of all ages. We searched Embase, Medline, PubMed, and Web of Science from inception to 22 August 2020. Fourteen cross-over RCTs (18 publications) were included. Systolic blood pressure (SBP) was significantly reduced after intervention (-2.28 [95% CI: -3.92, -0.64] mmHg). There were tendencies of reductions in diastolic blood pressure (-0.35 [-1.52, 0.83] mmHg), pulse pressure (PP) (-0.86 [-2.07, 0.34] mmHg), C-reactive protein (-0.23 [-0.63, 0.18] mg/L), and improvement in reactive hyperaemia index (RHI) (0.10 [-0.04, 0.24]) after indoor air purification, although the effects were not statistically significant. However, when restricting the analyses to RCTs using physical-type purifiers only, significant improvements in PP (-1.56 [-2.98, -0.15] mmHg) and RHI (0.13 [0.01, 0.25]) were observed. This study found potential evidence on the short-term cardiovascular benefits of using indoor air purifiers, especially for SBP, PP and RHI. However, under the Grading of Recommendations Assessment, Development and Evaluation framework, the overall certainty of evidence was very low, which discourage unsubstantiated claims on the cardiovascular benefits of air purifiers. We have also identified several key methodological limitations, including small sample size, short duration of intervention, and the lack of wash-out period. Further RCTs with larger sample size and longer follow-up duration are needed to clarify the cardiovascular benefits of air purification interventions.

This study aimed to examine the association of incense burning alone, a source of indoor air pollution, and jointly with passive smoking, with prenatal depressive symptoms. Information on incense exposure and depressive symptoms were collected at both early and late pregnancy using questionnaires in the Born in Guangzhou Cohort Study. Mixed-effects logistic regression models were used to assess the associations of incense exposure separately, and together with passive smoking, with prenatal depressive symptoms. Compared to the non-users, pregnant women with household incense burning had higher odds of depressive symptoms (odds ratio (OR), 1.17, 95% CI, 1.06, 1.28). Compared with non-users, women who occasionally (OR, 1.22, 95% CI, 1.09, 1.36) and frequently (1.51, 95% CI, 1.26, 1.80) smelled incense had higher odds of prenatal depressive symptoms. Higher duration of incense smelling was associated with higher odds of prenatal depressive symptoms compared with non-users. There was no strong evidence for an interaction of frequency of incense smelling and passive smoking in prenatal depressive symptoms. Prenatal exposure to incense burning was associated with higher odds of having depressive symptoms during pregnancy, and there is no evidence for interaction with concurrent exposure to passive smoking.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. Significance: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521

Electrically addressing spin systems is predicted to be a key component in developing scalable semiconductor-based quantum processing architectures, to enable fast spin qubit manipulation and long-distance entanglement via microwave photons. However, single spins have no electric dipole, and therefore a spin-orbit mechanism must be integrated in the qubit design. Here, we propose to couple microwave photons to atomically precise donor spin qubit devices in silicon using the hyperfine interaction intrinsic to donor systems and an electrically-induced spin-orbit coupling. We characterise a one-electron system bound to a tunnel-coupled donor pair (1P-1P) using the tight-binding method, and then estimate the spin-photon coupling achievable under realistic assumptions. We address the recent experiments on double quantum dots (DQDs) in silicon and indicate the differences between DQD and 1P-1P systems. Our analysis shows that it is possible to achieve strong spin-photon coupling in 1P-1P systems in realistic device conditions without the need for an external magnetic field gradient.

Background Tobacco smoking is estimated to account for more than 1 million annual deaths in China, and the epidemic continues to increase in men. Large nationwide prospective studies linked to different health records can help to periodically assess disease burden attributed to smoking. We aimed to examine associations of smoking with incidence of and mortality from an extensive range of diseases in China. Methods We analysed data from the prospective China Kadoorie Biobank, which recruited 512 726 adults aged 30–79 years, of whom 210 201 were men and 302 525 were women. Participants who had no major disabilities were identified through local residential records in 100–150 administrative units, which were randomly selected by use of multistage cluster sampling, from each of the ten diverse study areas of China. They were invited and recruited between June 25, 2004, and July 15, 2008. Upon study entry, trained health workers administered a questionnaire assessing detailed smoking behaviours and other key characteristics (eg, sociodemographics, lifestyle, and medical history). Participants were followed up via electronic record linkages to death and disease registries and health insurance databases, from baseline to Jan 1, 2018. During a median 11-year follow-up (IQR 10–12), 285 542 (55·7%) participants were ever hospitalised, 48 869 (9·5%) died, and 5252 (1·0%) were lost to follow-up during the age-at-risk of 35–84 years. Cox regression yielded hazard ratios (HRs) associating smoking with disease incidence and mortality, adjusting for multiple testing. Findings At baseline, 74·3% of men and 3·2% of women (overall 32·4%) ever smoked regularly. During follow-up, 1 137 603 International Classification of Diseases, 10th revision (ICD-10)-coded incident events occurred, involving 476 distinct conditions and 85 causes of death, each with at least 100 cases. Compared with never-regular smokers, ever-regular smokers had significantly higher risks for nine of 18 ICD-10 chapters examined at age-at-risk of 35–84 years. For individual conditions, smokers had significantly higher risks of 56 diseases (50 for men and 24 for women) and 22 causes of death (17 for men and nine for women). Among men, ever-regular smokers had an HR of 1·09 (95% CI 1·08–1·11) for any disease incidence when compared with never-regular smokers, and significantly more episodes and longer duration of hospitalisation, particularly those due to cancer and respiratory diseases. For overall mortality, the HRs were greater in men from urban areas than in men from rural areas (1·50 [1·42–1·58] vs 1·25 [1·20–1·30]). Among men from urban areas who began smoking at younger than 18 years, the HRs were 2·06 (1·89–2·24) for overall mortality and 1·32 (1·27–1·37) for any disease incidence. In this population, 19·6% of male (24·3% of men residing in urban settings and 16·2% of men residing in rural settings) and 2·8% of female deaths were attributed to ever-regular smoking. Interpretation Among Chinese adults, smoking was associated with higher risks of morbidity and mortality from a wide range of diseases. Among men, the future smoking-attributed disease burden will increase further, highlighting a pressing need for reducing consumption through widespread cessation and uptake prevention. Funding British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.

Mounting evidence suggests that the first few months of life are critical for the development of obesity. The relationships between the timing of solid food introduction and the risk of childhood obesity have been examined previously; however, evidence for the association of timing of infant formula introduction remains scarce. This study aimed to examine whether the timing of infant formula introduction is associated with growth z-scores and overweight at ages 1 and 3 years. This study included 5733 full-term (≥ 37 gestational weeks) and normal birth weight (≥ 2500 and < 4000 g) children in the Born in Guangzhou Cohort Study, a prospective cohort study with data collected at 6 weeks, 6, 12 and 36 months. Compared with infant formula introduction at 0–3 months, introduction at 4–6 months was associated with the lower BMI, weight-for-age and weight-for-length z-scores at 1 and 3 years old. Also, introduction at 4–6 months was associated with the lower odds of at-risk of overweight at age 1 (adjusted OR 0·72, 95 % CI 0·55, 0·94) and 3 years (adjusted OR 0·50, 95 % CI 0·30, 0·85). Introduction at 4–6 months also decreased the odds of overweight at age 1 year (adjusted OR 0·42, 95 % CI 0·21, 0·84) but not at age 3 years. Based on our findings, compared with introduction within the first 3 months, introduction at 4–6 months has a reduction on later high BMI risk and at-risk of overweight. However, these results need to be replicated in other well-designed studies before more firm recommendations can be made.

A systematic review and a meta-analysis were conducted to examine the overall prevalence of psychological health outcomes during COVID-19. Seven databases were systematically searched to include studies reporting on at least one psychological outcome. The pooled prevalence of primary psychological outcomes was 26% (95%CI: 21–32). Pooled prevalence for symptoms of PTSD was 33% (0–86), anxiety 28% (21–36), stress 27% (14–43), and depression 22% (13–33). The prevalence of psychological outcomes was similar in healthcare workers and in the general population (34% [24–44] and 33% [27–40] respectively). High prevalence figures support the importance of ensuring adequate provision of resources for mental health.

The majority of sleep research has focused on deleterious health outcomes, with little attention to positive sequels. A systematic review of the literature regarding sleep duration and/or sleep quality in relation to mental toughness and resilience amongst non-clinical, healthy populations was completed. Eight databases and selected sources for grey literature were searched from their inception to April 2021. A total of 1925 unique records (1898 from the database search and 27 from grey sources) were identified and screened against the pre-set inclusion and exclusion criteria. Of these, 68 studies were eligible and 63 were included in the meta-analysis. Pooled results indicated a weak, positive correlation between sleep duration and resilience (r = 0.11, p 0.001), and sleep quality (r = 0.27, p 0.001). The pooled correlation was slightly attenuated for prospective studies pertaining to sleep quality and resilience (r = 0.18, p 0.001). We found evidence of high publication bias for studies that explored the relationship between sleep quality and resilience. Sleep and resilience are positively correlated but additional research is needed to verify the direct relationship through carefully designed, prospective studies that capture both subjective and objective sleep estimates. For a more comprehensive understanding, complementary reviews that explore the sleep-resilience association are needed for clinical populations, and those who have suffered extreme hardship.

Genocea’s ATLAS platform is an empirical bioassay that uses patient autologous immune cells to identify both true neoantigens and Inhibigens࣪ for inclusion in or exclusion from neoantigen-targeted vaccines and cell therapies, respectively. In ATLAS, patient-derived antigen-presenting cells (APCs) are pulsed with E. coli expressing individual mutations identified from the patient mutanome ± listeriolysin O, enabling interrogation of both CD8+ and CD4+ T cell recognition. True neoantigens induce T cell activation and cytokine release, while Inhibigens lead to a downregulation of T cell responses and thus can promote tumor growth. Previous ATLAS screening of CD8+ T cells from mice carrying B16F10 mouse melanoma tumors identified both neoantigens and Inhibigens. Upon therapeutic vaccination, adjuvanted neoantigens generated immunogenicity and anti-tumor efficacy1. In contrast, therapeutic vaccination with multiple ATLAS-identified Inhibigens, alone or in combination with an otherwise-protective vaccine, led to accelerated tumor growth, impaired T cell responses, and abrogated tumor immune infiltration. Our current study further explores the mechanism of Inhibigen-specific responses through adoptive transfer of vaccine-experienced T cells into tumor-bearing recipient mice, as well as through analysis of T cell gene expression. Additionally, in order to determine whether Inhibigen identification and treatment translates into pro-tumor effects universally across tumor models, we performed ATLAS screening on CD4+ and CD8+ T cells isolated from mice bearing orthotopic KPC pancreatic cancer. Out of 73 total non-synonymous mutations, we successfully identified 14 CD4+ and 15 CD8+ true neoantigens, and 16 CD4+ and 18 CD8+ Inhibigens. This is the first known comprehensive characterization of endogenous antigens in this model. Therapeutic administration of neoantigens as adjuvanted peptide vaccines in KPC tumor-bearing mice led to smaller tumor sizes and reduced ascites volumes, whereas Inhibigen vaccination accelerated tumor growth. Mouse studies are ongoing and additional data will be presented. Taken together, our data from human cancer patients and two mouse cancer models support the importance of appropriate neoantigen selection and Inhibigen identification and exclusion from cancer therapies. Genocea’s GEN-011 neoantigen-targeted peripheral T cell (NPT) therapy candidate, designed using ATLAS-identified neoantigens and omitting Inhibigens, is being evaluated in an ongoing clinical trial (NCT04596033). Continued exploration of mechanisms of action of Inhibigen-specific responses may reveal new paradigms of cancer immune evasion. 1H Lam et al, Cancer Discov 2021;11:1-18 Citation Format: Hanna S. Starobinets, Victoria L. DeVault, Zoe C. Schmiechen, Ebony A. Miller, Eduardo Cruz, Meagan R. Rollins, Adam L. Burrack, Stephanie J. Rinaldi, Julie Arnold, Emily Tjon, Kyle Gonzalez, Dimitry Lineker, Hubert Lam, Ingunn M. Stromnes, Jessica B. Flechtner. ATLAS-identified Inhibigen-specific responses accelerate tumor growth in mouse melanoma and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2088.

Background: The novel coronavirus (COVID-19) has had a detrimental impact on individuals' psychological well-being; however, a multi-country comparison on the prevalence of suicidal ideation due to the virus is still lacking.Objectives: To examine the prevalence and correlates of suicidal ideation among the general population across 10 countries during the COVID-19 pandemic.Materials and methods: This was a cross-sectional study which used convenience sampling and collected data by conducting an online survey. Participants were sourced from 10 Eastern and Western countries. The Patient Health Questionnaire (PHQ-9) was used to measure the outcome variable of suicidal ideation. Ordinal regression analysis was used to identify significant predictors associated with suicidal ideation.Results: A total of 25,053 participants (22.7% male) were recruited. Results from the analysis showed that the UK and Brazil had the lowest odds of suicidal ideation compared to Macau (p < 0.05). Furthermore, younger age, male, married, and differences in health beliefs were significantly associated with suicidal ideation (p < 0.05).Conclusions: The findings highlight the need for joint international collaboration to formulate effective suicide prevention strategies in a timely manner and the need to implement online mental health promotion platforms. In doing so, the potential global rising death rates by suicide during the pandemic can be reduced.

Graphical abstract Averaged 24-hour variation of fine particulate matter (PM2.5) concentrations (µg/m3) recorded in the personal, kitchen, living room, and ambient monitors across the three study sites in the warm and cool season., Highlights • We collected detailed fuel use, time-activity, and air pollution data from 477 Chinese adults. • Mix of solid and clean fuels was common for cooking or heating in rural areas. • Real-time PM2.5 data at personal, household, and ambient environments are presented. • PM2.5 levels in rural areas with solid fuel use were 2–3 times higher than in urban areas. • Personal, household and ambient PM2.5 levels were 2–3 times higher in the cool season., Background Previous studies of the health impact of ambient and household air pollution (AAP/HAP) have chiefly relied on self-reported and/or address-based exposure modelling data. We assessed the feasibility of collecting and integrating detailed personal exposure data in different settings and seasons. Methods/design We recruited 477 participants (mean age 58 years, 72% women) from three (two rural [Gansu/Henan] and one urban [Suzhou]) study areas in the China Kadoorie Biobank, based on their previously reported fuel use patterns. A time-resolved monitor (PATS+CO) was used to measure continuously for 120-hour the concentration of fine particulate matter (PM2.5) at personal and household (kitchen and living room) levels in warm (May-September 2017) and cool (November 2017–January 2018) seasons, along with questionnaires on participants’ characteristics (e.g. socio-demographic, and fuel use) and time-activity (48-hour). Parallel local ambient monitoring of particulate matter (PM1, PM2.5 and PM10) and gaseous pollutants (CO, ozone, nitrogen oxides) was conducted using regularly-calibrated devices. The air pollution exposure data were compared by study sites and seasons. Findings Overall 76% reported cooking at least weekly (regular-cooks), and 48% (urban 1%, rural 65%) used solid fuels (wood/coal) for cooking. Winter heating was more common in rural sites than in urban site (74–91% vs 17% daily), and mainly involved solid fuels. Mixed use of clean and solid fuels was common for cooking in rural areas (38%) but not for heating (0%). Overall, the measured mean PM2.5 levels were 2–3 fold higher in the cool than warm season, and in rural (e.g. kitchen: Gansuwarm_season = 142.3 µg/m3; Gansucool_season = 508.1 µg/m3; Henanwarm_season = 77.5 µg/m3; Henancool_season = 222.3 µg/m3) than urban sites (Suzhouwarm_season = 41.6 µg/m3; Suzhoucool_season = 81.6 µg/m3). The levels recorded tended to be the highest in kitchens, followed by personal, living room and outdoor. Time-resolved data show prominent peaks consistently recorded in the kitchen at typical cooking times, and sustained elevated PM2.5 levels (> 100 µg/m3) were observed in rural areas where use of solid fuels for heating was common. Discussion Personal air pollution exposure can be readily assessed using a low-cost time-resolved monitor in different settings, which, in combination with other personal and health outcome data, will enable reliable assessment of the long-term health effects of HAP/AAP exposures in general populations.

Background In recent years, the FDA has approved engineered autologous T cell therapies with remarkable efficacy against hematological cancers. In addition, non-engineered tumor infiltrating lymphocyte (TIL) therapies have shown unprecedented benefit against solid tumors in early clinical trials. Despite their success, TIL products have limitations including the need for specialized surgery to obtain sterile tumor for T cells, low neoantigen breadth, and the potential for T cells that may be pro-tumor, exhausted, or not tumor-specific. These limitations may hinder efficacy and accessibility for certain patients. We have developed an autologous, peripheral blood-derived non-engineered T cell therapy, GEN-011, that embraces the advantages of TIL while improving on their limitations by targeting true tumor-specific neoantigens identified by the ATLASTM bioassay and avoiding potentially pro-tumor InhibigensTM.1 Methods Peripheral blood mononuclear cells and a tumor biopsy are collected from each subject; tumor DNA is sequenced by WES. The ATLAS bioassay is used to individually screen each tumor mutation with the patient‘s own T cells to identify neoantigen targets of pre-existing CD4+ and/or CD8+ T cell responses. The robust clinical scale manufacturing process, PLANETTM, expands the patient‘s peripheral blood T cells on ATLAS-identified stimulatory neoantigens. Results The PLANET process produces GEN-011 drug products (DP) containing billions of antigen-specific, cytolytic T cells. Development and engineering runs using peripheral blood T cells from cancer patients and healthy donors resulted in DPs containing >97% T cells, >90% of which were central and effector memory phenotypes. A median 534-fold increase in antigen-specific T cells was observed in GEN-011 DPs over their starting frequency in peripheral blood with up to 67% of cells upregulating activation markers upon antigen recognition. Additionally, DP T cells secrete up to 50,000 pg/mL of IFN-gamma in response to antigen stimulation. In cancer patient samples, DPs respond to up to 89% of intended neoantigen targets compared to Conclusions GEN-011 is an autologous, neoantigen-specific T cell product, with key advantages over TIL therapy. First, GEN-011 has an unparalleled breadth of neoantigen coverage, targeting up to 30 relevant neoantigens with non-exhausted CD4+ and CD8+ memory T cells to overcome non-tumor specific ‘passenger’ T cells. Second, GEN-011 avoids pro-tumor Inhibigens that may be detrimental to clinical responses. Third, GEN-011 does not require extra surgery or viable tumor for manufacturing. In conclusion, GEN-011 is a first-in-class transformational T cell therapy candidate with characteristics that should improve accessibility and efficacy for patients with solid tumors. Ethics Approval Informed consent was obtained from all individuals providing samples for this study. References DeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol. 2020; 204(1 Supplement):91.15. Fraser H, Pike R, Thirkell S, Arshad A, Jide-Banwo S, Bartley H, Rologi E, Pruchniak M, Patel S, Mootien J, Robertson J, Craig A, Salm M, Newton K, Goodsell L, Chan F, Wilson G, Frenk S, Ali I, Peggs K, Lowdell MW, Del Rosio L, Hayes A, Turajlic S, Islam F, Lawrence D, Jamal-Hanjani M, Forster MD, Samuel E. The development of a personalized autologous clonal neoantigen T cell therapy for the treatment of solid cancer using the VELOS™ manufacturing platform generates highly potent and reactive CD8+ and CD4+ T cells for clinical use [abstract]. Virtual Annual Meeting II of the American Association for Cancer Research; 2020 Jun 22–24. Creelan B, Wang C, Teer J, Toloza E, Mullinax J, Yao J, Koomen J, Kim S, Chiappori A, Saller J, Tanvetyanon T, Landin AM, Fang B, Yu X, Saltos A, Thompson Z, Noyes D, Conejo-Garcia J, Chen T-D, Haura E, Antonia S. Durable complete responses to adoptive cell transfer using tumor infiltrating lymphocytes (TIL) in non-small cell lung cancer (NSCLC): a phase I trial [abstract]. Virtual Annual Meeting II of the American Association for Cancer Research; 2020 Jun 22–24.

Background Personalized cancer immunotherapies can generate potent antitumor responses yet finding the right targets remains challenging. The ATLASTM platform employs ex vivo functional screening of tumor mutations using autologous cells to identify patient-specific neoantigens. Stimulatory neoantigens are identified by upregulation of inflammatory cytokine secretion and can be employed in vaccines or cell therapies. Conversely, ATLAS also identifies inhibitory neoantigens (termed Inhibigens) that lead to cytokine downregulation, and in murine models accelerate tumor growth and abrogate the efficacy of otherwise-protective vaccines. Here we further explore Inhibigen mechanism of action in humans and mice including whether checkpoint inhibition (CPI) can ameliorate Inhibigen-accelerated tumor growth. Methods Human and mouse ATLAS screens were performed as previously described.1 ATLAS-identified stimulatory or Inhibigen peptide vaccines were evaluated in a therapeutic B16F10 melanoma tumor model ± CPI. Immune responses were measured using ELISPOT, flow cytometry, and immunohistochemistry (IHC). Results In the GEN-009 personalized neoantigen vaccine trial (NCT03633110), Inhibigens were observed in 92% of patients (N=39). Of total mutations screened, 16% (1.8 - 47.5%) were classified as Inhibigens, which were found more often in the CD4 + (mean 10.3%; 0.5 - 42%) versus CD8 + T cell subset (mean 6.1%; 1.2–23%). No relationship between Inhibigen-specific responses and tumor type or mutational burden were observed. To study the functional effects of Inhibigen vaccination in vivo, a B16F10 mouse melanoma model was employed. Inclusion of Inhibigens in an otherwise protective vaccine abrogated efficacy and correlated with decreased T cell responses to vaccine antigens as well as a global depression of T cell cytokine secretion. Early experiments suggest that these decreases are not due to MHC competition. In addition, administration of a therapeutic vaccine containing an Inhibigen led to reduced tumor infiltration of CD8 + T cells and myeloid populations. A corresponding increase of classical Tregs in the tumor or periphery was not observed. Surprisingly, preliminary data show combination therapy with anti-CTLA4 partially ameliorated Inhibigen-accelerated tumor growth but anti-PD1 provided no additional benefit. Conclusions The nearly ubiquitous presence of Inhibigens in human cancer patients and the demonstrated pro-tumor effects in mice suggest that ATLAS-identified Inhibigens must be considered and omitted in the design of cancer immunotherapies. Furthermore, in mice, CPI co-administration has a modest (anti-CTLA4) or no (anti-PD1) effect on Inhibigen-accelerated tumor growth suggesting that Inhibigen profiling could guide CPI selection or predict clinical outcome. These data confirm the benefits of the ATLAS platform for neoantigen and Inhibigen identification. Ethics Approval All animal studies were undertaken in conformity with the Cambridge, MA City Ordinance 1086 of the city’s Municipal Code and in accordance with the policies and protocols approved by Genocea’s Institutional Animal Care and Use Committee (IACUC). Reference Nogueira C, Kaufmann JK, Lam H, Flechtner JB. Improving cancer immunotherapies through empirical neoantigen selection. Trends in Cancer 2018 Feb;4(2):97–100

Background Over 3.5 billion individuals worldwide are exposed to household air pollution from solid fuel use. There is limited evidence from cohort studies on associations of solid fuel use with risks of major eye diseases, which cause substantial disease and economic burden globally. Methods and findings The China Kadoorie Biobank recruited 512,715 adults aged 30 to 79 years from 10 areas across China during 2004 to 2008. Cooking frequency and primary fuel types in the 3 most recent residences were assessed by a questionnaire. During median (IQR) 10.1 (9.2 to 11.1) years of follow-up, electronic linkages to national health insurance databases identified 4,877 incident conjunctiva disorders, 13,408 cataracts, 1,583 disorders of sclera, cornea, iris, and ciliary body (DSCIC), and 1,534 cases of glaucoma. Logistic regression yielded odds ratios (ORs) for each disease associated with long-term use of solid fuels (i.e., coal or wood) compared to clean fuels (i.e., gas or electricity) for cooking, with adjustment for age at baseline, birth cohort, sex, study area, education, occupation, alcohol intake, smoking, environmental tobacco smoke, cookstove ventilation, heating fuel exposure, body mass index, prevalent diabetes, self-reported general health, and length of recall period. After excluding participants with missing or unreliable exposure data, 486,532 participants (mean baseline age 52.0 [SD 10.7] years; 59.1% women) were analysed. Overall, 71% of participants cooked regularly throughout the recall period, of whom 48% used solid fuels consistently. Compared with clean fuel users, solid fuel users had adjusted ORs of 1.32 (1.07 to 1.37, p < 0.001) for conjunctiva disorders, 1.17 (1.08 to 1.26, p < 0.001) for cataracts, 1.35 (1.10 to 1.66, p = 0.0046) for DSCIC, and 0.95 (0.76 to 1.18, p = 0.62) for glaucoma. Switching from solid to clean fuels was associated with smaller elevated risks (over long-term clean fuel users) than nonswitching, with adjusted ORs of 1.21 (1.07 to 1.37, p < 0.001), 1.05 (0.98 to 1.12, p = 0.17), and 1.21 (0.97 to 1.50, p = 0.088) for conjunctiva disorders, cataracts, and DSCIC, respectively. The adjusted ORs for the eye diseases were broadly similar in solid fuel users regardless of ventilation status. The main limitations of this study include the lack of baseline eye disease assessment, the use of self-reported cooking frequency and fuel types for exposure assessment, the risk of bias from delayed diagnosis (particularly for cataracts), and potential residual confounding from unmeasured factors (e.g., sunlight exposure). Conclusions Among Chinese adults, long-term solid fuel use for cooking was associated with higher risks of not only conjunctiva disorders but also cataracts and other more severe eye diseases. Switching to clean fuels appeared to mitigate the risks, underscoring the global health importance of promoting universal access to clean fuels., Ka Hung Chan and co-workers study associations between use of solid fuel for cooking and eye disorders in China., Author summary Why was this study done? Household air pollution from solid fuel use has been linked to higher risks of cataracts and a range of acute eye symptoms, but most previous studies used relatively crude exposure assessment methods and cross-sectional or case–control designs and were relatively small. The relationships of long-term solid fuel use with common eye diseases other than cataracts, including conjunctiva disorders, keratitis, and glaucoma, are poorly understood. What did the researchers do and find? We analysed data from 486,532 adults aged 30 to 79 years recruited from 10 areas of China into the China Kadoorie Biobank during 2004 to 2008 to assess the associations of self-reported long-term solid fuel use for cooking with risks of conjunctivitis, cataracts, disorders of sclera, cornea, iris and ciliary body (DSCIC), and glaucoma during approximately 10-year follow-up. Multivariable logistic regression was used to estimate odds ratios comparing long-term clean fuels and solid fuels users, as well as those who had switched from solid to clean fuels prior to the initial baseline survey. Long-term solid fuel use was associated with 32%, 17%, and 35% higher risks of conjunctiva disorders, cataracts, and DSCIC, respectively, but not associated with glaucoma. Individuals who had switched from solid to clean fuels appeared to have smaller risks than those who used solid fuels persistently. What do these findings mean? To our knowledge, this is one of the first cohort studies on the relationships between long-term solid fuel use and risks of multiple common eye diseases. Our findings support a significant association between solid fuel use and cataracts, but the strength of association appeared to be considerably weaker compared to that observed in previous studies; the associations with conjunctiva disorders and DSCIC indicate that solid fuel use may have more extensive harm on eye health, which should be further investigated.

Background The incidence of preterm birth (PTB, Methods In a retrospective population-based study, data were obtained from 2,535,000 singleton live births with 20–43 gestational weeks from 2001 to 2016 and recorded in the Guangzhou Perinatal Health Care and Delivery Surveillance System, in China. The age-period-cohort models were applied to investigate the temporal changes in incidences of PTB, stratified by parity. Results The incidence of preterm birth steadily increased from 5.1% in 2001 to 5.9% in 2016, with larger rise in primiparous mothers (from 5.0 to 5.9%) compared to multiparous mothers (from 5.6 to 5.9%). A J-shaped and a V-shaped relationship were found between maternal age and PTB among primiparous and multiparous mothers, respectively. A linear cohort effect was found among primiparous mothers with the lowest risk of PTB [risk ratio (RR) = 0.81, 95% confidence interval (CI): 0.74 to 0.89] in 1961 and the highest risk (RR = 1.06, 95% CI: 1.00 to 1.13) in 1997 compared to the mothers born in 1981. An inverse U-shaped association between maternal birth cohort and PTB was found in multiparous mothers. There were weak decreasing period effects on the trend of overall PTB among multiparous mothers and on the trend of extremely ( Conclusions Our findings showed the PTB incidences had been increasing in the past 16 years in Guangzhou, China and both maternal age and cohort effects contributed to these trends. Further studies are recommended on the impact of altered maternal age and parity on premature births and corresponding public education and public health policies.

Background Great growth inequalities between urban and rural areas have been reported in China over the past years. By examining urban/rural inequalities in physical growth among children Methods The height, body weight and nutrition status of children under 7 years old were obtained from two successive cross-sectional surveys and one health surveillance system. Student’s t-test, Spearman’s rank-order correlation and polynomial regression were used to assess the difference in physical growth between children in urban and rural areas and the association between socioeconomic index and secular growth changes. Results A height and weight difference was found between urban and rural children aged 0–6 years during the first two decades of our research (1985–2005), which gradually narrowed in both sex groups over time. By the end of 2015, elder boys (age group ≥5 year) and girls (age group ≥4 year) in rural areas were taller than their counterparts in urban areas (p P = 0.03) for boys, and a − 0.05 difference (P = 0.82) for girls. When GDP increased, the gap in boys’ weight-for-age z-score (WAZ from 0.25 to 0.01) and height-for-age z-score (HAZ from 0.55 to 0.03) between urban and rural areas diminished, and disappeared when the GDP per capita (USD) approached 25,000. In either urban or rural areas, the urbanization rate and GDP were positively associated with the prevalence of obesity (all R > 0.90 with P R P Conclusion Growth inequalities gradually decreased with economic development and urbanization, while new challenges such as obesity emerged. To eliminate health problems due to catch-up growth among rural children, comprehensive intervention programs for early child growth should be promoted in rural areas.

The term ‘occupational and environmental health’ includes any act of emission of any substance, likely to be hazardous in nature, which is either not originally present or is present in a higher concentration than normal in the natural atmosphere. Most air pollutants are generated from human activities (e.g. energy, transportation, industry, agriculture), but natural events in the living (e.g. methane emissions in wetlands) and non-living environment (e.g. volcanic eruptions) also contribute to atmospheric air pollution, although their relative importance has declined since the Industrial Revolution and the advent of modern fossil fuel-based economies. Pollutants may be classified as (1) primary (emitted directly into the atmosphere) or secondary (formed in the air through chemical reactions with other pollutants and gases); (2) indoor or outdoor; (3) gaseous or particulate.

Air pollution is a ubiquitous hazard in most parts of the world. Decades of epidemiological research have provided evidence on the long-term health effect of exposure to ambient fine particulate matter and ozone, and household air pollution from domestic solid fuel use for cooking. The Global Burden of Disease Study (GBD) estimated that ambient and household air pollution together accounted for about 4.6 million premature deaths and 147 million disability adjusted life years in 2017, representing the top environmental risk factor and the fifth leading risk factor for poor health globally. This chapter first describes the key concepts and methodology related to disease burden estimation in epidemiology, with a specific focus on the scope of the GBD; then, the existing evidence on the specific health effects of different air pollutants are examined, followed by a note on the limitations of the evidence and future research needs.

The importance of fieldwork in population health research has not diminished in the era of big data. Contemporary prospective biobank studies tend to collect large amounts of exposure and health outcome data from a large number of participants. Although disease outcome data are often obtained through linkages with registries and hospital records, the exposure data are generally collected directly from the participants, through questionnaire surveys (e.g., in-person, telephone, postal, or online), physical measurements, and collection and assays of biological samples (e.g., blood, urine, and saliva) at baseline recruitment and at other time points. There are many legal, logistic, and practical challenges in establishing large biobank studies, many of which are related to the fieldwork. Careful planning and organisation, efficient coordination and management, and effective implementation and monitoring are critical to ensure a successful launch and smooth operation of fieldwork. This chapter delineates key considerations and procedures involved in planning and organising fieldwork in biobank studies. Moreover, it describes certain novel methodological approaches relevant for the smooth operation of assessment centres and acquisition of high quality data. The general approaches described should also be applicable to other population-based studies (e.g., cross-sectional surveys and case–control studies).

Candidate adoptive T cell therapies (ACT), such as tumor infiltrating lymphocyte (TIL) treatments, have resulted in unprecedented and durable efficacy in clinical trials. Despite this, the manufacturing requires viable tumor resection, and TIL expansion conditions have the potential to promote T cell exhaustion. Moreover, a large proportion of patients do not respond to treatment, possibly due to exhaustion or to bystander T cells that are not tumor-specific present in the product candidates. In addition, we have shown that naturally occurring pro-tumor T cell responses to tumor-specific antigens we term Inhibigens™ are generated in nearly every subject with cancer; these T cells may be inadvertently expanded in the non-specific TIL manufacturing process. In animal models, Inhibigen-specific responses drive tumor hyperprogression. To avoid these pro-tumor T cells and improve upon ACT limitations, we are developing GEN-011, a neoantigen-targeted, peripheral T cell (NPT) therapy. GEN-011 is designed to contain primarily tumor-specific T cells with broad specificity and limited exhaustion, starting from easily accessible peripheral blood. Putatively beneficial neoantigen targets and deleterious pro-tumor Inhibigen targets are identified through measurement of cytokines in the assay supernatants of an in vitro ATLAS™ screen, in which each mutation identified in a patient's tumor is screened with the patient's own peripheral CD4+ and CD8+ T cells in a recall (overnight) assay, without algorithm prioritization. Next, the patient's peripheral T cells and monocyte-derived dendritic cells are incorporated into the PLANET™ manufacturing process where they are specifically stimulated with up to 30 ATLAS-verified neoantigens, avoiding Inhibigens, in a scalable, closed system. Development and engineering runs performed at scale show that the NPTs are up to 96% tumor-specific, with responses maintained for up to 89% of the intended neoantigen targets. They are non-exhausted effector and central memory T cells that express both proliferative and tissue homing markers. In addition to being highly polyfunctional, secreting multiple combinations of IFNγ, Granzyme B, TNFα, and MIP1α in response to specific neoantigens, they are also cytolytic in vitro and express memory-progenitor stem-like cell markers. The TITAN™ clinical trial evaluating GEN-011 NPTs is ongoing (NCT04596033). TiTAN is an open-label, multi-center Phase1/2a trial evaluating safety, tolerability, T cell persistence and proliferation, and clinical efficacy. The TiTAN clinical trial is testing two dosing regimens, a repeated lower dose regimen of GEN-011 without lymphodepletion and a single high dose administration of GEN-011 NPTs after lymphodepletion. Both groups will receive interleukin-2 after GEN-011 NPT dosing. By enriching healthy, broadly-specific neoantigen-targeted T cells and avoiding Inhibigens, the GEN-011 NPTs may represent an accessible and promising ACT for treating solid tumors. Citation Format: James Perry, Pranay D. Khare, Mercay Reuter, Daniel B. DeOliveira, Manish Jain, Colleen Winstead, Hubert Lam, Thomas Davis, Ray Stapleton, Jessica B. Flechtner. GEN-011: A neoantigen-targeted peripheral blood-derived T cell therapy that has broad neoantigen specificity and high T cell purity while avoiding pro-tumor T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P005.

Particulate matter (PM) air pollution is one of the major causes of morbidity and mortality in China. In this study, we estimated the short-term effects of PM on cause-specific hospitalization in Yichang, China. Daily data for PM level, meteorological factors, and hospital admissions (total hospitalization counts = 391,960) in Yichang between 2015 and 2017 were collected. We conducted a time-series study and applied a generalized additive model to evaluate the association between every 10 μg/m3 increment of PM and percent increase of hospitalization. We found positive and statistically significant associations between PM and hospital admissions for multiple outcomes, including all-cause, total respiratory, total cardiovascular diseases, and disease subcategories (hypertensive disease, coronary heart disease, stroke and the stroke subtype, chronic obstructive pulmonary disease, and lower respiratory infection). Each 10 μg/m3 increase in PM2.5 at Lag01 (a moving average of Lag0 to Lag1), was significantly associated with an increase of 1.31% (95% CI: 0.79%, 1.83%), 1.12% (95% CI: 0.40%, 1.84%), and 1.14% (95% CI: 0.53%, 1.75%) in hospitalizations for all-cause, CVD, and respiratory, respectively. The association for PM10 with all-cause, CVD, and respiratory admissions was similar but weaker than PM2.5. The effect on admissions persisted for up to 7 days, and peaked at Lag01. The associations between PM and all-cause hospitalizations were stronger among older individuals and in cold seasons. It is therefore important to continue implementation of emission abatement and other effective measures in Yichang and other cities in China.

Objective To assess potential risk factors in identifying women at risk for gestational diabetes mellitus (GDM). Methods The present study included data collected as part of a prospective cohort study, and included women with singleton pregnancies who underwent initial prenatal examination at a tertiary women and children's hospital in Guangzhou, China between February 1, 2012, and December 31, 2015. Maternal characteristics and medical history were investigated to evaluate associations with GDM. A risk factor scoring system for the prediction of GDM was generated using logistic regression. Results Overall, 1129 (13.5%) of 8381 women were diagnosed with GDM. Women older than 35 years had a 3.95‐fold increased risk of GDM (95% confidence interval 2.80–5.58) compared with women aged 16–25 years; obese women had a 6.54‐fold higher risk (95% confidence interval 3.50–12.23) compared with underweight women. A risk scoring system was established based on age, body mass index, family history of diabetes, weight gain, and history of GDM. Screening for women with a score of 12 or more would have reduced the number undergoing oral glucose tolerance testing by 2131 (25.4%) patients with a sensitivity of 87% for GDM detection. Conclusion The assessment of risk factors for GDM could provide a foundation for improving risk‐based screening strategies in this and similar populations.

BackgroundSelecting neoantigens that generate robust anti-tumor T cell responses remains a challenge for cancer immunotherapy design. The ATLASTM platform, a functional recall assay using patient autologous cells, identifies both stimulatory and inhibitory (Inhibigen) neoantigens via up- or downregulation of T cell cytokine secretion.1 We propose that stimulatory neoantigens are ideal targets for cancer vaccines and T cell therapies. In contrast, data suggest that Inhibigens be excluded, due to their association with accelerated tumor growth and dampened immunity in a murine melanoma model.2 While detrimental to cancer immunotherapy, the Inhibigen-associated downregulation of cytokine production may be beneficial in the context of autoimmunity.MethodsATLAS screens were performed as previously described.1 2 Peptide vaccines containing tumor-specific neoantigens ± Inhibigens were evaluated in prophylactic and therapeutic B16F10 melanoma tumor models for immunogenicity and efficacy. RNAseq analysis was performed on T cells sorted from draining lymph nodes of vaccinated tumor-bearing mice. For experimental autoimmune encephalomyelitis (EAE) studies, mice were administered a vaccine containing MOG peptide ± the melanoma MMP9FS Inhibigen. Immune responses and phenotypic analyses for both models were measured by flow cytometry, ELISPOT, and immunohistochemistry.ResultsIn the melanoma model, inclusion of the Inhibigen MMP9FS accelerated tumor growth in a non-dose dependent manner and abrogated immune responses. RNAseq of T cells from tumor-bearing mice vaccinated with MMP9FS showed a higher level of differentially expressed genes (adjusted P value of 5 distinct pathways/gene) as compared to stimulatory controls, indicating Inhibigen-specific effects on T cells. In the EAE model of autoimmunity, animals treated with MOG peptide + MMP9FS exhibited dampened anti-MOG immune responses, delayed disease onset, reduced disease incidence and scoring (average 1 vs. 3) and decreased spinal cord immune infiltration as compared to control vaccination. These data indicate that Inhibigen administration has the potential to ameliorate autoimmune sequelae, independent of cognate antigen expression.ConclusionsFunctional identification and exclusion of Inhibigens from cancer immunotherapies may be critical to protective immunity since their inclusion can result in quelling of otherwise beneficial immune responses. Conversely, Inhibigen-specific responses can dampen destructive autoimmune sequelae. Mechanistic studies show altered T cell signaling pathways in the context of therapeutic Inhibigen vaccination. These data suggest that Inhibigen-specific responses, while detrimental for the treatment of cancer, may have a therapeutic benefit in other disease contexts.ReferencesNogueira C, Kaufmann JK, Lam H, Flechtner JB. Improving cancer immunotherapies through empirical neoantigen selection. Trends in Cancer 2018;4(2):97–100.Lam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021;11(3):696–713.Ethics ApprovalAll animal studies were undertaken in conformity with the Cambridge, MA Ordinance 1086 of the city's Municipal Code and in accordance with the policies and protocols approved by Genocea's Institutional Animal Care and Use Committee (IACUC).

The current study explores the mechanism of Inhibigens: a new class of immune-dampening cancer neoantigens. Inhibigens are identified through Genocea's ATLASTM platform, an empirical and unbiased bioassay that utilizes autologous patient cells to characterize tumor mutations that elicit anti-tumor CD4+ and CD8+ immune responses. Unexpectedly, ATLAS also identifies inhibitory neoantigens (Inhibigens) that lead to downregulation of T cell inflammatory cytokine secretion. Previous studies demonstrated that when a single ATLAS-identified Inhibigen was administered to B16F10 tumor-bearing mice, it completely abrogated immunogenicity and efficacy of a protective vaccine. Thus, it is critical that detrimental Inhibigens be excluded from targeted immunotherapies and further studied to understand their global importance in cancer. Here we report progress in uncovering mechanisms of Inhibigen function. In ATLAS screening assays, patient-derived antigen-presenting cells (APCs) are fed with E. coli bacteria expressing individual mutations from the patient's mutanome with or without pore-forming listeriolysin O (cLLO), and subsequently exposed to patient-derived CD8+ or CD4+ T cells, respectively; T cell cytokine secretion determines antigen-specific responses. Unlike in silico approaches, ATLAS accounts for the complexity of antigen processing, the diversity of MHC class I and II alleles across races and ethnicities, and the diversity of T cell repertoires across individuals. ATLAS screening of B16F10 mouse melanoma previously identified stimulatory neoantigens and Inhibigens that were either protective or deleterious to tumor progression when included in vaccines, respectively. Current studies explore the tumor microenvironment (TME) and systemic immunity in Inhibigen-administered mice ± checkpoint inhibitors (CPI). Inhibigens accelerated tumor growth compared to protective vaccines, abrogated vaccine-driven infiltration of T cells and myeloid cells into the TME, and impaired the synergistic effects of vaccination and CPI therapy with corresponding deficiencies in the TME. In vitro studies thus far exclude cell killing and MHC competition as Inhibigen mechanisms of action. Ongoing studies evaluating Inhibigen modulation of APC and T cell function in vitro and in vivo will be presented. Our data enforce the necessity of identifying Inhibigens empirically and excluding them from cancer vaccines and immunotherapies. Genocea's GEN-009 and GEN-011 phase 1/2 clinical trials utilize ATLAS to identify optimal neoantigens and omit Inhibigens from cancer vaccines and T cell therapies. Ongoing exploration of Inhibigen phenotypes and mechanisms will illuminate new paradigms of cancer immunology and potentially pave the way for novel cancer immunotherapies. Citation Format: Hanna Starobinets, Victoria L. Devault, Stephanie Rinaldi, Julie Arnold, Osaruese Odeh, Cindy Nguyen, Jessica B. Flechtner, Hubert Lam. InhibigensTM subvert otherwise-efficacious cancer vaccines and immunotherapies in conjunction with alterations in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1762.

Spatio–temporal models of ambient air pollution can be used to predict pollutant levels across a geographical region. These predictions may then be used as estimates of exposure for individuals in analyses of the health effects of air pollution. Integrated nested Laplace approximations is a method for Bayesian inference, and a fast alternative to Markov chain Monte Carlo methods. It also facilitates the SPDE approach to spatial modelling, which has been used for modelling of air pollutant levels, and is available in the R-INLA package for the R statistics software. Covariates such as meteorological variables may be useful predictors in such models, but covariate misalignment must be dealt with. This paper describes a flexible method used to estimate pollutant levels for six pollutants in Suzhou, a city in China with dispersed air pollutant monitors and weather stations. A two-stage approach is used to address misalignment of weather covariate data.

The Born In Guangzhou Cohort Study (BIGCS) is a large-scale prospective observational study investigating the role of social, biological and environmental influences on pregnancy and child health and development in an urban setting in southern China. Pregnant women who reside in Guangzhou and who attend Guangzhou Women and Children’s Medical Center (GWCMC) for antenatal care in early pregnancy (less than 20 weeks’ gestation) are eligible for inclusion. Study recruitment commenced in February 2012, with an overall participation rate of 76.3%. Study recruitment will continue until December 2018 to achieve the target sample size of 30 000 mother-child pairs. At 30 April 2016, a total of 75 422 questionnaires have been collected, while 14 696 live births have occurred with planned follow-up of cohort children until age 18 years. During the same period a total of 1 053 000 biological samples have been collected from participants, including maternal, paternal and infant blood, cord blood, placenta, umbilical cord, and maternal and infant stool samples. The dataset has been enhanced by record linkage to routine health and administrative records. We plan future record linkage to school enrolment and national examination records.

Steven Sadhra,1 Om P Kurmi,2 Sandeep S Sadhra,1 Kin Bong Hubert Lam,2 Jon G Ayres1 1Institute of Occupational and Environmental Medicine, University of Birmingham, Edgbaston, Birmingham, 2Nuffield Department of Population Health, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK Background: The association between occupational exposure and COPD reported previously has mostly been derived from studies relying on self-reported exposure to vapors, gases, dust, or fumes (VGDF), which could be subjective and prone to biases. The aim of this study was to assess the strength of association between exposure and COPD from studies that derived exposure by job exposure matrices (JEMs).Methods: A systematic search of JEM-based occupational COPD studies published between 1980 and 2015 was conducted in PubMed and EMBASE, followed by meta-analysis. Meta-analysis was performed using a random-effects model, with results presented as a pooled effect estimate with 95% confidence intervals (CIs). The quality of study (risk of bias and confounding) was assessed by 13 RTI questionnaires. Heterogeneity between studies and its possible sources were assessed by Egger test and meta-regression, respectively.Results: In all, 61 studies were identified and 29 were included in the meta-analysis. Based on JEM-based studies, there was 22% (pooled odds ratio =1.22; 95% CI 1.18–1.27) increased risk of COPD among those exposed to airborne pollutants arising from occupation. Comparatively, higher risk estimates were obtained for general populations JEMs (based on expert consensus) than workplace-based JEM were derived using measured exposure data (1.26; 1.20–1.33 vs 1.14; 1.10–1.19). Higher risk estimates were also obtained for self-reported exposure to VGDF than JEMs-based exposure to VGDF (1.91; 1.72–2.13 vs 1.10; 1.06–1.24). Dusts, particularly biological dusts (1.33; 1.17–1.51), had the highest risk estimates for COPD. Although the majority of occupational COPD studies focus on dusty environments, no difference in risk estimates was found for the common forms of occupational airborne pollutants.Conclusion: Our findings highlight the need to interpret previous studies with caution as self-reported exposure to VGDF may have overestimated the risk of occupational COPD. Keywords: COPD, occupation, airborne substances, job exposure matrices

Background The cesarean section (CS) rate has risen globally during the last two decades. Effective and feasible strategies are needed to reduce it. The aim of this study was to assess the CS rate change after a two-stage intervention package that was designed to reduce the overall CS rate in Guangzhou, China. Methods and findings This intervention package was implemented by the Health Commission of Guangzhou Municipality in 2 stages (October 2010–September 2014 and October 2014–December 2016) and included programs for population health education, skills training for healthcare professionals, equipment and technical support for local healthcare facilities, and capacity building for the maternal near-miss care system. A retrospective repeated cross-sectional study was conducted to evaluate influences of the intervention on CS rates. A pre-intervention period from January 2008 to September 2010 served as the baseline. The primary outcome was the CS rate, and the secondary outcomes included maternal mortality ratio (MMR) and perinatal mortality rate (PMR), all obtained from the Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS). The Cochran-Armitage test was used to examine the trends of the overall CS rate, MMR, and PMR across different stages. Segmented linear regression analysis was used to assess the change of the CS rate over the intervention period. A total of 1,921,932 records of births and 108 monthly CS rates from 2008 to 2016 were analyzed. The monthly CS rate declined across the intervention stages (Z = 75.067, p < 0.001), with an average rate of 42.4% at baseline, 39.8% at Stage 1, and 35.0% at Stage 2. The CS rate declined substantially among nulliparous women who delivered term singletons, with an accelerating decreasing trend observed across Stage 1 and Stage 2 (the difference in slopes: −0.09 [95% CI −0.16 to −0.02] between Stage 1 and baseline, p = 0.014; −0.11 [95% CI −0.20 to −0.02] between Stage 1 and Stage 2, p = 0.017). The CS rate in the remaining population increased during baseline and Stage 1 and subsequently decreased during Stage 2. The sensitivity analysis suggested no immediate impact of the universal two-child policy on the trend of the CS rate. The MMR (Z = −4.368, p < 0.001) and PMR (Z = −13.142, p < 0.001) declined by stage over the intervention period. One of the main limitations of the study is the lack of a parallel control group. Moreover, the influence of temporal changes in the study population on the CS rate was unknown. Given the observational nature of the present study, causality cannot be confirmed. Conclusions Apparent decline in the overall CS rate was observed in Guangzhou, China, after the implementation of a two-stage intervention package. The decline was most evident among nulliparous women who delivered term singletons. Despite some limitations for causal inference, Guangzhou’s experience in controlling the CS rate by implementing composite interventions with public health education and perinatal healthcare service improvement could have implications for other similar areas with high rates of CS., Xiu Qiu and colleagues report on the cesarean section rate in Guangzhou, China following implementation of a two-stage intervention package., Author summary Why was this study done? Despite the association between cesarean section (CS) and a wide range of adverse maternal and neonatal outcomes, a nationwide study in China reported an important public health problem, with the CS rate rising from 28.8% in 2008 to 34.9% in 2014. Evaluation of the effectiveness and feasibility of interventions for reducing CS rate is needed to provide implications for other settings with similar high rates. What did the researchers do and find? We retrospectively evaluated the change of the CS rate before and after a two-stage intervention package consisting of strategies for public health education and perinatal healthcare service improvement. It was implemented by the government of Guangzhou, China, from October 2010 to December 2016 to control the CS rate in the city. Data of 1,921,932 births between 2008 and 2016 were obtained from a city-wide health surveillance system. The average CS rate in all births decreased from 42.4% at baseline (Jan 2008–Sep 2010) to 39.8% at Stage 1 (October 2010–September 2014) and to 35.0% at Stage 2 (October 2014–December 2016), with nulliparous singletons at term largely accounting for the decline. Along with the decreasing CS rate, maternal and perinatal mortality also declined across different stages. What do these findings mean? Comprehensive intervention strategies reported in this study could safely reduce the CS rate, providing valuable experience for other areas with similar high CS rates. Nulliparous women should be the target population for the control of CS rate. Given the lack of comparable groups and the temporal change in the study population, the contribution of this intervention package should be interpreted with caution.