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Faith S Luyster,1 Reginald E Dunn,2 Diane S Lauderdale,3 Mercedes R Carnethon,4 Andrew M Tucker,5 Robert A Vogel,6 Andrew E Lincoln,2 Kristen L Knutson,7 Elliot J Pellman,8–10 Patrick J Strollo Jr11 1School of Nursing, University of Pittsburgh, Pittsburgh, PA, 2Sports Medicine Research Center, MedStar Health Research Institute, Baltimore, MD, 3Department of Public Health Sciences, University of Chicago, 4Department of Preventive Medicine, Northwestern University, Chicago, IL, 5MedStar Sports Medicine, MedStar Union Memorial Hospital, Baltimore, MD, 6Cardiology Section, Department of Veterans Affairs Medical Center, Denver, CO, 7Department of Medicine, University of Chicago, Chicago, IL, 8ProHealth Care Associates, Lake Success, 9Department of Medicine, 10Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, 11Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Purpose: Limited data from former National Football League (NFL) players suggest that obstructive sleep apnea (OSA) may be highly prevalent after retirement. It remains unclear whether the high prevalence of OSA in retired players is comparable to nonathletes. This retrospective analysis compared sleep apnea (SA) risk in retired NFL players to a community cohort (CARDIA Sleep study), and examined associations between SA risk and cardiovascular risk factors, including subclinical atherosclerosis.Materials and methods: Retired NFL players (n=122) were matched to CARDIA Sleep participants by age ±2 years (range 37–55 years), body mass index ±2 kg/m2, race, and male sex. Participants underwent electron-beam computed tomography to measure coronary artery calcium (CAC) and completed the Berlin Questionnaire to determine SA risk. The presence of CAC was defined as an Agatston score >0.Results: Retired NFL players had a greater prevalence of high SA risk than the matched CARDIA Sleep participants (27% vs 11.5%, P=0.002). Compared to the CARDIA Sleep participants, retired players were less likely to smoke, and had higher blood pressure, lower fasting glucose levels, and higher cholesterol levels. However, there was no difference in the prevalence of detectable CAC (30% vs 30%, P=1). In both players and the community cohort, SA risk was not significantly associated with CAC after controlling for age, race, and body mass index.Conclusion: Retired NFL players have a greater prevalence of high SA risk but similar prevalence of CAC compared with a well-matched community cohort.Keywords: sleep apnea, cardiovascular risk, coronary artery calcium, national football league

Objective: To examine whether sleep duration and quality are associated with fasting glucose, fasting insulin, or estimated insulin resistance in a community-based sample of early middle-aged adults.Research Design and Methods: This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Habitual sleep duration and fragmentation were estimated from 6 days of wrist actigraphy collected in 2003-2005. Insomnia was defined as self-reported difficulty falling asleep or waking up in the night three or more times per week plus average sleep efficiency of <80% based on actigraphy. Fasting blood samples to measure glucose and insulin were collected after the sleep measures during the CARDIA clinical examination in 2005-2006. Insulin resistance was estimated using the homeostatic model assessment (HOMA) method. Analyses were cross-sectional and stratified by the presence of diabetes.Results: There was no association between sleep measures and fasting glucose, insulin, or HOMA in the 115 subjects without diabetes. Among the 40 subjects with diabetes, after adjustment for covariates, 10% higher sleep fragmentation was associated with a 9% higher fasting glucose level, a 30% higher fasting insulin level, and a 43% higher HOMA level. Insomnia was associated with a 23% higher fasting glucose level, a 48% higher fasting insulin level, and an 82% higher HOMA level.Conclusions: The observed association between poor sleep quality and higher glucose, insulin, and estimated insulin resistance among subjects with diabetes warrants further examination of the effect of sleep disturbances on glucose control in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Numerous studies have found an association between shorter sleep duration and higher body mass index (BMI) in adults. Most previous studies have been cross-sectional and relied on self-reported sleep duration, which may not be very accurate. In the Coronary Artery Risk Development in Young Adults (CARDIA) Sleep Study (2000-2006), the authors examine whether objectively measured sleep is associated with BMI and change in BMI. They use several nights of wrist actigraphy to measure sleep among participants in an ongoing cohort of middle-aged adults. By use of linear regression, the authors examine whether average sleep duration or fragmentation is associated with BMI and 5-year change in BMI, adjusting for confounders. Among 612 participants, sleep duration averaged 6.1 hours and was grouped into 4 categories. Both shorter sleep and greater fragmentation were strongly associated with higher BMI in unadjusted cross-sectional analysis. After adjustment, BMI decreased by 0.78 kg/m(2) (95% confidence interval: -1.6, -0.002) for each increasing sleep category. The association was very strong in persons who reported snoring and weak in those who did not. There were no longitudinal associations between sleep measurements and change in BMI. The authors confirmed a cross-sectional association between sleep duration and BMI using objective sleep measures, but they did not find that sleep predicted change in BMI. The mechanism underlying the cross-sectional association is not clear. [ABSTRACT FROM AUTHOR]

Despite mounting evidence that sleep duration is a risk factor across diverse health and functional domains, little is known about the distribution and determinants of sleep. In 2003-2004, the authors used wrist activity monitoring and sleep logs to measure time in bed, sleep latency (time required to fall asleep), sleep duration, and sleep efficiency (percentage of time in bed spent sleeping) over 3 days for 669 participants at one of the four sites of the Coronary Artery Risk Development in Young Adults (CARDIA) study (Chicago, Illinois). Participants were aged 38-50 years, 58% were women, and 44% were Black. For the entire sample, mean time in bed was 7.5 (standard deviation (SD), 1.2) hours, mean sleep latency was 21.9 (SD, 29.0) minutes, mean sleep duration was 6.1 (SD, 1.2) hours, and mean sleep efficiency was 80.9 (SD, 11.3)%. All four parameters varied by race-sex group. Average sleep duration was 6.7 hours for White women, 6.1 hours for White men, 5.9 hours for Black women, and 5.1 hours for Black men. Race-sex differences (p < 0.001) remained after adjustment for socioeconomic, employment, household, and lifestyle factors and for apnea risk. Income was independently associated with sleep latency and efficiency. Sleep duration and quality, which have consequences for health, are strongly associated with race, sex, and socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: Adjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.Patients and Methods: The vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.Results: No clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following in vitro stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4+ T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, lambda-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.Conclusion: This pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: The nuclear factor-kappaB (NF-kappaB) family is a set of transcription factors with key roles in the induction of the inflammatory response and may be the link between inflammation and cancer development. This pathway has been shown to influence ovarian epithelial tissue repair. Inhibitors of kappaB (IkappaB) prevent NF-kappaB activation by sequestering NF-kappaB proteins in the cytoplasm until IkappaB proteins are phosphorylated and degraded.Methods: We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in NFKBIA and NFKBIB (the genes encoding IkappaBalpha and IkappaBbeta, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.Results: The minor allele for one synonymous SNP in NFKBIA, rs1957106, was associated with decreased risk (p = 0.03).Conclusion: Considering the number of single-SNP tests performed and null gene-level results, we conclude that NFKBIA and NFKBIB are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-kappaB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Studies of children have found an inverse association between sleep duration and overweight on the basis of parental report of sleep duration. Studies in adolescents have been inconsistent but used varied measures of sleep. We used a nationally representative sample of adolescents that included 2 different measures of sleep duration (24-hour time diaries and self-reported usual sleep hours) to examine whether the association with overweight is sensitive to how sleep is measured in a single study population. We expected that the 2 measures of sleep would be strongly correlated and that the time-diary sleep would be more strongly associated with overweight risk because it is likely the more accurate measure of sleep. METHODS: In 2001-2002, adolescents from the Child Development Supplement of the Panel Study of Income Dynamics completed 24-hour time diaries on a random weekday and weekend. Adolescents also self-reported average sleep duration. Both sleep measures were categorized into quartiles. Height and weight were measured, and a BMI z score for age and gender was calculated. Overweight was defined as above the 95th percentile. RESULTS: The final sample included 767 male and 779 female subjects who were aged 10 to 19 years. Mean time-diary sleep was nearly 9 hours on weekdays and >10 hours on weekends. Mean self-reported sleep duration was 8 hours. Time-diary sleep and self-reported sleep were weakly correlated. Time-diary sleep was not significantly associated with overweight. Self-reported sleep was associated with overweight, but the association was not linear. When both sleep measures were included in the same model, their effects on overweight were independent. CONCLUSIONS: The weak correlation between self-reported sleep and time-diary sleep and the independence of their associations with overweight raise questions about what different measures of sleep duration in adolescents represent. [ABSTRACT FROM AUTHOR]

Study Objectives: To evaluate wearable devices and machine learning for detecting sleep apnea in patients with stroke at an acute inpatient rehabilitation facility (IRF)., Methods: A total of 76 individuals with stroke wore a standard home sleep apnea test (ApneaLink Air), a multimodal, wireless wearable sensor system (ANNE), and a research-grade actigraphy device (ActiWatch) for at least 1 night during their first week after IRF admission as part of a larger clinical trial. Logistic regression algorithms were trained to detect sleep apnea using biometric features obtained from the ANNE sensors and ground truth apnea rating from the ApneaLink Air. Multiple algorithms were evaluated using different sensor combinations and different apnea detection criteria based on the apnea-hypopnea index (AHI ≥ 5, AHI ≥ 15)., Results: Seventy-one (96%) participants wore the ANNE sensors for multiple nights. In contrast, only 48 participants (63%) could be successfully assessed for obstructive sleep apnea by ApneaLink; 28 (37%) refused testing. The best-performing model utilized photoplethysmography (PPG) and finger-temperature features to detect moderate-severe sleep apnea (AHI ≥ 15), with 88% sensitivity and a positive likelihood ratio (LR+) of 44.00. This model was tested on additional nights of ANNE data achieving 71% sensitivity (10.14 LR+) when considering each night independently and 86% accuracy when averaging multi-night predictions., Conclusions: This research demonstrates the feasibility of accurately detecting moderate-severe sleep apnea early in the stroke recovery process using wearable sensors and machine learning techniques. These findings can inform future efforts to improve early detection for post-stroke sleep disorders, thereby enhancing patient recovery and long-term outcomes., Clinical Trial: SIESTA (Sleep of Inpatients: Empower Staff to Act) for Acute Stroke Rehabilitation, https://clinicaltrials.gov/study/NCT04254484?term=SIESTA&checkSpell=false&rank=1, NCT04254484., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The National Heart, Lung, and Blood Institute convened a virtual workshop in September 2022 to discuss "Optimal Instruments for Measurement of Diet, Physical Activity, and Sleep." This report summarizes the proceedings, identifying current research gaps and future directions for measuring different lifestyle behaviors in adult population-based studies. Key discussions centered on integrating report-based methods, like questionnaires, with device-based assessments, including wearables and physiological measures such as biomarkers and omics to enhance self-reported metrics and better understand the underlying biologic mechanisms of chronic diseases. Emphasis was placed on the need for data harmonization, including the adoption of standard terminology, reproducible metrics, and accessible raw data, to enhance the analysis through artificial intelligence and machine learning techniques. The workshop highlighted the importance of standardizing procedures for integrated behavioral phenotypes using time-series data. These efforts aim to refine data accuracy and comparability across studies and populations, thereby advancing our understanding of lifestyle behaviors and their impact on chronic disease outcomes over the life course.

Study Objectives: Sleep characteristics are associated with cardiovascular disease (CVD) risk and both sleep and CVD risk vary by gender. Our objective was to examine associations between polysomnographic sleep characteristics and CVD risk after excluding moderate-severe sleep apnea, and whether gender modifies these associations., Methods: This was a cross-sectional study with at-home polysomnography in adults in Brazil (n= 1,102 participants with apnea-hypopnea index (AHI)<15 events/hour). Primary exposures were N3, REM, wake after sleep onset (WASO), arousal index (AI) and AHI, and outcomes were blood pressure (BP) and lipid levels., Results: Associations between sleep and BP varied by gender. In women, more N3 was associated with lower systolic BP (-0.40 mmHg per 10 minutes, 95%CI -0.71, -0.09), lower diastolic BP (-0.29 mmHg per 10 minutes, 95%CI -0.50, -0.07), and lower odds of hypertension (OR 0.94, 95%CI 0.89, 0.98). In men, more WASO was associated with higher systolic BP (0.41 mmHg per 10 minutes, 95%CI 0.08, 0.74) and higher odds of hypertension (OR 1.07, 95%CI 1.01, 1.14). No interactions by gender were observed for lipids. More WASO was associated with lower total cholesterol (-0.71 per 10 minutes, 95%CI -1.37, -0.05). Higher AHI was associated with higher total cholesterol (+0.97 per event/hour, 95%CI 0.24, 1.70) and higher LDL (+0.84 per event/hour, 95%CI 0.04, 1.64)., Conclusions: N3 is more strongly associated with BP in women, which is consistent with other studies demonstrating gender differences in BP control and CVD risk and adds a novel risk factor. Longitudinal and interventional studies are required to determine whether changes in N3 result in BP changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In this study, we tested a novel approach of "repurposing" a biomarker typically associated with breast cancer for use in melanoma. HER2/neu is a well characterized biomarker in breast cancer for which effective anti-HER2/neu therapies are readily available. We constructed a lentivirus encoding c-erb-B2, an animal (rat) homolog to HER2/neu. This was used to transfect B16 melanoma in vitro for use in an orthotopic preclinical mouse model, which resulted in expression of rat c-erb-B2 as a neoantigen target for anti-c-erb-B2 monoclonal antibody (7.16.4). The c-erb-B2-expressing melanoma was designated B16/neu. 7.16.4 produced statistically significant in vivo anti-tumor responses against B16/neu. This effect was mediated by NK-cell antibody-dependent cell-mediated cytotoxicity. To further model human melanoma (which expresses < 5% HER2/neu), our c-erb-B2 encoding lentivirus was used to inoculate naïve (wild-type) B16 tumors in vivo, resulting in successful c-erb-B2 expression. When combined with 7.16.4, anti-tumor responses were again demonstrated where approximately 40% of mice treated with c-erb-B2 lentivirus and 7.16.4 achieved complete clinical response and long-term survival. For the first time, we demonstrated a novel strategy to repurpose c-erb-B2 as a neoantigen target for melanoma. Our findings are particularly significant in the contemporary setting where newer anti-HER2/neu antibody-drug therapies have shown increased efficacy., (© 2024. The Author(s).)

Introduction: For retroperitoneal sarcomas (RPS), aggressive surgical resection offers the only chance for a cure; however, 5-year survival remains below 65%. Therefore, there is a critical need to identify drivers of poor clinical outcomes., Materials and Methods: To identify biomarkers of tumors likely to recur following curative intent resection, we performed genomic and transcriptomic sequencing for 47 and 34 patients, respectively, with non-metastatic RPS at a single, high-volume sarcoma center., Results: At the DNA level, alterations in TERT were associated with poor disease-free survival (DFS) and overall survival (OS). Increased RNA expression of gene sets related to growth signaling and DNA repair were associated with poor DFS and OS. Infiltration of CD8 + T-Cells and activated dendritic cells were associated with poor DFS and OS., Conclusion: These findings may help to better identify and treat non-metastatic, high-risk RPS., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy., Methods: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS)., Results: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event., Conclusion: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222., Competing Interests: Conflicts of interest KK is listed as a coinventor on a patent entitled ‘Immunity to folate receptors’, which is owned by the Mayo Clinic and was previously licensed to Marker Therapeutics. KK reports receiving commercial research support from Marker Therapeutics. REO reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, Marker Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health. RMW reports grants or funding from Anixa Biosciences, Merck, OnTarget; consulting, DSMB, or advisory fees from Eisai, Sonnet Biotherapeutics, Genentech, Abbvie, Shattuck Labs, Merck, GSK/Tesaro, Legend Biotech, Novocure, Clovis, AstraZeneca, Regeneron, Mersana, Seagen; travel support from Eisai, Tapimmune/Marker Therapeutics; speakers bureau fees from GSK, CurioScience, Onclive; stock from Ovation Diagnostics. MSB is listed as a coinventor on pending patents entitled, “Combinations of Dendritic Cell-Based Vaccines” and “Checkpoint Inhibitors and Dendritic Cell-Based Vaccines and Uses Thereof;” reports institutional research support from Alkermes, Bristol-Myers Squibb, Genentech, Marker Therapeutics, Merck, nFerence, Pharmacyclics, Regeneron, Sorrento, TILT Biotherapeutics, Transgene, and Viewpoint Molecular Therapeutics; and is has served as a consultant/SAB member for Marker Therapeutics, Sorrento Therapeutics, TILT Biotherapeutics, and Viewpoint Molecular Targeting., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sleep and circadian disturbances are common and are experienced more often by Black compared to White individuals. We conducted an observational study of sleep that was ancillary to an ongoing cohort study, Coronary Artery Disease in Young Adults (CARDIA). The goal of the ancillary study will be to examine potential determinants of sleep/circadian disparities between Black and White adults in future analyses. Herein we describe the study design and methodology. Our ancillary study coincided with the Year 35 examination of the CARDIA study and was conducted in two phases (due to the SARS-COV-2 pandemic). Phase 1 involved only questionnaires to assess chronotype, restless legs syndrome, and the household sleep environment. Phase 2 involved three additional questionnaires to assess sleep quality, daytime sleepiness and insomnia symptoms, as well as two sleep devices. Participants wore a wrist activity monitor to assess sleep-wake patterns and light levels for 7 days and a home sleep apnea test for 1 night. A subset also had devices objectively record light, temperature, and sound levels in their bedrooms for 7 days. Sample sizes ranged based on assessment from 2200 to 2400, completing Phase 1 questionnaires, 899 with valid wrist actigraphy data, and 619 with a valid sleep apnea test. The data will be part of the full CARDIA dataset, which is available to researchers., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Study Objectives: Stroke can result in or exacerbate various sleep disorders. The presence of behaviors such as daytime sleepiness poststroke can indicate underlying sleep disorders which can significantly impact functional recovery and thus require prompt detection and monitoring for improved care. Actigraphy, a quantitative measurement technology, has been primarily validated for nighttime sleep in healthy adults; however, its validity for daytime sleep monitoring is currently unknown. Therefore this study aims to identify the best-performing actigraphy sensor and algorithm for detecting daytime sleep in poststroke individuals., Methods: Participants wore Actiwatch Spectrum and ActiGraph wGT3X-BT on their less-affected wrist, while trained observers recorded daytime sleep occurrences and activity levels (active, sedentary, and asleep) during non-therapy times. Algorithms, Actiwatch (Autoscore AMRI) and ActiGraph (Cole-Kripke, Sadeh), were compared with on-site observations and assessed using F2 scores, emphasizing sensitivity to detect daytime sleep., Results: Twenty-seven participants from an inpatient stroke rehabilitation unit contributed 173.5 hours of data. The ActiGraph Cole-Kripke algorithm (minute sleep time = 15 minutes, bedtime = 10 minutes, and wake time = 10 minutes) achieved the highest F2 score (0.59). Notably, when participants were in bed, the ActiGraph Cole-Kripke algorithm continued to outperform Sadeh and Actiwatch AMRI, with an F2 score of 0.69., Conclusions: The study demonstrates both Actiwatch and ActiGraph's ability to detect daytime sleep, particularly during bed rest. ActiGraph (Cole-Kripke) algorithm exhibited a more balanced sleep detection profile and higher F2 scores compared to Actiwatch, offering valuable insights for optimizing daytime sleep monitoring with actigraphy in stroke patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Background: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied., Methods: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC., Results: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (T EMRA ) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response., Conclusions: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + T EMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer., Trial Registration: NCT02022202 . Registered 20 December 2013., (© 2024. The Author(s).)

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m 2 , and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes. NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Background: Cancer neoantigens arise from protein-altering somatic mutations in tumor and rank among the most promising next-generation immuno-oncology agents when used in combination with immune checkpoint inhibitors. We previously developed a computational framework, REAL-neo, for identification, quality control, and prioritization of both class-I and class-II human leucocyte antigen (HLA)-presented neoantigens resulting from somatic single-nucleotide mutations, small insertions and deletions, and gene fusions. In this study, we developed a new module, SPLICE-neo, to identify neoantigens from aberrant RNA transcripts from two distinct sources: (1) DNA mutations within splice sites and (2) de novo RNA aberrant splicings., Methods: First, SPLICE-neo was used to profile all DNA splice-site mutations in 11,892 tumors from The Cancer Genome Atlas (TCGA) and identified 11 profiles of splicing donor or acceptor site gains or losses. Transcript isoforms resulting from the top seven most frequent profiles were computed using novel logic models. Second, SPLICE-neo identified de novo RNA splicing events using RNA sequencing reads mapped to novel exon junctions from either single, double, or multiple exon-skipping events. The aberrant transcripts from both sources were then ranked based on isoform expression levels and z-scores assuming that individual aberrant splicing events are rare. Finally, top-ranked novel isoforms were translated into protein, and the resulting neoepitopes were evaluated for neoantigen potential using REAL-neo. The top splicing neoantigen candidates binding to HLA-A*02:01 were validated using in vitro T2 binding assays., Results: We identified abundant splicing neoantigens in four representative TCGA cancers: BRCA, LUAD, LUSC, and LIHC. In addition to their substantial contribution to neoantigen load, several splicing neoantigens were potent tumor antigens with stronger bindings to HLA compared with the positive control of antigens from influenza virus., Conclusions: SPLICE-neo is the first tool to comprehensively identify and prioritize splicing neoantigens from both DNA splice-site mutations and de novo RNA aberrant splicings. There are two major advances of SPLICE-neo. First, we developed novel logic models that assemble and prioritize full-length aberrant transcripts from DNA splice-site mutations. Second, SPLICE-neo can identify exon-skipping events involving more than two exons, which account for a quarter to one-third of all skipping events., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The advent of immune checkpoint blockade therapy has revolutionized cancer treatments and is partly responsible for the significant decline in cancer-related mortality observed during the last decade. Immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1), have demonstrated remarkable clinical successes in a subset of cancer patients. However, a considerable proportion of patients remain refractory to immune checkpoint blockade, prompting the exploration of mechanisms of treatment resistance. Whereas much emphasis has been placed on the role of PD-L1 and PD-1 in regulating the activity of tumor-infiltrating T cells, recent studies have now shown that this immunoregulatory axis also directly regulates myeloid cell activity in the tumor microenvironment including tumor-infiltrating dendritic cells. In this review, I discuss the most recent advances in the understanding of how PD-1, PD-L1, and programmed cell death ligand 2 regulate the function of tumor-infiltrating dendritic cells, emphasizing the need for further mechanistic studies that could facilitate the development of novel combination immunotherapies for improved cancer patient benefit., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Introduction: Studies suggest that the generation of durable T-cell immunity following coronavirus disease 2019 (COVID-19) vaccination protects against severe disease. The aim of this study was to measure cell-mediated immune response (CMIR) 1-2 months and 6 months after a third dose of a COVID-19 mRNA vaccine., Methods: This prospective study (HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease [IBD]) evaluated CMIR at 28-65 days (t 1 ) after dose 2, 28-65 days (t 2 ) (n = 183) and 6 months (±45 days) (t 3 ) (n = 167) after a third dose of an mRNA COVID-19 vaccine. A small cohort had blood sample available 28-65 days (t 4 ) (n = 55) after a fourth dose. Primary outcomes were CMIR at (t 2 ) and (t 3 ). Secondary outcomes included the effect of immunosuppressing IBD medications on CMIR and response at (t 4 )., Results: All patients had measurable CMIR at all time points. CMIR increased at t 2 compared with that at t 1 (median 1,467 responding cells per million (interquartile range [IQR] 410-5,971) vs 313 (94-960) P < 0.001). There was no significant waning in t 2 vs t 3 or significant boosting at t 4 . Those on anti-tumor necrosis factor monotherapy had a higher CMIR compared with those not on this therapy at t 2 (4,132 [IQR 1,136-8,795] vs 869 [IQR 343-3,221] P < 0.001) and t 3 (2,843 [IQR 596-6,459] vs 654 [IQR 143-2,067] P < 0.001). In univariable analysis, anti-tumor necrosis factor monotherapy was associated with a higher CMIR at t 2 ( P < 0.001) and t 3 ( P < 0.001) and confirmed in a multivariable model ( P < 0.001)., Discussion: A third dose of a COVID-19 vaccine boosts CMIR, and the response is sustained in patients with IBD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Gender and age are well-established determinants of health and sleep health that influence overall health, which also often varies by gender and age. Sleep architecture is an important component of sleep health. The goal of this analysis was to examine whether associations between age and sleep stages differ by gender in the absence of moderate-severe obstructive sleep apnea (OSA) in a rural setting in Brazil. This study conducted polysomnography recordings in the Baependi Heart Study, a cohort of Brazilian adults. Our sample included 584 women and 309 men whose apnea-hypopnea index was ≤15 events/h. We used splines to distinguish non-linear associations between age, total sleep time, wake after sleep onset (WASO), N2, N3, and rapid-eye-movement sleep. The mean (standard deviation; range) age was 47 (14; 18-89) years. All sleep outcomes were associated with age. Compared to men, women had more N3 sleep and less WASO after adjusting for age. Model-based comparisons between genders at specific ages showed statistically higher mean WASO for men at ages 60 (+13.6 min) and 70 years (+19.5 min) and less N3 for men at ages 50 (-13.2 min), 60 (-19.0 min), and 70 years (-19.5 min) but no differences at 20, 30, 40 or 80 years. The other sleep measures did not differ by gender at any age. Thus, even in the absence of moderate-severe OSA, sleep architecture was associated with age across adulthood, and there were gender differences in WASO and N3 at older ages in this rural community., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objective: The objective of this study was to examine the association between the timing of dietary macronutrients and sodium intake and sleep quantity and quality., Methods: This was a cross-sectional study that included 34 adults between 21 and 50 years of age. The main outcome measures were objective sleep measures assessed from three nights of wrist actigraphy including sleep duration, fragmentation, and wake after sleep onset (WASO), and one night of polysomnography (PSG), including rapid eye movement (REM) sleep, non-REM stage 2 (N2), stage 3 (N3), and WASO. Multiple linear regression models and linear mixed models were used to estimate the associations between sleep measures and dietary measures (carbohydrates, fats, saturated fats, proteins, and sodium). Dietary timing was examined in two ways: (1) the average amount of each nutrient consumed within 3 hours of sleep start, and (2) the interval between the final intake of each nutrient and sleep., Results: Average fat intake within 3 hours of sleep was associated with greater WASO from PSG ( β  = 4.48, p  = 0.01). No other associations were found between the macronutrients or sodium intake ( p  > 0.05) within 3 hours of sleep and the sleep parameters from PSG or actigraphy. Similarly, no associations were found between any of the PSG or actigraphy sleep measures and the interval between final nutrient intakes and sleep with sleep duration., Conclusions: The study suggests that greater fat but not carbohydrate, protein, saturated fat, or sodium intake close to sleep may be associated with greater sleep disruption; however, no other associations were observed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Introduction: Fatigue, brain fog, and sleep disturbance are among the most common symptoms of postacute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality of life in patients with neurologic manifestations of PASC (Neuro-PASC)., Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH Toolbox cognitive tests, and 7 days of wrist actigraphy., Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p  < 0.001), and later sleep midpoint ( p  = 0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with the severity of fatigue ( p  < 0.001), anxiety ( p  = 0.05), and depression ( p  < 0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency, and latency were associated with decreased performance in attention and processing speed., Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Study Objectives: People with diabetes and prediabetes are more likely to have sleep-disordered breathing (SDB), but few studies examined sleep architecture in people with diabetes or prediabetes in the absence of moderate-severe SDB, which was the aim of our cross-sectional study., Methods: This cross-sectional sample is from the Baependi Heart Study, a family-based cohort of adults in Brazil. About 1074 participants underwent at-home polysomnography (PSG). Diabetes was defined as fasting glucose >125 mg/dL or HbA1c > 6.4 mmol/mol or taking diabetic medication, and prediabetes was defined as HbA1c ≥ 5.7 & <6.5 mmol/mol or fasting glucose ≥ 100 & ≤125 mg/dl. We excluded participants with an apnea-hypopnea index (AHI) ≥ 30 in primary analyses and ≥ 15 in secondary analysis. We compared sleep stages among the 3 diabetes groups (prediabetes, diabetes, neither)., Results: Compared to those without diabetes, we found shorter REM duration for participants with diabetes (-6.7 min, 95%CI -13.2, -0.1) and prediabetes (-5.9 min, 95%CI -10.5, -1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (-13.7 min, 95%CI -26.8, -0.6), longer slow-wave sleep (N3) duration (+7.6 min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes. Results were similar when restricting to AHI < 15., Conclusions: People with diabetes and prediabetes had less REM sleep than people without either condition. People with diabetes also had more N3 sleep. These results suggest that diabetes and prediabetes are associated with differences in sleep architecture, even in the absence of moderate-severe sleep apnea., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Stress and diabetes coexist in a vicious cycle. Different types of stress lead to diabetes, while diabetes itself is a major life stressor. This was the focus of the Chicago Biomedical Consortium's 19 th annual symposium, "Stress and Human Health: Diabetes," in November 2022. There, researchers primarily from the Chicago area met to explore how different sources of stress - from the cells to the community - impact diabetes outcomes. Presenters discussed the consequences of stress arising from mutant proteins, obesity, sleep disturbances, environmental pollutants, COVID-19, and racial and socioeconomic disparities. This symposium showcased the latest diabetes research and highlighted promising new treatment approaches for mitigating stress in diabetes., Competing Interests: RMS declares that he has received honoraria from CVS/Health and the American Medical Forum; neither of which relate this manuscript. SAO is a co-founder, equity holder, and consultant for OptiKIRA, LLC. All other authors have no competing interests to declare., (© The Author(s) 2023.)

Introduction: Cognitive dysfunction, a leading cause of mortality and morbidity in the USA and globally, has been shown to disproportionately affect the socioeconomically disadvantaged and those who identify as black or Hispanic/Latinx. Poor sleep is strongly associated with the development of vascular and metabolic diseases, which correlate with cognitive dysfunction. Therefore, sleep may contribute to observed disparities in cognitive disorders. The Epidemiologic Study of Disparities in Sleep and Cognition in Older Adults (DISCO) is a longitudinal, observational cohort study that focuses on gathering data to better understand racial/ethnic sleep disparities and illuminate the relationship among sleep, race and ethnicity and changes in cognitive function. This investigation may help inform targeted interventions to minimise disparities in cognitive health among ageing adults., Methods and Analysis: The DISCO study will examine up to 495 individuals aged 55 and older at two time points over 24 months. An equal number of black, white and Hispanic/Latinx individuals will be recruited using methods aimed for adults traditionally under-represented in research. Study procedures at each time point will include cognitive tests, gait speed measurement, wrist actigraphy, a type 2 home polysomnography and a clinical examination. Participants will also complete self-identified assessments and questionnaires on cognitive ability, sleep, medication use, quality of life, sociodemographic characteristics, diet, substance use, and psychological and social health., Ethics and Dissemination: This study was approved by the Northwestern University Feinberg School of Medicine Institutional Review Board. Deidentified datasets will be shared via the BioLINCC repository following the completion of the project. Biospecimen samples from the study that are not being analysed can be made available to qualified investigators on review and approval by study investigators. Requests that do not lead to participant burden or that conflict with the primary aims of the study will be reviewed by the study investigators., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing., Methods: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies., Results: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells., Conclusions: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy., Competing Interests: Competing interests: MC is an inventor on a patent filed by the University of Arkansas, entitled ‘Inhibition of dendritic cell-driven regulatory T cell activation and potentiation of tumor antigen-specific T cell responses by interleukin-15 and MAP kinase inhibitor.’ KLK and MB are inventors on a patent filed by the Mayo Clinic, entitled ‘Dendritic Cell Based Vaccines Combined with Pembrolizumab for the Treatment of Advanced Ovarian Cancer.’, (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: The US Preventive Services Task Force recently released guidelines suggesting little evidence of benefit to screening asymptomatic adults for obstructive sleep apnea (OSA). Our goal was to provide important context to this statement. Specifically, we examined associations between common OSA symptoms, excessive daytime sleepiness and snoring, and OSA severity for different racial/ethnic and sex groups., Methods: Analyses were performed on 2 samples. One combined 2 observational studies that included full polysomnography, the Epworth Sleepiness Scale (ESS), and questions about snoring (mean [standard deviation] age 39 [15.2] years). The second sample was the Multi-Ethnic Study of Atherosclerosis study of older adults (mean [standard deviation] age 69 [9.1] years), which also included polysomnography, ESS and a question about snoring. Apnea-hypopnea index represented OSA severity. For each racial/ethnic-sex group we estimated correlations between apnea-hypopnea index and ESS and the sensitivity and specificity of excessive daytime sleepiness (ESS >10) or frequent snoring to predict moderate-to-severe OSA (apnea-hypopnea index >15 events/h)., Results: A weak significant correlation between OSA severity and ESS was found only in White men in the first sample and Black men in the second sample. Screening tool characteristics for ESS and snoring were poor except for moderate specificity in some racial/ethnic-sex groups., Conclusions: Excessive daytime sleepiness and snoring are commonly used to identify symptomatic patients. Our results suggest that the accuracy of these symptoms to identify OSA varies by race/ethnicity and sex. Therefore, focus on common symptoms as an OSA screen could systematically leave out certain patient populations who would benefit from treatment., Citation: Stepney D, Attarian HP, Knutson KL. Association between severity of obstructive sleep apnea and its common symptoms varies by race, ethnicity, and sex. J Clin Sleep Med . 2023;19(10):1727-1733., (© 2023 American Academy of Sleep Medicine.)

Background: Some patients with inflammatory bowel disease (IBD) on immunosuppressive therapies may have a blunted response to certain vaccines, including the messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines. However, few studies have evaluated the cell-mediated immune response (CMIR), which is critical to host defense after COVID-19 infection. The aim of this study was to evaluate the humoral immune response and CMIR after mRNA COVID-19 vaccination in patients with IBD., Methods: This prospective study (HERCULES [HumoRal and CellULar initial and Sustained immunogenicity in patients with IBD] study) evaluated humoral immune response and CMIR after completion of 2 doses of mRNA COVID-19 vaccines in 158 IBD patients and 20 healthy control (HC) subjects. The primary outcome was the CMIR to mRNA COVID-19 vaccines in patients with IBD. The secondary outcomes were a comparison of (1) the CMIR in patients with IBD and HC subjects, (2) CMIR and humoral immune response in all participants, and (3) correlation between CMIR and humoral immune response., Results: The majority (89%) of patients with IBD developed a CMIR, which was not different vs HC subjects (94%) (P = .6667). There was no significant difference (P = .5488) in CMIR between immunocompetent (median 255 [interquartile range, 146-958] spike T cells per million peripheral blood mononuclear cells) and immunosuppressed patients (median 377 [interquartile range, 123-1440]). There was no correlation between humoral and cell-mediated immunity after vaccination (P = .5215). In univariable analysis, anti-tumor necrosis factor therapy was associated with a higher CMIRs (P = .02) and confirmed in a multivariable model (P = .02). No other variables were associated with CMIR., Conclusions: Most patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While observational studies suggested the safety of COVID-19 mRNA vaccines in rheumatic disease patients, laboratory evidence is lacking., Methods: Here we evaluated seroreactivity, clinical manifestions, and multiple disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases., Results: Most patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Patients with systemic lupus erythematosus (SLE) or psoriatic arthritis (PsA) remained without significant flares post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I interferon (IFN) signature genes were highly variable but did not show consistent or significant increases. Frequency of double negative 2 (DN2) B cells remained largely stable., Discussion: Our data provide experimental evidences indicating the efficacy and safety of repeated COVID-19 mRNA vaccination in rheumatic disease patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 An, Figueroa-Parra, Zhou, Li, Jaquith, McCarthy-Fruin, Sletten, Warrington, Weyand, Crowson, Chumsri, Knutson, Sanchez-Rodriguez, Thanarajasingam, Duarte-García and Zeng.)

The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers., (© 2023. The Author(s).)